SK56296A3 - Piperidinal, pyrrolidinal and hexahydro-1h-azepinal derivatives, manufacturing process thereof and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention is directed to certain piperidine, pyrrolidine, and hexahydro-1H-azepine compounds of general structural formula (I) wherein R1, R3, R4, R5, A, W, X, Y, and n are as defined herein. These compounds promote the release of growth hormone in humans and animals. This property can be utilized to promote the growth of food animals to render the production of edible meat products more efficient, and in humans, to treat physiological or medical conditions characterized by a deficiency in growth hormone secretion, such as short stature in growth hormone deficient children, and to treat medical conditions which are improved by the anabolic effects of growth hormone. Growth hormone releasing compositions containing such compounds as the active ingredient thereof are also disclosed.

Description

Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives, process for their preparation and pharmaceutical compositions containing them

Technical field

The present invention relates to piperidine, pyrrolidine and hexahydro-1H-azepine derivatives that promote growth hormone release, to a process for the preparation of the same, and to pharmaceutical compositions containing them and to increase endogenous growth hormone release and to treat osteoporosis. In addition, suitable for or on the above can be used to increase feed utilization.

BACKGROUND OF THE INVENTION

Growth hormone, which is secreted by the pituitary gland, stimulates the growth of all body tissues that are capable of growth. In addition, growth hormone has some basic effects on metabolic processes in the body. In particular, these effects are: 1) increasing the rate of protein synthesis in all cells, 2) reducing the rate of utilization of carbohydrates in all cells, and 3) increasing the mobilization of free fatty acids and their use for energy purposes. In the case of growth hormone deficiency, various disorders, such as dwarf, occur.

Various ways are known for the release of growth hormone. In addition, administration of various substances, such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucogone, vasopressin, leads to increased secretion of this substance, in addition, hypoglycaemia following insulin administration, sleep and physical exercise indirectly increase growth hormone release from pituitary gland. apparently through the hypothalamus such that there is a decrease in secretion of solitary or an increase in secretion of a known growth hormone (GRF) release factor or unknown endogenous factor or all of these agents.

If it is desired to increase the concentration of growth hormone, this problem has hitherto been usually solved by administering exogenous growth hormone or by administering GRF or peptide compounds that promote growth hormone production and / or release. In any event, the peptide nature of the compounds requires their administration by injection. The primary source of growth hormone was the pituitary glands of the deceased, from which the growth hormone was extracted. Thus, this was a very costly procedure and was also associated with the risk of transmission of various diseases from the source used to the patient to whom growth hormone was administered. Later, recombinant growth hormone was already available, the administration of which is no longer associated with any risk of disease transmission, but it is still a very expensive product which, moreover, needs to be administered by injection or nasal spray.

A number of other compounds capable of stimulating the release of endogenous growth hormone have been developed, including, for example, peptidyl compounds, related GRF, or peptides disclosed in U.S. Pat. These peptides, whose molecule is substantially smaller than the growth hormone molecule, are still cleavable by various proteases. As is the case with most peptide-like substances, their potential oral bioavailability is very low. U.S. Pat. 5,206,235, 5,283,241, 5,284,841, 5,310,737 and 5,317,017. Non-peptide substances with a benzolactam structure that promote growth hormone secretion are described. Also described are low molecular weight peptide analogs that are very stable in various physiological environments and can be administered parenterally, nasally, and orally.

SUMMARY OF THE INVENTION

The present invention provides certain piperidine, pyrrolidine and hexahydro-az-azepine compounds that stimulate the release of natural endogenous growth hormone. These agents can be used to treat conditions in which it is desirable to stimulate growth hormone production or secretion. For example, growth hormone deficiency in humans or in animals the need to increase feed utilization, in which case increased growth hormone concentrations can achieve higher productivity in milk production or in fattening animals. The present invention also provides a process for the manufacture of said compounds and pharmaceutical compositions comprising said compounds for administration to a human or other animal to enhance growth hormone secretion.

The present invention therefore provides novel piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of formula I

UP ⁴ t I II r! -J-N "C" and "N

(I) where r! is selected from the group consisting of alkyl having 1 to 10 carbon atoms, aryl, arylalkyl having 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl having 3 to 7 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety, alkyl-C-alkyl; C 1 -C 5 alkyl, aryl (C 0 -C 5 alkyl) -K- (C 1 -C 5 alkyl), and (C 3 -C 7 cycloalkyl) (C 0 -C 5 alkyl) ) -K- (C 1 -C 5 alkyl) wherein K is O, S (O) _m , N (R ² ) C (O), C (O) N (R ² ), OC (O), C (0) 0,

-CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, wherein R ² and alkyl radicals are optionally substituted with 1 to 9 atoms halogen, S (O) _m R ^2a , 1 to 3 OR ^{2 2a} or C (O) OR ^2a and aryl is optionally substituted with 1 to 3 alkyl radicals having 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 to 2 groups OR, methylenedioxy groups, -S (O) _m R, 1 to 2 -CF 3 groups,

-OCF ^, nitro, -N ^(R2) C (O) (R ²⁾ -C (O) OR ^2,

-C (O) N ^{(R2) (R2),} -lH-tetrazol-5-yl, -SO 2 N (R ²⁾ (R ^2), -N ^(R2) SO2 phenyl, or -N (R ²⁾ SO ₂ R ² ,

ABOUT

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 3 to 8 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing O, S or NR ^a,

R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group, _r 3 represents a hydrogen atom, - (CH ₂ ) _n -phenyl, - (CH ₂ ) _n -naphthyl, alkyl of 1 to 10 carbon atoms, or cycloalkyl of 3 to 7 carbon atoms, wherein the phenyl, naphthyl and cycloalkyl ring of 3 to 7 carbon atoms may be substituted with 1 to 3 substituents selected from alkyl of 1 to 6 carbon atoms, halogen or one of the following groups -OR ² , -NHSO 4 F ⁶ , - (CH ₂ ) _r OR ⁶ , - (CH 2) _r N (R ² ) (R ⁶ ), - (CH ₂ ) _r (R ⁶ ),

- (CH ₂ ) _r C (O) OR ² , - (CH 2) r C (O) OR ⁶ , - (CH 2) _r OC (O) OR ² ,

- (CH ₂ ) _r OC (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) R ⁶ ,

- (CH ₂ ) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ ,

- (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ ,

- (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ ,

- (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ ,

- (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ),

- (CH _{2) y} N (R ⁶⁾ C (O) N (R ²⁾ (R ^6), - (CH 2) r -N (R ²⁾ SO 2 R ^6, (CH _{2) y} N (R ²⁾ SO 2 R ^2, - (CH 2) _r N (R ⁶ ) SO ₂ R ² ,

- (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ),

- (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² ,

- (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (O) R ² ,

- (CH ₂ ) _r CONHC (O) R ⁶ , - (CH ₂ ) _r C ₀ NHSO ₂ R ⁶ ,

- (CH ₂ ) _r CONHSO ₂ R ² , - (CH ₂ ) _r CONHSO ₂ N (R ² ) (R ² ),

- (CH ₂ ) _r COnHSO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ^6, and - (CH ₂ ) _r S (O) _m R ² ,

R ^8a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group,

W is hydrogen, cyano or one of the groups -C (O) OR ^8, -C (0) 0R ^2, -C (0) 0 _{(CH2) 1} aryl,

-C (O) N (R ²⁾ (R ^2); -C (O) N (R ² ) (R ⁸ ), -C (O) N (R ² ) (CH 2) 4 aryl, -CH 2 N (R ² ) C (O) R ⁸ , -CH 2 N (R ² ) C (O) (CH 2) 1 -aryl, - (CH ² ) r R ² , -CH (OH) R ² , -CH (OH) (CH 2) ₁ -aryl, -C (O) R ² , -C (O (CH ₂ ) ₁ aryl, 1H-tetrazol-5-yl, 5-amino-1,2,4-oxadiazol-3-yl

O and 5-methyl-1,2,4-oxadiazol-3-yl, wherein R is hydrogen, alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms, substituted with one of OR ² , C (O) ) OR ² , CON (R ² ) (R ² ), N (R ² ) C (O) R ² ,

N (R ² ) C (O) N (R ² ) (R ² ) and aryl means phenyl, pyridyl or 1H-tetrazol-5-yl,

X is selected from hydrogen, -C = N,

- _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl,

- (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² ,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), (CH ₂ ) _q C (O) N (R ² ) (R ² ),

- (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² ,

- (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q OC (O) R ² ,

- (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) N (R ² ) (CH ₂ ) _t -aryl,

- (CH ₂ ) _q OC (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) R ² ,

- (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² ,

- _{(CH2) q} N ^(R2) S02N ^{(R2) (R2),} - (CH 2) _q S (O) _m R ^2, and

- (CH ₂ ) S (O) _m (CH ₂ ) _t -aryl, wherein the R, (CH ₂ ) _q and (CH ₂ ) _X groups are optionally substituted with 1 to 2 alkyl groups of 1 to 4 carbon atoms, hydroxyl groups C1 -C4 lower alkoxy, carboxyl, CONH2, S (O) _m CH3, C1 -C4 carboxylate alkyl or 1H-tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl , thiazolyl or 1H-tetrazol-5-yl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -CON (R ² ) (R ² ), -C (O) OR ² , 1 to 3 alkyl groups C 1 -C 4 -S (O) _m R ² or 1H-tetrazol-5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms,

- (CH 2) _t -aryl, - (C ^ Q-cycloalkyl of 3 to 7 carbon atoms, - (CH 2) q k-C 1 -C 6 alkyl, - _{(CH2) q-K-} (CH ₂ ) _t aryl, - (CH ₂ ) _q -K- (CH ₂ ) _t (C 3 -C 7 cycloalkyl containing O, NR ² or S) and - (C 1-6 q-K- (C 3 -C 7 cycloalkyl) 7 carbon atoms) where K is O, S (O) _m , C (O) NR ² , CH = CH, OC, N (R ² ) C (O), C (O) NR ² , C (O) O or OC (O) wherein the alkyl, R, (CH 2) q and (CH 2) _t are optionally substituted with C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 lower alkoxy, carboxyl, -CONH 2 or C 1 -C 4 carboxylate alkyl and aryl means phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isototyl optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -C (O) OR ² , -C (O) N (R ² ) (R ² ), nitro, cyano, benzyl, 1 to 3 alkyl of 1 to 4 carbon atoms, -S (O) _m R ² or 1 H -tetrazol-5-yl provided that at least one of

Q of R, V, X and Y have a meaning different from that of a hydrogen atom,

R 1 and R 5 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, 1 to 3 alkanoyloxy groups of 1 to 10 carbon atoms, 1 to 3 alkoxy groups of 1 to 6 carbon atoms , phenyl, phenoxy 7, 2-furyl, C 1 -C 6 alkoxycarbonyl, or S (O) _m C 1 -C 6 alkyl, or may and R 2 together form - (CH 2) j L ^and (CH 2) e -, wherein L ^a represents a group C (R ² ) 2 · O, S (O) m or N (R), and d and e independently represent the whole

0 to 1 and R is as defined above,

A represents a group

R ⁷ r ⁷ - (CH ₂ ) _x -O- (CH ₂ ) - or _-Z - (CH ₂ ) _x -C- (CH ₂ ) -

R ^7a _R 7a wherein x and y independently represent an integer of 0, 1, 2 or 3,

Z is NR or 0 ^and wherein R ^a is H or alkyl of 1 to 6 carbon atoms, R 6 is H, C 1 -C 6 alkyl or (CH 2) _v -aryl, wherein the alkyl, and (CH 2) _V is optionally substituted with 1 to 2 O (R ² ), S (O) m R ² , 1H-tetrazol-5-yl, C (O) OR ² , C (O) N (R ² ) (R ² ) ² ) or SO ² N (R ² ) (R ² ) or N (R ² ) C (O) N (R ² ) (R ² ) and aryl means phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolan-1-yl, benzimidazol-2-yl, triazolinonyl, optionally substituted with C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino or hydroxyl,

R 1 and R 2 ^{, and} independently represent hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl, wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) O-alkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 7 carbon atoms,

N (R2) (R2) C (0) N (R 2) (R _{2), and} b and _e may be _{of the} R? and R? ^{and be} attached to one or both of the groups a and r5 to form alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R? or R ^and wherein the bridge contains 1 to 5 carbon atoms, or may be R? and R 6 ^and together form a cycloalkyl ring of 3 to 7 carbon atoms,

1 m means means about, 0 1 or 2, 1 or 2, n means 1 2 or 3, q means 0 1 , 2, 3 or r means 0 1 , 2 or 3 T means 0 1 , 2 or 3 in means 0 1 or 2,

as well as pharmaceutically acceptable salts thereof and their individual diastereomers.

When n = 1, the compound contains a pyrrolidine ring, when n = 2, the compound contains a piperidine ring, and when n = 3, the compound contains a hexahydro-1Hazepine ring.

In the above structural formula and throughout the application, the groups referred to have the following meaning:

The alkyl groups have a straight or branched chain of the indicated length and optionally double or triple bonds. Examples of alkyl groups include methyl (Me), ethyl (et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), sec-butyl (s-Bu), tert-butyl (t-butyl). -Bu), pentyl, isopentyl, hexyl, isohexyl, allyl, propynyl, butadienyl, hexenyl and the like.

Alkoxy groups have a straight or branched chain with the indicated number of carbon atoms and may contain double or triple bonds. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, allyloxy, propinyloxy, isobutenyloxy, hexenyloxy and the like.

The halogen atom may be a fluorine, chlorine, bromine or iodine atom.

The term aryl during the application, unless otherwise indicated, means aromatic rings, for example carbon or heterocyclic aromatic rings of the group phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl. pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, optionally substituted with 1 to 3 alkyl radicals of 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 to 2 are substituted with -OR, methylenedioxy, -S (O) _m R, 1 up to 2 -CF 3, -OCF 3, nitro, -N (R ² ) C (O) (R ² ), -C (O) OR ² ,

-C (0) N ^{(R2) (R2),} -lH-tetrazol-5-yl, -S02N ^{(R2) (R2),} -N (R ²⁾ S02fenyl or -N (R ²⁾ SO ₂ R ^2, wherein R ² is as defined above.

Some of the above groups may occur more than once in the above formula, in which case each of the meanings is independent of the other meanings of the same group.

In one embodiment, the invention relates to derivatives of structural formula A1

HHO r ⁴

^{1 11} I 'R ¹ -pNCAN (Al) c = a (W-Chase

M-x

R ³ Y where r! is selected from the group consisting of alkyl aryl, arylalkyl of 1 to 6 parts, cycloalkylalkyl of 3 to 10 carbon atoms, carbon atoms of alkyl of up to 7 carbon atoms in cycloalkyl of up to about 6 carbon atoms in the alkyl portion, alkyl-C-alkyl of 1 up to 5 carbon atoms in each alkyl moiety, aryl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) or (cycloalkyl of 3 to 7 carbon atoms) (alkyl of 0 to 5 carbon atoms) ) -K- (C 1 -C 5 alkyl) wherein K is O, S (O) _m , N (R ² ) C (O), C (O) N (R ² ), OC (O),

C (O) O, -CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, wherein R and the alkyl radicals are optionally substituted with 1 to 9 halogen atoms, S (O) _m R ^2a , 1 to 3 groups

OR ^2a or C (O) OR ^2a and aryl is optionally substituted with up to 3 alkyl radicals of 1 to 6 carbon atoms, 9 to 3 halogen atoms, 1 to 2 OR groups, methylenedioxy, -S (O) _m R, 1 to 6 2 -CF ₃ groups,

-OCF ₃ , nitro, -N (R ² ) C (O) (R ² ), -C (O) OR 4,

-C (0) N ^{(R2) (R2),} -lH-tetrazol-5-yl, -SO 2 N (R ²⁾ (R ^2), -N ^(R2) S02 phenyl, or -N (R ² ) SO ₂ R ²

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 3 to 8 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^3a group,

R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group,

Rf is hydrogen, - _{(CH2) r-phenyl,} - _{(CH2) r-naphthyl,} alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, where phenyl, naphthyl and the cycloalkyl ring of 3 to The 7 carbon atoms may be substituted with 1 to 3 substituents selected from alkyl of 1 to 6 carbon atoms, halogen or one of the following groups -OR ² , -NHSO ² CF ³ , - (CH 2) _r OR ⁶ , - (CH 2) _r N (R ² ) (R ⁶ ), - (CH ₂ ) _r (R ⁶ ),

- (CH ₂ ) _r C (O) OR ² , - (CH 2) r C (O) OR ⁶ , - (CH 2) _r OC (O) OR ² ,

- (CH ₂ ) _r C (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) R ⁶ ,

- (CH ₂ ) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ ,

- (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ ,

- (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ ,

- (CH ₂ ) _r N (R ⁶ ) c (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ ,

- (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ ,

- (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² ,

- (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ),

- (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² ,

- (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (O) R ² ,

- (CH ₂ ) _r CONHC (O) R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ⁶ ,

- (CH ₂ ) _r C0NHSO ₂ R ² , - (CH ₂ ) _r C0NHSO ₂ N (R ² ) (R ² ),

- (CH _{2) r} CONHSO ₂ N (R ²⁾ (R ^6), - (CH 2) r -N (R ²⁾ SO 2 N (R ²⁾ (R ^6),

- (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ^6, and - (CH ₂ ) _r S (O) _m R ² ,

R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group,

V is selected from -CN, -C (O) OR ⁸ , -C (O) OR ² ,

-C (O) O (CH ₂ ) ₁ -aryl, -C (O) N (R ² ) (R ² ); -C (O) N (R ² ) (R ⁸ ), -C (O) N (R ² ) (CH ₂ ) ₁ -aryl, -CH ₂ N (R ² ) C (O) R ⁸ ,

-CH ₂ N (R ² ) C (O) (CH 2) 1 -aryl, - (CH ² ) r OR ² , -CH (OH) R ² , -CH (OH) (CH 2) ₁ -aryl, -C (O R ² , -C (O) (CH ₂ ) 1 L -aryl, 1H-tetrazol-5-yl, 5-amino-1,2,4-oxadiazol-3-yl

Q and 5-methyl-1,2,4-oxadiazol-3-yl wherein R ° is hydrogen, alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms substituted with one of OR ² , C ( 0) 0R ^2, CON (R ²⁾ (R ²⁾ N (R ²⁾ C (O) R ^2,

N (R ² ) C (O) N (R ² ) (R ² ) and aryl means phenyl, pyridyl or 1H-tetrazol-5-yl,

X is selected from hydrogen, -C = N,

- _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl,

- (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² ,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl,

- _{(CH2) q} N ^(R2) C (0) N ^{(R2) (R2),} - _{(CH2) q} C (O) N (R ²⁾ (R ^2),

- (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² ,

- (CH ₂ ) _q C (O) 0 (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q OC (O) R ² ,

- (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) N (R ² ) (CH 2 -aryl,

- (CH ₂ ) _q OC (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) R ² ,

- (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² ,

- (CH ₂ ) _q N (R ² ) SO ² N (R ² ) (R ² ), - (CH 2) _q S (O) _m R ² and - (CH ₂ ) S (O) _m (CH ₂ ) _t - aryl, wherein the group R, _{(CH2) q} and _{(CH2) t} optionally substituted by 1 to 2 alkyl groups of 1 to 4 carbon atoms, hydroxy groups, lower alkoxy groups having 1 to 4 carbon atoms, carboxyl, _CONH2, With (O) _m CH ₃ , C 1 -C 4 carboxylate alkyl or 1 H -tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl, thiazolyl or 1 H -tetrazol-5-yl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -CO (R ² ) (R ² ), -C (O) OR ² , 1 to 3 alkyl groups of 1 to 4 carbon atoms, -S (O) _m R ^2, or H-tetrazol-5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms,

- (CH ₂ ) _q -aryl, - (CH ₂ ) _q -cycloalkyl of 3 to 7 carbon atoms, - (CH ₂ ) _q -K-alkyl of 1 to 6 carbon atoms in the alkyl moiety, - (CH ₂ ) _q -K- (CH _{2) t} aryl, - _{(CH2) q-K- (CH2) χ} (cycloalkyl of 3-7 carbon atoms, containing 0, ^NR2, or s), and - _{(CH2) q} -K - (CH ₂ ) _t - (C 3 -C 7 cycloalkyl) wherein K is O, S (O) _m , C (O) NR ² , CH = CH, OC, N (R ² ) C (O) , C (O) NR ² , C (O) O or OC (O), wherein the alkyl, R, (CH ₂ ) _q and (CH ₂ ) _t are optionally substituted with C 1 -C 4 alkyl, hydroxyl , C 1 -C 4 lower alkoxy, C 1 -C 4 NH _2, or C 1 -C 4 carboxylate alkyl and aryl means phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² groups, - C (O) OR ² , -C (O) N (R ² ) (R ² ), nitro, cyano, benzyl, 1 to 3 C 1 -C 4 alkyl, -S (O) _m R or 1H -tetrazol-5-yl,

R ⁴ and R ⁵ independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, 1 to 3 alkanoyloxy groups of 1 to 10 carbon atoms, 1 to 3 alkoxy groups of 1 to 6 atoms carbon, phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety or S (O) _m- alkyl of 1 to 6 carbon atoms in the alkyl moiety, or R ⁴ and R 6 together may form group

- (CH 2) (jL ^and (CH 2) e -, wherein L ^a represents C (R ² ) 2, O,

ABOUT

S (O) _m or N (R), d and e are independently an integer from 1 to 3 and R is as defined above,

A represents a group

R ⁷ R ⁷ - (CH _{2) x} O - _(CH2) - or _- - (CH _{2) x} - C- _(CH2) -

R ^7a _R 7a wherein x and y independently represent an integer of 0, 1, 2 or 3,

Z is NR or 0 ^and wherein R ^a is H or alkyl of 1 to 6 carbon atoms, x

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or (C 1-6 -aryl), wherein the alkyl groups and the (C 1-6) groups are optionally substituted with 1 to 2 O (R ² ), S (O) m R ² , 1H -tetrazol-5-yl, C (O) OR ² , C (O) N (R ² ) (R ² ) or SO ² N (R ² ) (R ² ) or N (R ² ) C (O) N (R ² ) ² ) (R ² ) and aryl means phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolan-1-yl, benzimidazol-2-yl, triazolinonyl, optionally substituted with an alkyl residue of 1 to (C 6 -C 6), (C 3 -C 6) cycloalkyl, amino or hydroxyl;

R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) O-alkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or R ⁷ and R ^{7a may} be linked to one or both of R ⁴ and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R ⁷ or R ^7a , wherein the bridges contain 1; up to 5 carbon atoms or R ⁷ and R ^7a together may form a cycloalkyl ring of 3 to 7 carbon atoms,

1 m n means means means about, about, 1 1 1 2 or 2, or 2, or 3 q means 0 1 , 2, 3 or 4 r means 0 1 , 2 or 3 T means 0 1 , 2 or 3 in means 0 1 or 2

as well as pharmaceutically acceptable salts and individual diastereomers thereof.

Preferred compounds of the first embodiment are, for example, compounds of formula Ala

HHO r ⁴

II II ' _R 1 - pNCAN C = O R ⁵ <ch ₂ Kw

H-x

R ³ Y (Ala) wherein

R &lt; ¹ & gt ^; is selected from arylalkyl having 1 to 4 carbon atoms, 1 to 10 carbon atoms, carbon in the alkyl portion, cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl portion, carbon atoms) -K- (alkyl of 1 to 2 carbon atoms) -, aryl (alkyl of 0 to 2 carbon atoms) -K- (alkyl of 1 to 2 carbon atoms) or (cycloalkyl of 3 to 7 carbon atoms) ( alkyl of 0 to 2 carbon atoms) -K (alkyl of 1 to 2 carbon atoms) wherein K is O, S (O) _m , OC (O), C (O) O, and the alkyl groups are optionally further substituted with 1 to 2 carbon atoms 7 halogen atoms, S (O) _m R ² , 1 to 3 OR ² or C (O) OR ² and aryl means phenyl, naphthyl, indolyl, pyridyl, benzothienyl, benzofuranyl, optionally further substituted with 1 to 2 alkyl groups of 1 to 2 4 carbon atoms, 1 to 2 OR ² , S (O) _m R ² or C (O) OR ² ,

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 4 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing an oxygen, sulfur or NR ^3a group, and

R represents a hydrogen atom, phenyl optionally substituted in the ortho position with an alkyl group having 1 to 6 carbon atoms, -NHSO 2 CF 3, - (CH 2) _r - (1H-tetrazol-5-yl),

- (CH ₂ ) _r C (O) OR ² , - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ),

R ^3a represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms,

V is selected from -CN, -C (O) OR ² , -C (O) N (R ² ) (R ² ),

-C (O) N (R ² ) (CH ₂ ) 4 phenyl, 1H-tetrazol-5-yl or

- (CH ₂ ) _r OR ² ,

X is selected from hydrogen, - (CH ₂ ) _q C (O) N (R ² ) (R 2) or - (CH ₂ ) _q C (O) OR ² ,

Y is hydrogen, alkyl of 1 to 8 carbon atoms, - (CH _{2) t} phenyl, - _{(CH2) t} pyridyl, or - (CH _{2) t} thiazolyl,

R ⁴ and R ⁵ independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, S (O) _m- alkyl of 1 to 6 carbon atoms or phenyl, r 6 is an atom hydrogen or alkyl of 1 to 6 carbon atoms,

A represents a group

R ⁷ (CH ₂ ) x — c - _R 7a where x is 0 or 1,

R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl 1, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) O-alkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl of 5 to 7 carbon atoms, N (R ² ) (R ² ) or C (O) N (R ² ) (R ² ) or R ⁷ and R ^{7a may} be joined to one or both R ⁴ and R 8 to form alkylene bridges between the terminal nitrogen atom and the alkyl portion of R ⁷ or R ^7a to form 5- or a 6-membered ring or R ⁷ and R ^7a together may form a cycloalkyl ring having 3 carbon atoms,

1 means 0 or 1 m means 0 1 or 2, n means 2 q means 0 or 1 r means about, 1, 2 or 3, T means 0 or 1

as well as pharmaceutically acceptable salts and individual diastereomers thereof.

Even more preferred compounds of the first embodiment are those of Formula (Alb)

HHO r ⁴ = I II 'r1 — p · ^- N ^- C ^- Α ^- Ν C = O ^r5

(Alb) where

R ¹ is selected from alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 3 carbon atoms in the alkyl moiety or aryl (alkyl of 0 to 1 carbon atom) -K- (alkyl of 1 to 2 carbon atoms) wherein K is 0 or S (O) m and aryl is phenyl, naphthyl, pyridyl or indolyl, optionally further substituted with 1 to 2 alkyl groups of 1 to 4 carbon atoms, 1 to 2 halogen atoms, 1 to 2 OR ² , S (O) mR ² or C (O) OR ² ,

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 5 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^3a group,

Q

R is H, phenyl, substituted in the ortho alkyl group having 1 to 3 carbon atoms or - (CH _{2) r} - (lH-tetrazol-5-yl), or - (CH _{2) r} C (O) OR ² ,

R ^3a represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms,

V is selected from -CN, -C (O) OR ^2, or -C (O) N (R ² ) (R ² ),

X is selected from hydrogen or C (O) O (R ² ),

Y is hydrogen, benzyl, picolyl or thiazolylmethyl.

R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted with 1 to 2 hydroxy groups,

A represents a group

R ⁷ (CH ₂ ) x - CH -

R ^7a wherein x represents 0 or 1,

R ⁷ and R ^{7a are} independently hydrogen, C 1 -C 4 alkyl, m is 0, 1 or 2, r is 0, 1 or 2, as well as pharmaceutically acceptable salts and individual diastereomers thereof.

The most preferred sulfur compounds of the first embodiment are the following:

b 'V

COoEt y

- ^ ^ NH N'C,

C = 0

ABOUT

ΪΛΥ

NH,

C = 0

S y

C ^ NH, jj ^^ j ^ \ ^x-C0 2 ^{Et H,} and Y

HN ^{1 H}

C NH,

as well as pharmaceutically acceptable salts and individual diastereomers of these compounds.

A second embodiment of the invention includes compounds which can be represented by Structural Formula B1

R ¹

HH 0 _R 4

I II,

- NCAN C = O _r 5

(BI) where

R ¹ is selected from the group consisting of alkyl having 1 to 10 carbon atoms, aryl, arylalkyl having 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl having 3 to 7 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety, alkyl-K- alkyl of 1 to 5 carbon atoms in each alkyl moiety, aryl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) or (cycloalkyl of 3 to 7 carbon atoms) (alkyl of 0 to S) carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) wherein K is O, S (O) _m , N (R ² ) C (O), C (O) N (R ² ), OC (O) )

C (O) O, -CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuran, thiazolyl or benzimidazolyl, wherein R and the alkyl radicals are optionally substituted with 1 to 9 halogen atoms, S (O) _m R ^2a , 1 to 3 OR ^{2 2a} or C (O) OR ^2a, and aryl is optionally substituted with 1 to 3 alkyl radicals having 1 to 6 carbon atoms,

0 to 3 halogen atoms, 1 to 2 OR groups, methylenedioxy, -S (O) _m R, 1 to 2 -CFg groups,

-OCF-j, nitro, -N (R ² ) C (O) (R ² ), -C (O) OR,

-C (0) N (R ²⁾ (R ²⁾ H-tetrazol-5-yl, -S02N ^{(R2) (R2),} -N ^(R2) S02 phenyl, or -N (R ²⁾ S0 ₂ R ²

ABOUT

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 3 to 8 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing an oxygen, sulfur or NR ^3a group, wherein R ^3a represents a hydrogen atom or a C 1-6 alkyl group optionally substituted by a hydroxyl group,

2

R represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group,

R ³ is - (CH _{2) r} -phenyl, - _{(CH2) r-naphthyl,} alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, where phenyl, naphthyl and the cycloalkyl ring of 3 to 7 carbon atoms it may be substituted

R ^3a

X to 3 substituents selected from alkyl of 1 to 6 carbon atoms, halogen or one of the following groups -OR ² , -NHSO ² CF 3, - (CH 2) r OR ⁶ , - (CH 2) r N (R ² ) ( R ⁶ ), - (CH 2) _r (R ⁶ ), - (CH ₂ ) _r C (O) OR ² ,

- (CH ₂ ) _r C (O) OR ⁶ , - (CH ² ) _r OC (O) OR ² , - (CH 2) _r OC (O) R ⁶ ,

- (CH ₂ ) _r C (O) R ² , - (CH 2) r C (O) R ⁶ , - (CH 2) _r C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² ,

- (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² ,

- (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² ,

- (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² ,

- (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ ,

- (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² ,

- (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ),

- (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² ,

- (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (O) R ² ,

- (CH ₂ ) _r CONHC (O) R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ⁶ ,

- (CH ₂ ) _r C0NHSO ₂ R ² , - (CH ₂ ) _r C0NHSO ₂ N (R ² ) (R ² ),

- (CH _{2) r} CONHSO ₂ N (R ²⁾ (R ^6), - (CH 2) r -N (R ²⁾ SO 2 N (R ²⁾ (R ^6),

- (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ⁶ and - (CH ₂ ) _r S (O) _m R ² , represents an atom hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group, is selected from hydrogen, -C = N,

- _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl,

- _{(CH2) q} N ^(R2) S02 (CH2) t aryl, - (CH 2) q N (R ^{2) 2} S02R,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ),

- (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² ,

- (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q 0 C (O) R ² ,

- (CH ₂ ) _q OC (O) (CH ₂ ) ₁ -aryl, - (CH ₂ ) _q OC (O) N (R ² ) (CH 2) taryl, - (CH 2) q OC (O) N (R) ² ) (R ² ), - (CH 2) _q C (O) R ² ,

- (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² ,

- _{(CH2) q} N (R ²⁾ SO 2 N (R ²⁾ (R ^2), - (CH 2) _q S (0) _m R ² and - (CH _{2) q} S (O) _{m (CH2) t} -aryl, wherein the groups R ² , (CH ₂ ) _q and (CH ₂ ) _t are optionally substituted with 1 to 2 alkyl groups of 1 to 4 carbon atoms, hydroxyl groups, lower alkoxy groups of 1 to 4 carbon atoms, CONH ₂ groups, With (O) _m CH 3, carboxylate alkyl esters of 1 to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl, optionally substituted with 1 to 3 atoms halogen, 1 to 3 -OR ² , -CON (R ² ) (R ² ), -C (O) OR ² , 1 to C 1 -C 4 alkyl groups, -S (O) _m R or 1H-tetrazole -5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms,

- (CH ₂ ) _q -aryl, - (CH ₂ ) _q -cycloalkyl of 3 to 7 carbon atoms in the cycloalkyl moiety, - (CH ₂ ) _q -K- (alkyl of 1 to 6 carbon atoms), - (CH _{2) q} -K- (CH ₂ ) _t -aryl, - (CH ₂ ) _q -K (CH ₂ ) _t - (C 3 -C 7 cycloalkyl containing 0, NR ² or S) or - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 3 -C 7 cycloalkyl) wherein K is O, S (O) _m ,

C (O) NR ² , CH = CH, C = C, N (R ² ) C (O), C (O) NR ² , C (O) O or OC (O), wherein alkyl, R ² , ( CH ₂ ) _q and (CH ₂ ) _t are optionally substituted with C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, -CNH _2, or C 1 -C 4 carboxylate alkyl and aryl means phenyl , naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with up to 3 halogen atoms, 1 to 3 -OR groups ^2, 1 and N (R ²⁾ (R ²⁾ -C (0) 0R ^2, -C (0) N ^{(R2) (R2),} nitro, -NHC (0) R, cyano, benzyl, 1 to 3 alkyl groups of 1 to 4 atoms

O, -S (O) _m R or 1H-tetrazol-5-yl,

R 1 and R 2 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, 1 to 3 alkanoyloxy groups of 1 to 10 carbon atoms, 1 to 3 alkoxy groups of 1 to 6 carbon atoms, phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety or S (O) _m- alkyl of 1 to 6 carbon atoms in the alkyl moiety, or may and R 2 together form a group - (CH2) ^dL (CH2) e, wherein L ^a is C (R ²⁾ 2 »0, S (0) m or N (R ^f), d and e independently represent an integer of 1 to 3 and R is as this meaning,

A means one of the groups

R ⁷ - (CH ₂ ) _x -O- (CH ₂ ) - or _Z (CH ₂ ) _x -O- (CH ₂ ) -

^R7 and R7a where x and y are independently an integer of 0, 1, 2 or 3,

Z is NR or 0 ^and wherein R ^a is H or alkyl of 1 to 6 carbon atoms, £

R is H, C 1 -C 6 alkyl or (CH 2) _v -aryl, wherein alkyl and (CH 2) _W is optionally substituted by 1 to 2 groups, 0 ^(R2), S (O) m R ^2, 1H-tetrazol-5-yl, C (O) OR ² , C (O) N (R ² ) (R ² ) or SO ² N (R ² ) (R ² ) or N (R ² ) C (O) N (R ²⁾ (R ² ) and aryl means phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolan-1-yl, oxadiazolyl, benzimidazol-2-yl, triazolinon-1-yl, optionally substituted with (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, amino or hydroxyl;

R ^z and ^{R, independently} are H, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl, where the substituents are imidazolyl, FE25, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , cycloalkyl of 3 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or R ⁷ and R ^{7a may} be joined to one or both of R ⁴ and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl portion of R ⁷ or R ^7a wherein the bridges contain 1 to 5 carbon atoms or R ⁷ and R ^7a together form a cycloalkyl ring of 3 to 7 carbon atoms,

m means 0 1 or 2 n means 1 2 or 3 q means 0 1 , 2, 3 or 4 r means 0 1 , 2 or 3 T means 0 1 , 2 or 3 in means 0 1 or 2

as well as pharmaceutically acceptable salts and individual diastereomers thereof.

Preferred compounds of this second embodiment are, for example, compounds of formula Bla

H H 0]

I II

N-C-A-N

C = 0

(Bla) Where

R 1 is selected from the group consisting of alkyl of 1 to 10 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl moiety, (C 1 -C 2 alkyl), aryl (C 2 -C 2 alkyl) -K- (C 1 -C 2 alkyl) or (C 3 -C 7 cycloalkyl) ( alkyl of 0 to 2 carbon atoms) -K- (alkyl of 1 to 2 carbon atoms) wherein K is O, S (O) _m , OC (O) or C (O) O and the alkyl groups are optionally substituted with 1 to 2 carbon atoms 7 halogen atoms, S (O) _m R ² , 1 to 3 OR ² or C (O) OR ² and aryl means phenyl, naphthyl, indolyl, pyridyl, benzimidazolyl, azaindolyl, benzothienyl or benzofuranyl, which are optionally further substituted by 1 up to 2 alkyl groups having 1 to 4 carbon atoms, 1 to 2 halogen atoms, 1 to 2 OR ² groups, -S (O) _m R ² or -C (O) OR ² ,

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 4 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^3a group,

R is phenyl, optionally substituted with 1 to 2 alkyl groups of 1 to 6 carbon atoms, 1 to 2 halogen atoms or 1 to 2 -OR groups, and optionally further substituted in ortho position by one of the -NHSO ₂ CF ₃ groups - (CH ₂₎ OR ⁶ , - (CH ² ) _r N (R ² ) (R ⁶ ), - (CH 2) _r (R ⁶ ),

- (CH ₂ ) _r C (O) OR ² , - (CH 2) r C (O) OR ⁶ , - (CH 2) _r O C (O) OR ² ,

- (CH ₂ ) _r OC (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) R ⁶ ,

- (CH ₂ ) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ ,

- (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ ,

- (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ ,

- (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ ,

- (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ ,

- (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² ,

- (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ),

- (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (0) R ² , - (CH ₂ ) _r SO ₂ NHC (0) OR ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² ,

- (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (O) R ² ,

- (CH ₂ ) _r CONHC (O) R ⁶ , - (CH ₂ ) _r C ₀ NHSO ₂ R ⁶ ,

- (CH ₂ ) _r C0NHSO ₂ R ² , - (CH ₂ ) _r C0NHSO ₂ N (R ² ) (R ² ),

- (CH ₂ ) _r COnHSO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ⁶ and - (CH ₂ ) _r S (O) _m R ² ,

R ^3a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms,

X is selected from hydrogen,

- (CH ₂ ) _q N (R ² ) C (O) R ² , - (CH ₂ ) _q N (R ² ) C (O) (CH ² ) _t -aryl,

- (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH ₂ ) _q N (R ² ) SO ₂ (CH ₂ ) _t -aryl,

- (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH 2) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _x -aryl,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² ,

- (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) R ² ,

- (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q S (O) _m R ² and - (CH 2) q S (O) m (CH 2) t -aryl, the groups R ² is optionally substituted by hydroxyl, carboxyl, CO ² H ² , S (O) _m CH 3, carboxylate alkyl of 1 to 4 carbon atoms in the alkyl moiety or tetrazolyl and aryl means phenyl, naphthyl, pyridyl or alebo-tetrazolyl, optionally substituted with 1 up to 2 halogen atoms, 1 to 2 -OR ² , -CONH ₂ ,

ABOUT

-C (O) OR, 1 to 3 alkyl groups having 1 to 4 atoms

O, -S (O) _m R or 1H-tetrazol-5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms,

- (CH ₂ ) _t -aryl, - (CH ₂ ) - (cycloalkyl of 5 to 6 carbon atoms), - (CH ₂ ) _q -K- (alkyl of 1 to 6 carbon atoms), - (CH ₂ ) _q -K- (CH _{2) t} -aryl, - _{(CH2) q-K- (CH2) χ} - (cycloalkyl of 3 to 7 carbon atoms, containing 0, ^NR2, or s), or - _{(CH2) q} -K- (CH ₂ ) _t - (C 5 -C 6 cycloalkyl) wherein K is O, S (O) _m , wherein the alkyl groups are optionally substituted with a hydroxyl group, a carboxyl group, -CONH _2, or a carboxylate alkyl ester of 1 to 6 carbon atoms; With 4 carbon atoms in the alkyl moiety or 1H-tetrazoly-5-yl, aryl means phenyl, naphthyl, pyridyl, ol-tetrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl and is optionally substituted with 1 to 3 carbon

Halogen, 1 to 3 -OR, 1 to 2 -N (R ² ) (R ² ), -C (O) OR ² , -C (O) N (R ² ) (R ² ), cyano, to 2 alkyl groups having 1 to 4 carbon atoms, n

-S (O) _m R or 1H-tetrazol-5-yl,

R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted alkyl of 1 to 6 carbon atoms, wherein the substituents are 1 to 5 halogen atoms, 1 to 3 hydroxy groups, S (O) _m- alkyl of 1 to 6 R 6 is hydrogen, alkyl of 1 to 6 carbon atoms, or (CH 2) _v -aryl, the alkyl groups and (CH 2) _v being optionally substituted with 1 to 2 O (R ² ), S ( O) _m R ² , C (O) OR ² , C (O) N (R ² ) (R ² ) or

SO ₂ N (R ² ) (R ² ) or N (R ² ) C (O) N (R ² ) (R ² ) and aryl means phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl , oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino or hydroxyl,

A represents a (CH ₂ ) x -O-R ^{7a group} wherein x is 0 or 1

R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , cycloalkyl of 5 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or ⁷ and R ^{7a may} be joined to one or both of the groups29 and R8 to form alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R ⁷ or R ^7a , wherein the bridges contain 5 to 6 carbon atoms or R ⁷ and R ^7a together form a cycloalkyl ring of 3 carbon atoms,

n means 2 m means about, 1 or 2, q means about, 1 , 2 or 3 r means about, 1 , 2 or 3 T means about, 1 , 2 or 3 in means 0 1 or 2,

as well as pharmaceutically acceptable salts and individual diastereomers thereof.

More preferred compounds in the compound of Formula BIb of this second embodiment are

H. H ₄ r ¹ —ccan;

^{1 11} _n 5

C = 0 0 ^R .N (BIb)

where

R1 is selected from alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 3 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl and 1 to 3 carbon atoms in the alkyl moiety, aryl (alkyl of 0 to 1) carbon atom) -K- (C 1 -C 2 alkyl) wherein K is O, S (O) _m and aryl is phenyl, naphthyl, indolyl, pyridyl, azaindolyl, benzimidazolyl, optionally substituted with 1 to 2 alkyl groups of 1 C4 alkyl, 1 to 2 halogen, 1 to 2 of oR ^2, S (O) _m R ² or -C (0) 0R ^2,

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 5 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^3a group,

R is phenyl optionally substituted with 1 to 2 alkyl groups of 1 to 6 carbon atoms, 1 to 2 atoms

O-halogen or 1 to 2 -OR groups and optionally further substituted in ortho position by any one of -NHSO ₂ CF ₃ , - (CH ₂ ) _r OR ⁶ , - (CH ₂ ) _r N (R ² ) (R ⁶ ), - ( _CH2) ^(R6),

- (CH ₂ ) _r C (O) OR ⁶ , - (CH ² ) _r OC (O) R ² , - (CH 2) _r OC (O) R ⁶ ,

- (CH ₂ ) _r C (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² ,

- (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² ,

- (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² ,

- (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² ,

- (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ ,

- (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² ,

- (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ),

- (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r CO ₂ NHSO ₂ R ⁶ ,

- (CH ₂ ) _r COnHSO ₂ R ² , - (CH ₂ ) _r S (O) m R ^6, and - (CH 2) _r S (O) _m R ² ,

R ^3a represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms,

X is selected from hydrogen,

- (CH ₂ ) _q N (R ² ) C (O) R ² , - (CH ₂ ) _q N (R ² ) C (O) (CH ² ) _t -aryl,

- (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² ,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ),

- (CH ₂ ) _q N (R ² ) C (O) OR ² - (CH 2) q C (O) N (R ² ) (CH 2) _t -aryl,

- (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) 0 (CH ₂ ) _t -aryl,

- (CH ₂ ) _q OC (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) t -aryl, - (CH ² ) _q S (O) _m R ² and - (CH 2) _q S (O) _m ( CH ₂ ) _t -aryl wherein the R ² groups are optionally substituted by hydroxyl, carboxyl, -CONH 2, -S (O) _m CH 3, in the form of a C 1 -C 4 carboxylate alkyl or tetrazolyl group and aryl represents phenyl, naphthyl or pyridyl, optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR groups,

ABOUT

-C (O) OR, 1 to 3 alkyl groups having 1 to 3 atoms

O, -S (O) _m R or 1H-tetrazol-5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms,

- _{(CH2) t-ary1,} - (CH ₂₎ q (C 5 -C 7 cycloalkyl), - (C ^ iQ-K (C 1 -C 6 alkyl), - _{(CH2) q} -K- (CH ₂ ) _t -aryl or - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 5 -C 6 cycloalkyl, wherein K is S (O) _m , the alkyl groups being optionally substituted hydroxyl, carboxyl, -CONH2 or C1-C4 carboxylate alkyl or 1H-tetrazoly-5-yl, aryl means phenyl, naphthyl, pyridyl, thiazolyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl and is optionally substituted by 1 to 2 halogen, 1 to 2 -OR ^2, 1 to 2 -N (R ²⁾ (R ^2),

-C (O) OR 1 to 2 alkyl groups of 1 to 4 atoms

O is C, -S (O) _m R, or-1H-tetrazol-5-yl, R 1 and R 5 independently represent hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted alkyl of 1 to 3 carbon atoms, wherein the substituents are 1 to 2 hydroxy, r 6 is hydrogen, alkyl of 1 to 6 carbon atoms or (CH 2) _v -aryl, the alkyl groups and (CH 2) _v being optionally substituted with 1 to 2 O (R ² ), S (O) ) mR ² , C (O) OR ² , C (O) N (R ² ) (R ² ), SO ² N (R ² ) (R ² ) or N (R ² ) C (O) N (R ² ) ( R ² ) and aryl represents phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with C 1 -C 6 alkyl, cycloalkyl with (C 3 -C 6) atoms, amino or hydroxyl groups;

A represents a group

R ⁷ (CH ₂ ) X -OR ^7a wherein x is 0 or 1

R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 2 carbon atoms, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , or R ⁷ and R ^{7a can} be linked to each other to form a C 3 cycloalkyl group,

m means about, 1 or 2, q means about, 1 , 2 or 3 r means 0 1 , 2 or 3 T means 0 1 , 2 or 3 in means about, 1 or 2,

as well as pharmaceutically acceptable salts and individual diastereomers thereof.

More preferred compounds in the second embodiment of the invention are those of formula (IIc) h ₄

R ¹ —C> NCAN: \ ^{11 11} n ⁵ c = oo ^K (BIc) where

R1 is selected from groups

and their regioisomers where not specifically mentioned,

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 5 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^2a group,

R is phenyl, optionally substituted in the ortho position with a substituent selected from the following groups -NHSO ₂ CF ₃ , - (CH ₂ ) _r OR ⁶ , - (CH 2) r (R ⁶ ), - (CH 2) _r C (O ) OR ² ,

- (CH ₂ ) _r C (O) OR ⁶ , - (CH ₂ ) _r OC (O) R ² , - (CH 2) _r O C (O) R ⁶ ,

- (CH ₂ ) _r C (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² ,

- (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² ,

- (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² ,

- (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² ,

- (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ),

- (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ ,

- (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² ,

- (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ),

- (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ),

- (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ ,

- (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r CONHSO ₂ R ⁶ ,

- (CH ₂ ) _r COnHSO ₂ R ² , - (CH ₂ ) _r S (O) m R ^6, and - (CH 2) _r S (O) _m R ² ,

R ^3a represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms,

X represents a hydrogen atom or one of the following groups

0 0 0 CH ₃

Ao-CHo Λ ₀ ' ^ε * A ₀ - ^ ch ₃ A _o A _CH3

0 '‘CH,

OH

0 'o

ch ₃ .N

CH,

And _the / ^ oh 0H

A _N 'CH ₃ A _n -e .. J,

H H H

O CH, CH ₃ JL ³ N and CH ₃

H ³

Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms,

- (CH ₂ ) 4 - aryl, - (CH ₂ ) - (cycloalkyl of 5 to 7 carbon atoms), - (CH ₂ ) _q -K- (alkyl of 1 to 6 carbon atoms), - (CH ₂ ) q K - (CH ₂ ) _t -aryl or - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 5 -C 6 cycloalkyl, wherein K is S (O) _m , the alkyl groups being optionally substituted by a hydroxyl group , carboxy, -C0NH karboxylátalkylesterom ₂ or C 1 -C 4 alkyl or lH-tetrazole-5-yl, aryl is phenyl, naphthyl, pyridyl, thiazolyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrimidinyl or imidazolyl a is optionally substituted by 1 to 2 halogen atoms, 1 to 2 -OR groups, 1 to 2 is -C (O) OR, 1 to 2 alkyl groups having 1 to 4 carbon atoms, -S (O) _m R or 1H-tetrazol-5-yl,

A is selected from the groups CH ₃ h ₃ c ^ ch ₃ h ₃ c ck ₃ h ₃ c ch ₃ 9 ^h 3 Γ Ύ χγ V7 VV Vy Xx

N ^ \

H,

r

and r 5 are independently selected from -H-CH ₃ -CH ₂ CH ₃

OH OH 6 is hydrogen, alkyl of 1 to 6 carbon atoms or (CH 2) _v -aryl, the alkyl and o (CH 2) _v groups being optionally substituted with halogen, OR,

-N (R ² ) (R ² ), C 3 -C 6 cycloalkyl, 1H-tetrazol-5-yl, C (O) OR, C (O) N (R ² ) (R ² ), SO ₂ N (R ² ) (R ² ) or N (R ² ) C (O) N (R ² ) (R ² ) and aryl are selected from the following aromatic groups and their regioisomers

wherein the aromatic groups are optionally substituted with an alkyl group having 1 to 2 carbon atoms;

-N (R) (R) or hydroxy, m is 0, 1 or 2, q is 0 or 1, r is 0, 1, 2 or 3, t is 0 or 1, v is 0 or 1, as well as pharmaceutical acceptable salts and individual diastereomers of these compounds.

Representative and even more preferred compounds of the second embodiment are:

Η Η

Ν

SO ₂ NHCH ₃

d _in cis d ₂ . trans d _in trans d _? cis d _{1 (} cis d ₂ , trans d _{1 (} trans d ₂₎

as well as pharmaceutically acceptable salts and individual diastereomers thereof, if not mentioned.

All of these more preferred compounds of the second embodiment contain at least one center of asymmetry. Additional centers of asymmetry may occur in the molecule depending on the nature of the substituents on the piperidine ring. Each of these centers of asymmetry then gives rise to the two optical isomers, all optical isomers in the separated, pure or partially pure state, their racemic mixtures or any other mixtures and mixtures of diastereomers are within the scope of the invention.

The most preferred compounds of the second embodiment are:

OEt

cis d _in cis d ₂

as well as the salts of these compounds, aspects and their individual dias specifically mentioned.

acceptable from the pharmaceutical rheomer if it is not

A third embodiment of the invention relates to compounds which can be represented by structural formula C1

H H O /

I II /

N-C-A-N

(Cl) where

R ¹

R is selected from alkyl of 1 to 10 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, (cycloalkylalkyl of 3 to 7 carbon atoms) (alkyl of 1 to 6 carbon atoms) -, (alkyl of 1 to 6 carbon atoms) up to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) -, aryl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms), or (cycloalkyl of 3 to 7 carbon atoms) ) alkyl (C 0-5 alkyl) -K- (C 1 -C 5 alkyl), wherein K is O, s (O), N (R ²⁾ C (O),

C (O) N (R ^Z ), OC (O), C (O) O, -CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, wherein R and alkyl radicals are optionally substituted with 1 to 9 halogen atoms, S (O) m R ^2a , 1 to 3 OR ^2a or C (O) OR ^2a groups, and aryl is optionally substituted with 1 to 3 alkyl radicals having 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 to 2 OR groups, methylenedioxy groups, -S (O) mR, 1 to 2 -CF ₃ groups, -OCF 3, nitro groups, -N (R ² ) C groups (0) (R ^2),

-C (O) OR ² , -C (O) N (R ² ) (R ² ), 1H-tetrazol-5-yl,

-SO ₂ N (R ² ) (R ² ), -N (R ² ) SO 2 -phenyl or -N (R ² ) SO ² R ² represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 atoms in the case where two alkyl groups having 1 to 6 carbon atoms are bonded to one atom, they may together form a ring of 3 to 8 members, optionally containing an oxygen, sulfur or NR ^3a group, where R ^3a represents a hydrogen atom or alkyl of 1 to 6 carbon atoms optionally substituted by a hydroxyl group,

R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group,

X is selected from hydrogen, -C = N,

- (CH ₂ ) _q N (R ² ) C (O) R ² , - (CH ₂ ) _q N (R ² ) C (O) (CH ² ) _t -aryl,

- (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² ,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ),

- (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² ,

- (CH ₂ ) _q C (O) 0 (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q 0 C (O) R ² ,

- _{(CH2) q} 0C (0) _{(CH2) t} aryl, - _{(CH2) q} 0C (0) N (R ²⁾ (CH 2) χaryl, - (CH 2) q0C (0) N (R ² ) (R ² ), - (CH 2) _q C (O) R ² ,

- (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² ,

- _{(CH2) q} N ^(R2) S02N ^{(R2) (R2),} - (CH 2) _q S (0) _m R ² and - _(CH2) S (0) _m (CH _{2) t} - aryl, wherein the group R, _{(CH2) q} and _{(CH2) t} optionally substituted by 1 to 2 alkyl groups of 1 to 4 carbon atoms, hydroxy, C 1 -C 4 alkyl, carboxy, C0NH _2, s (O) _m CH 3, in the form of a carboxylate alkyl ester of 1 to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl, optionally substituted with 1 to 3 atoms halogen, 1 to 3 groups -OR, -CO (R ² ) (R ² ), -C (O) OR ² , 1 to 3 alkyl groups

O with 1 to 4 carbon atoms, -S (O) _m R or 1H-tetrazol-5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, - (CH ₂ ) _t -aryl, - (CH ₂ ) - (cycloalkyl of 3 to 7 carbon atoms), - (CH ₂ ) _q -K-alkyl of 1 -C 6 alkyl, - _{(CH2) q-K- (CH2) t} aryl, - _{(CH2) q-K- (CH2) t} (C 3 -C 7 alkyl, containing 0, NR ² or S) and - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 3 -C 7 cycloalkyl) wherein K is O, S (O) _m , C (O) NR ² ,

CH = CH, OC, N (R ² ) C (O), C (O) NR ² , C (O) 0 or 0C (0),

O wherein alkyl, R, (CH ₂ ) q and (CH ₂ ) _t are optionally substituted with C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 lower alkoxy, carboxyl, -CONH _2, or in the form of carboxylate alkyl ester C 1-4 alkyl and aryl means phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -C (O) OR ² , -C (O) N (R ² ) (R ² ), nitro, cyano, benzyl, 1 to 3 alkyl groups (C 1 -C 4) -s (O) _m R or 1H-tetrazol-5-yl, provided that X represents a hydrogen atom, Y has a meaning different from that of a hydrogen atom,

R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, 1 to 3 alkanoyloxy groups of 1 to 10 carbon atoms, 1 to 3 alkoxy groups of 1 to 6 carbon atoms , phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety or S (O) m-alkyl of 1 to 6 carbon atoms in the alkyl moiety, or R ⁴ and R 8 together may form a group - (CH2) ^ ^& ί (0Η2) e, wherein L ^a is C (R ²⁾ 2,

ABOUT

O, S (O) _m or N (R), d and e are independently an integer of 1 to 3 and R is as defined above,

A means one of the groups

R ⁷ - (CH ₂ ) _x -C- (CH ₂ ) - or -Z- (CH ₂ ) _X -C- (CH ₂ ) -

R? ^and R ^7a wherein x and y independently represent an integer of 0, 1, 2 or 3,

Z is NR or 0 ^and wherein R ^a is H or alkyl of 1 to 6 carbon atoms,

R ⁷ and R ^7a independently represent hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , cycloalkyl of 3 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or can be R ⁷ and R ^{7a may} be joined to one or both of R ⁴ and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl part of R ⁷ or R ^7a , wherein the bridges contain 1 to 5 carbon atoms or R ⁷ and R ^7a together form a cycloalkyl ring of 3 to 7 carbon atoms,

m means about, 1 or 2 n means 1 2 or 3 q means about, 1, 2, 3 or 4, T means about, 1, 2 or 3

as well as pharmaceutically acceptable salts thereof and their individual diastereomers.

Preferred compounds of the third embodiment are those of the formula Cla ^HH R ⁴

II / ^Rl -C * -NC 'AN

I ^{11 X} rC = o ⁰ R ⁵ (Customs)

where

R ³ is selected from C 1 -C 10 alkyl, aryl (C 1 -C 4 alkyl) -, (C 3 -C 6 cycloalkyl) (C 1 -C 4 alkyl) -, (C 1 -C 4 alkyl) up to 4 carbon atoms) -K- (alkyl of 1 to 2 carbon atoms) -, aryl (alkyl of 0 to 2 carbon atoms) -K- (alkyl of 1 to 2 carbon atoms) - or (cycloalkyl of 3 to 7 atoms) (alkyl having 0 to 2 carbon atoms) -K- (alkyl having 1 to 2 carbon atoms), wherein K is O, S (O) _m , OC (O), C (O) O, wherein the alkyl groups are optionally substituted with 1 to 7 halogen atoms, S (O) _m R ² , 1 to 3 OR ² or C (O) OR ² and aryl means phenyl, naphthyl, indolyl, azaindolyl, pyridyl, benzothienyl or benzofuranyl, optionally substituted with 1 up to 2 alkyl groups having 1 to 4 carbon atoms, or 2 halogen atoms, 1 or 2 -OR ² , S (O) _m R ² or C (O) OR ² groups,

ABOUT

R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 4 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing O, s or NR ^a, wherein R ^a is hydrogen or C 1 -C 4 alkyl,

X is selected from hydrogen,

- (CH ₂ ) _q N (R ² ) C (O) R ² , - (CH ₂ ) _q N (R ² ) C (O) (CH ² ) _t -aryl,

- (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH ₂ ) _q N (R ² ) SO ₂ (CH ₂ ) _t -aryl,

- (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH 2) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl,

- _{(CH2) q} N ^(R2) C (0) N ^{(R2) (R2),} - _{(CH2) q} C (O) N (R ²⁾ (R ^2),

- (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² ,

- (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) R ² ,

- (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q S (O) _m R ² and - (CH ₂ ) S (O) _m (CH ₂ ) _t -aryl, o wherein R is optionally substituted by hydroxyl, carboxyl, CONH ₂ , S (O) _m CH ₂ , in the form of a C 1 -C 4 carboxylate alkyl ester or tetrazole group and aryl is phenyl, naphthyl, pyridyl or 1H- tetrazol-5-yl, optionally substituted with 1 to 2 halogen atoms, 1 to -OR ² , -CONH ₂ , -C (O) OR ² , 1 to 3 C 1 -C 4 alkyl, -S (O) _m R or 1H-tetrazol-5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms,

- (CH 2) _t -aryl, - (CH 2) q - (C 1 -C 6 cycloalkyl), - (C 1 -C 6 -alkyl of 1 to 6 carbon atoms in the alkyl moiety), - (CH ₂ ) _q -K- _{(CH2) x} -aryl, - _{(CH2) q-K-} (Cl · ^). ^ (cycloalkyl of 3 to 7 carbon atoms containing O, s or NR ^Z), and - (0Η ₂₎ η-Κ- (CH 2) _t - (C 1 -C 6 cycloalkyl) wherein K is O, S (O) _m and the alkyl groups are optionally substituted with a hydroxyl group, a carboxyl group, -CONH 2, or in the form of a carboxylate alkyl ester of 1 to 4 carbon atoms in aryl is phenyl, naphthyl, pyridyl, ΙΗ-tetrazolyl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -C (O) OR ² , -C (O) N (R ² ) (R ² ), cyano, 1 to 2 C 1 -C 4 alkyl, benzyl, -S (O) _m R or 1H-tetrazol-5-yl provided that when X is a hydrogen atom, Y has a meaning different from that of a hydrogen atom,

R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, S (O) _m- alkyl of 1 to 6 carbon atoms in the alkyl moiety or phenyl,

A is (CH ₂ ) x -O- _R 7a wherein x is 0 or 1,

R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , cycloalkyl of 5 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or ⁷ and R ^{7a may} be joined to one or both of R ⁴ and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl portion of R ⁷ or R ^7a , wherein the bridges contain 5 to 6 atoms or R ⁷ and R ^7a together form a cycloalkyl ring with 3 carbon atoms,

m means 0 1 or 2, n means 2 q means about, 1, 2 or 3 T means about, 1, 2 or 3

as well as pharmaceutically acceptable salts thereof and their individual diastereomers.

Highly preferred compounds of the third embodiment are those of formula (C1b)

HH 4 _η II / ^R

R ¹ -C'-NCAN.

¹ OR ⁵

C = 0 ^U (CI b) x Y where

R ³ is selected from the group consisting of alkyl of 1 to 10 carbon atoms, aryl (alkyl of 1 to 3 carbon atoms), (cycloalkyl of 3 to 7 carbon atoms) (alkyl of 1 to 3 carbon atoms), or aryl (alkyl of 1 to 3 carbon atoms) (C 1 -C 2 alkyl) -K- (C 1 -C 2 alkyl) - wherein K is O, S (O) _m and aryl is phenyl, naphthyl, indolyl, azaindolyl, pyridyl or benzimidazolyl, optionally substituted with 1 to 2 (C 1 -C 4) alkyl, 1 or 2 halogen atoms, 1 or 2 -OR, S (O) _m R ² or C (O) OR ² groups,

R ² is H, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein in case of one atom are attached two alkyl groups having 1 to 6 carbon atoms, may together form a ring of 5 to 7 optionally containing oxygen, sulfur or NR ^3a , wherein R ^3a is hydrogen or C 1 -C 4 alkyl,

X is selected from hydrogen,

- (CH ₂ ) _q N (R ² ) C (O) R ² , - (CH ₂ ) _q N (R ² ) C (O) (CH ² ) _t -aryl,

- (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² ,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl,

- (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ),

- (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH 2) q C (O) N (R ² ) (CH 2) _t -aryl,

- (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) 0 (CH ₂ ) _t -aryl,

- (CH ₂ ) _q OC (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl,

- (CH ₂ ) _q S (O) _m R ² and - (CH ₂ ) _q S (O) _m (CH ₂ ) t -aryl, wherein R ² is optionally substituted by hydroxyl, carboxyl, CONH 2, SCO 2 CH 2, in the form of a carboxylate alkyl ester having 1 to 4 carbon atoms in the alkyl moiety or a tetrazole group and aryl is phenyl, naphthyl or pyridyl, optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR ² , -C (O) OR ² , 1 to 2 3 alkyl groups of 1 to 4 carbon atoms, -S (O) _m R or 1H-tetrazol-5-yl,

Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms,

- (CH ₂ ) _t -aryl, - (CH ₂ ) - (C 5 -C 7 cycloalkyl), - (CH ₂ ) _q -C 1 -C 6 alkyl in the alkyl moiety, - (CH ₂ ) _q -K- (CH ₂ ) _t -aryl or - (CH ₂ ) _q -K (CH ₂ ) (C 5 -C 6 cycloalkyl) wherein K is S (O) _m and the alkyl groups are optionally substituted with a hydroxyl group , carboxyl, -CO ₂ NH ₂ or in the form of a carboxylate alkyl ester of 1 to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl, aryl means phenyl, naphthyl, pyridyl, thiazolyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl, optionally substituted 1 to 2 halogen atoms, 1 to 2 -OR ² , -C (O) OR ² ,

-N (R ² ) (R ² ), 1 to 2 C 1 -C 4 alkyl, -S (O) _m R or 1 H -tetrazol-5-yl, provided that when X is an atom hydrogen, Y has a meaning different from that of a hydrogen atom,

R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted alkyl of 1 to 3 carbon atoms, wherein the substituents may be 1 to 2 hydroxy groups,

A represents a group

R ⁷ (CH ₂ ) x -R ^7a where x is 0 or 1,

R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, substituted alkyl of 1 to 6 carbon atoms, wherein the substituents are selected from imidixolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (0) _m R ² , C (O) OR ² , or R ⁷ and R ^7a together may form a cycloalkyl ring of 3 carbon atoms,

m means 0 1 or 2, q means 0 1 , 2 or 3 T means 0 1 , 2 or 3

as well as pharmaceutically acceptable salts thereof and their individual diastereomers.

Even more preferred compounds of the third embodiment are those of the formula C 1c = y, R ⁴ R 1 ^- C ^- N ^- CAN (II) R ⁵

C = 0 O

where r! is selected from groups

MeO

H H

or the regioisomers of these compounds, unless otherwise specified, are hydrogen or one of the following groups:

and ₀ ' ^ch ' and ₀ ' ^e * oo

O CH ₃ <CH ₃ o ch ₃

CH,

OH

O 'o

ch ₃ o

Ah ... - ^0H

CH ₃ '0 oo

ΌΗ

O CH ₃

_Λ ν ^ ₃ Ά ^'ει N - ^CH3

N ' ⁱⁿ °' N '' CH ₃

HH ³

ABOUT

A

NH, hA ' ^CH '

H

CH ₃ -NH

O CH ₃

AA

CH, ° 1 sAch ₃ ° <· _ < ^NH ' ^NH V -nh' ^s ₃

First

A.

-HN N H

ABOUT

X '.CH-HN O .SCH,

Y represents a hydrogen atom or one of the following groups:

or regioisomers of the following groups, unless specifically specified, provided that when X is hydrogen, Y has a meaning different from that of hydrogen, is selected from:

\ ₃ \ _x ch ₃ h ₃ c CH 3 P ^H 3, CH ₃ H ₃ C., CH ₃

/ V7 ⁵ ww κΓ * ν

H, C.

CH, .CH, kV W

NH

R ⁴ and r ⁵ are independently selected from -H-CH ₃ -CH ₂ CH ₃

CH,

CH ₂ OH

OH

OH as well as their pharmaceutically acceptable salts and diastereomers.

The most preferred compounds of the third embodiment are

1 H (CH ₂ ) ₂ SCH ₃ o

.OEt

 'C

II o

ABOUT

and pharmaceutically acceptable salts and individual diastereomers thereof, except where specifically indicated.

The following abbreviations are used throughout the application, the meanings of which are given below:

BOC t-butyloxycarbonyl

BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

CBZ benzyloxycarbonyl

DIBAL-H diisobutylaluminium hydride

DMF N, N-dimethylformamide

EDC

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

FAB-MS fast atom bombardment mass spectroscopy

GHRP growth hormone releasing peptide

HOBT hydroxybenztriazole

LAH lithium aluminum hydride

HPLC high pressure liquid chromatography

MHz megahertz

MPLC medium pressure liquid chromatography

NMM N-methylmorpholine

NMR nuclear magnetic resonance

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMS tetramethylsilane

In all cases, the compounds of the invention have at least one center of asymmetry as indicated by the asterisk in structural formula I above. Additional centers of asymmetry may be present in the molecule, depending on the nature of the various substituents in the molecule. Each center of asymmetry gives rise to two optical isomers. These isolated, pure or partially purified optical isomers, racemic mixtures or diastereomer mixtures thereof are also within the scope of the invention. In the case of the center of asymmetry, represented by an asterisk in formula (I), it has been shown that the absolute stereochemistry of the more potent and thus more advantageous isomer can be represented by formula (II).

(Ii)

r! and the substituents on the nitrogen atom are in the plane of the structure in which the C = 0 group also lies. The configuration of the center of asymmetry corresponds to that of the D-amino acid. In most cases it is referred to as the R-configuration, although this may vary depending on the use of R ³ in the labeling of the stereochemical R and S configurations.

The group V may also be present in the R or configuration

Both are substances that can favorably influence growth hormone secretion, although more generally the R configuration is more effective. In addition, the group V may be in the cis or trans position with respect to the substituents X, Y or R. In the case of the center of asymmetry carried by the X and Y groups, compounds with a useful level of growth hormone secretion can be obtained for both R and S configurations. In addition, the configurations of the highly preferred compounds of the invention will be described below. The groups V, X and Y may also be in the cis or cis position

-a trans with respect to the substituent R. In some highly preferred compounds, the cis or trans position is also relative to

O substituent R mentioned. All of these are within the scope of the invention and stereochemical orientations are given for some of the preferred materials. When the carbon atom represented by the asterisk in formula I is in a defined configuration, usually in the D configuration, diastereomers are formed according to the absolute configuration on the carbon atoms bearing the groups

Q

V, X, Y and R. These diastereomers are referred to as d 1, d ₂ , d ₃ , d ₄ and beyond, and may optionally be synthesized individually or may be chromatographically separated using conventional procedures or as hereinafter described. The absolute stereochemistry of these compounds can be determined by crystallography using X-rays on crystalline products or crystalline intermediates, from which they are then formed derivatives, optionally using a reagent that contains an asymmetric center of known absolute configuration.

The compounds of the invention are usually isolated in the form of pharmaceutically acceptable acid addition salts, for example in the form of salts derived from inorganic or organic acids. Examples of such acids are hydrochloric, nitric, sulfuric, phosphoric, formic, acetic, trifluoroacetic, propionic, maleic, succinic, malonic, methanesulfonic and the like. In addition, some compounds having an acidic function, such as a carboxyl group, can be isolated in the form of inorganic salts of sodium, potassium, lithium, calcium, magnesium and the like, or even in the form of salts with organic bases.

The preparation of the compounds of the formula I according to the invention can be carried out in a stepwise or convergent synthetic manner. In the following reaction schemes, the procedures that can be used to obtain the compounds of Formula I step by step will be described in more detail.

In the above procedures, standard coupling reactions used in peptide coupling and standard conditions for carrying out these reactions are essentially the binding of a carboxylic acid with an amine in the presence of an acid activating agent such as EDC, DCC and BOP. in an inert solvent such as dichloromethane in the presence of a catalyst such as HOBT. The possible use of amine and carboxylic acid protecting groups to facilitate the desired reaction and to suppress undesirable side reactions as much as possible is well documented. Conditions for removal of protecting groups present are reviewed in Greene T., Vuts P.

G. M., Protective Groups in Organic Synthesis, John Viley &amp; Sons, Inc., New York, NY 1991. CBZ and BOC protecting groups were frequently used during the synthesis, the conditions for removing these groups are well known. Removal of the CBZ group can be achieved by a variety of known methods, for example by catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide, for example palladium on activated carbon in a protic solvent, for example ethanol. If catalytic hydrogenation is not possible due to the presence of other potentially reactive groups, the CBZ groups may also be removed by treatment with 62% hydrogen bromide in acetic acid or with a mixture of TFA and dimethylsulfide. The BOC protecting group may be removed in a solvent such as methylene chloride or methanol or even ethyl acetate by treatment with a strong acid such as trifluoroacetic acid or hydrochloric acid, or even with gaseous hydrogen chloride.

The protected amino acid derivatives of formula 1 are in many cases commercially available, with the L-protecting group being, for example, BOC or CBZ. Other protected amino acid derivatives corresponding to the above formula can be prepared by methods known in the literature, for example, according to Villiams RM, Synthesis of Optically Active Alpha-Amino Acids, Pergamon Press: Oxford, 1989. A variety of piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of formula (2) is commercially available or known from the literature, other compounds may be prepared according to the procedures described for the preparation of known compounds, some of which will be described hereinafter. These are conventional procedures for carrying out conventional reactions and purification of the resulting products as commonly practiced in the art. The purification is in particular crystallization and chromatography, optionally in reverse phase.

Scheme 1

H Ϋ

R ¹ —N — L CO ₂ H. N _X W (CH ₂ ) _n y

R '

R ^J

N-L

C = 0

NW (CH ₂ ) _n y

M-x (3)

Intermediates of formula 3 can be synthesized according to Scheme 1. The amines of formula 2, the preparation of which will be described later in the absence of known compounds, are reacted with protected amino acids of formula 1 wherein L is a suitable protecting group under standard conditions to effect the peptide bond.

Scheme 2

H H

R-j-p-L

C = 0

I.W (CH ₂ ) _n y -4-x removal

HH-J-R ¹ NH C = 0

NW (CH ₂ ) n Y

M-x

Conversion of the intermediate of Formula 3 to the intermediate of Formula 4 can be accomplished according to Scheme 2, deprotection of L, for example CBZ, BOC and the like, by conventional procedures.

Scheme 3 o

HO-C-A-N

H H O]

III-f-N-C-A-N C = O

R ^J

N-H

M> ^W (CH ₂ ) _n >

C = 0 LR ⁴ removal = H

KW (CH ₂ ) _n V

Π-Χ + or

-H ₂ 0 ⁰ L n

HO-C-A-N

H H O l II /

N-C-A-N

C = 0

Ä W (CH ₂ ) _n y

M-x

R ³ Y

Intermediates of formula (5) in which A is attached to a carbonyl group by a carbon atom and thus represents a group of formula - (CH ₂ ) _X -C (R ⁷ ) (R ^7a ) - (CH ₂ ) _y - may be prepared according to Scheme 3 by reacting intermediates of formula 4 with an amino acid of formula 5 under conditions conventional to effect peptide bonding. Amino acids of formula 5, as well as amino acids of formula 1, are commonly supplied or readily prepared. Also, when R ⁴ or R ³ is a hydrogen atom, protected amino acids of formula 6, wherein L is a protecting group as defined above, may be used for the coupling reaction. From compound 7 was deprotected L in known manner to provide the product of formula I wherein R ⁴ is hydrogen.

Scheme 4

H H O H

II II / _R 1 —NCAN C = O R ⁵

Ä W (CH ₂ ) _n V

M-x

R ³ Y (I) reductive alkylation epoxide opening

H H 0 r4

I II.

_R 1-- _N _q_ _A _ _N or C ⁼ O R 4 * NW

X

R ³ Y (I) wherein R ⁴ is alkyl optionally substituted

Compounds of formula I wherein R ⁴ and / or R ³ are hydrogen may be further processed to novel compounds of formula I (with the most preferred side chain R ⁴ = CH ₂ -CH (OH) -CH ₂ X, wherein X is hydrogen or OH) which are substituted at the amino acid as shown in Scheme 4. Reductive alkylation of a compound of formula I with an aldehyde is carried out under known conditions, for example, by catalytic hydrogenation with hydrogen in the presence of a platinum, palladium or nickel catalyst or reducing agents such as sodium cyanoborohydride in a protic solvent such as methanol or ethanol in the presence of an acid. A similar conversion can also be accomplished by opening the epoxy ring.

Scheme 5

- | - NH X - ^{U -} Z - (CH ₂ ) r - (CH ₂ ) y N c = o

7a ^N 1 / ^w (CH ₂ ) _n y

M-x

R ³ Y (4) (8) or formula I

0 = C = N- (CH _{2) x} -J- _(CH2) y N, 7 (9)

Compounds of formula I wherein A is Z- (CH ₂ ) _X -C (R ⁷ ) (R ^7a ) - (CH ₂ ) _y - and Z is NR 4 or O may be prepared according to the scheme 5 by reacting a compound of formula 4 with a reagent of formula 8 in which X represents a well-cleavable group, for example a chlorine, bromine or iodine atom or an imidazole group. It is also possible to react the compound of formula 4 with an isocyanate of formula 9 in an inert solvent such as 1,2-dichloroethane to give products of formula I wherein Z is NH.

The compounds of the formula I according to the invention can also be prepared in a convergent manner as described in the following Reaction Schemes 6, 7 and 8.

Scheme 6

R ⁴ HOOC-A-N- r ⁵ HH 0 R ⁴ R ¹ -—J— NCAN- H H (5) COOM r ¹ —N-H COOM + or (11) (10) L HOOC-A-N-R ⁵ HH 0 L 1 I ^{1 11 1} d -1 -1 — MP Δ M

COOM (12a)

Protected carboxylic acid protected amino acid derivatives of formula (10) are commonly obtainable in a number of cases. In particular, they are compounds in which M is methyl, ethyl or benzyl. Other protected amino acids in the form of esters can be prepared by conventional procedures as commonly practiced in the art. Some of these procedures involve reacting an amino acid with an alcohol in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid with azeotropic removal of water. Other methods include reacting the protected amino acid with a diazoalkane or alcohol and an acid activating agent such as EDC, DCC in the presence of a catalyst such as DMAP followed by deprotection of L.

Intermediates of formula 11 or 11a can be prepared as shown in Scheme 6, i.e. by coupling an amino acid ester of formula 10 to amino acids of formula 6 or 7. If a urea-type bond is to be present in the product of formula 11a, it can be introduced as shown in Scheme 5.

Scheme 7 ^H HOR ⁴ R ¹ - [- NCA N-R ⁵

COOM (10)

R ¹

H? 2 ^{r4 —} NC-NCOOH (12)

HH 9 LR ¹ - (- NCANR ⁵

COOM (12a)

R ^J

H H O L

II II — N-C-A-NCOOH (12a)

R ⁵

Conversion of esters of formula 11 or 11a to acid 12 or 12a as an intermediate can be accomplished by a variety of known procedures, for example as shown in Scheme 7. For example, the methyl ester or ethyl ester can be hydroxylated by treatment with lithium hydroxide in a protic solvent such as aqueous methanol. For example, removal of the benzyl group can be accomplished by a series of reduction procedures, such as hydrogenation in the presence of a palladium catalyst in a protic solvent such as methanol. The allyl ester can be cleaved with a tetrakistriphenylphosphine palladium catalyst in the presence of 2-ethylhexanoic acid in a variety of solvents, such as ethyl acetate and dichloromethane, as described in J. Org. Chem., 42, 587 (1982).

Scheme 8 ^H H 0 R ⁴ R ¹ —NCA-N-R ⁵

COOH fj w (12) (CH ₂ j _n V

R x

At 9 h ¹ W, ^{R 3 y} R 1 fNCANR ^Ï

COOH (3)

removal of r ⁴ = h 1 (7)

The acid of formula 12 or 12a can then be treated to give the final product of formula I or a compound of formula 7 as described in Scheme 8. Coupling of piperidine, pyrrolidine or hexahydro-1H-azepine derivatives of formula 2 to the acid of formula 12 or 12a, wherein L is a suitable protecting group can be readily performed under conditions conventional to effect peptide bonding. Conversion of the compound of formula 7 to the product of formula I can be achieved by deprotection of L. If R ⁴ and / or R 6 is hydrogen, optionally substituted alkyl groups can be attached to the nitrogen atom by the method of Scheme 4.

The 2-substituted piperidine, pyrrolidine or hexahydro-1H-azepine derivatives are commercially available or can be prepared by methods known in the literature. Hereinafter, only some of the processes for the manufacture of these substances will be presented.

H .N Scheme A9

Mx ^Rs (Α1Ϊ)

1) Na ₂ WO ₂ , H ₂ O ₂

2) NaCN, HCl

(CH y-CN

M-x

R @ ₁ (CH2

(A2a) hci / h ₂ o

- after ₂ h

R, Y (A15) and T.

In the process of S. Murashi Shiot, Tetrahedron Lett., 28, 6469-6472, 1987, alpha-hydroxylaminonitriles of formula (I) can be obtained by catalytic oxidation of cyclic amines such as piperidines, pyrrolidines or hexahydro-1H-azepines with hydrogen peroxide followed by hydrogen cyanide. A14, which by reduction according to Murahashi SI, Kodera Y., Tetrahedron Letters, 26, 4633-4636, 1985, produce the alpha-aminonitriles of formula A2a. In cases where X and Y do not simultaneously represent a hydrogen atom and / or n have a different meaning from 2, regioisomers and diastereoisomers may be formed, which can then be isolated by chromatographic methods. Hydrolysis of the aminonitrile under acidic or basic conditions yields the amino acid. Alternatively, the hydroxyaminonitrile is first hydrolyzed and the product obtained is then reduced by palladium catalyzed hydrogenation to provide the amino acid of formula A15. The amino acid and derivatives thereof prepared as described above are racemic compounds.

A nitrile of formula A2a can also be prepared by oxidizing a compound of formula A13 to an imine as described in Goti and Romani, Tetrahedron Letters, 35, 6567-6570, 1994, followed by reaction with cyanide. Group V can also be introduced by direct alkylation of compounds A13 with a Boe protecting group by butyllithium followed by addition of electrophiles, known as Beak alkylation and described in Beak and Lee, J. Org. Chem., 55, 2578-2580, 1990. Asymmetric introduction of Group V can also be achieved using a chiral catalyst according to Kerrick and Beak, J. Am. Chem. Soc., 113, 9708-9710, 1991.

Scheme A10

HH (CH ₂ R yCO ₂ H- _C H ₂ {yW

M - x M - x

R ³ YR ³ Y (A15) (A2) (A15)

R ² OH (ΟΗ ₂ >> ^Οθ 2 ^Η)

M-x

R ³ Y (A16)

HOBt,

R ² R ²

Η ^{Η +} (ch ₂ Í in ^c ° 2 ^r2

Π-χ

R ³ Y (A2b)

L

EPC _(CH2) ^ ² CONr2r MH

R ³ Y (A2c)

L. N (CH ₂ ) _n

CN tetrazoles or other heterocycles (A17)

The carboxyl functional group at the 2-position of the compound of formula A15 can be converted to an ester, amide, nitrile, acylsulfonamide or V-defined groups to give a compound of formula 2, the necessary procedures are well documented in the literature, for example The Practice of Peptide Synthesis , M. Bodanszky and A. Bodanszky, Springer-Verlag, 1984. L- represents a suitable protecting group, for example BOC, CBZ and the like. The carboxyl group can also be converted to the next higher homolog or homologous acid derivative, for example, an amide or an ester by an Arndt-Eistert reaction. It is also possible to obtain the ester homolog directly using the ynolate anions as described by C.J. Kowalski and R.E., Reddy, J. Org. Chem., 57, 7194-7208 (1992). The resulting acid and / or ester can be converted to the next higher homolog and vice versa.

Scheme All (CH ^ yw

M-x

R ^{3 Y} (A ¹⁹ ) (CH 2 YW)

- M-x

R ³ Y (A2)

Scheme All depicts a general procedure for introducing a group Y when X is a group

O-electrons, for example -CN or -CO ₂ R, where R is alkyl, aryl or arylalkyl of 1 to 4 carbon atoms in the alkyl moiety. It is the preparation of known substances or substances which can be prepared by the above-mentioned processes or by processes known for the production of known substances. The Y group can be introduced by first reacting the compounds of Formula A18 with a strong base, for example, potassium bis (trimethylsilyl) amide or lithium diisopropylamide, followed by treatment with alkylating agents such as alkyl halides, arylalkyl halides, acyl halides or halogen halides. for example in THF at -100 ° C to room temperature. Thioderivatives in which sulfur is directly bound to an alkyl or aryl group can be prepared in a similar manner by reaction with a disulfide. The halides used in the course of the reaction are commercially available or are substances which can be prepared according to the procedures described in the literature for the production of known compounds. The protecting group L in compounds of formula A19 may be removed by conventional methods to give compounds of formula 2.

Scheme A12

N

or _Y (CH _{3) 2} NCOC

1) H2O2

(2) TMSCN (A20) ΌΝ

or Y x 2) H ₂ / Pto ₂

1) HCl / H 2 O ^{M c} ° 2 ^H

YX '3 or YR · ⁵ (A22)

For the production of cis-homoproline derivatives, the method of Shuman R.T., Ornstein P.L., Paschal J.V., Gesellchen P.D., J. Org. Chem., 55, 738-741, Scheme A12, 1990. Substituted pyridines of formula A20, many of which are commercially available or can be prepared by known methods, are converted to the corresponding N-oxides by reaction with hydrogen peroxide. Reaction of pyridine N-oxide with trimethylsilyl cyanide and dimethylcarbamyl chloride affords the 2-nitrile of formula A21. If regioisomers are formed due to the presence of the substituent at the 3-position, they can easily be separated by chromatography. Hydrolysis of the nitrile to acid in an acidic or alkaline medium followed by hydrogenation, catalyzed by platinum oxide, yields piperidinecarboxylic acid. The formation of functional derivatives of this acid has been described above and in part in Scheme A10.

The amino acids obtained by this synthetic method are racemic. Methods for separating the RS-alpha amino acid in various ways are described, for example, in Toone E. J., and Jones J. B., Can. J. Chem., 65, 2722 (1987); Okamoto S., Hijikato A., Biochem, Biophys. Res. Commun., 101, 440 (1981); Greenstein, J. P., Vinitz, M., Chemistry of the Amino Acids, Viley: New York, 1961, Vol. Thus, it is possible to prepare the separated isomers R and S in this way. It is also possible to convert racemic piperidine, pyrrolidine and hexahydro-azepine derivatives directly to growth hormone secretion enhancers or to intermediates thereof, and the resulting diastereomeric mixtures can also be used. at a suitable stage, chromatographically to give the enantiomerically pure compounds.

Scheme A13

It is also possible to perform an asymmetric synthesis to give optically pure piperidine, pyrrolidine and hexahydro-1H-azepine derivatives. For example, optically active piperidine-2-carboxylic acid derivatives of formula A15a or A15b can be prepared using the aza-Diels-Adler reaction as described in Bailey et al., J. Chem. Soc. Perkin Trans. I, 1337-1340, 1991. Reaction between a chiral imine of formula A23 and a diene of formula A24 in the presence of one equivalent of TFA and a catalytic amount of water yields addition products A25 and A26 with good diastereoselectivity. The two diastereoisomers may be separated from each other and each may be hydrogenated to reduce the double bond and to remove the auxiliary chiral group. In this way, all four isomers can be prepared. Scheme A13 depicts the preparation of the two isomers A15a and A15b with the S configuration at the center of chirality in the COOH group.

Two additional R-isomers in the same chiral center can be prepared in a similar manner using the compound of Formula A26.

Scheme B9

The synthesis of substituted pyridines of formula 2 wherein n = 2 has been described in detail in a number of publications, for example, in S. M. N. Efange et al., J. Med. Chem., 36, 1278-1283 (1993) and M. S. Berridge et al., J. Med. Chem., 36, 1284-1290, 1993, a 4-substituted pyridine intermediate of formula B13 was used to prepare 4-substituted tetrahydropiperidine derivatives of formula B14 in which L = methyl as depicted in Scheme B9. Removal of the L group from the piperidine derivatives of formula B14 may be accomplished by a variety of known methods including the use of cyanogen bromide according to H. Ong et al., J. Med. Chem., 23, 981-986 (1983) and the procedure using ACE-C1 according to R. Olofson et al., J. Org. Chem., 23, 2795, 1984. In the case of intermediates of formula B14 in which L = Bn, it is possible to simultaneously remove the benzyl group and hydrogenate the olefin using platinum or palladium as a catalyst in a protic solvent such as methanol. It is also possible to directly convert intermediate B13 to piperidine derivatives of formula B15 in which L is a hydrogen atom by reduction with platinum oxide in a protic solvent such as methanol in the presence of a catalytic amount of acid.

L

TfO Y

Scheme ΒΙΟ L (CH ₂ R ³ - Xa -R ³ Y (B17) [Xa = B (OH) ₃ or SnMe ₃ ]

R ³ YR ³ Y (B20)

Other procedures, as shown in Scheme B10, can also be used to obtain compounds of Formula 2. For example, the cross-linking of an enol triflate of Formula B16 wherein L is a protecting group and X and Y are as defined in Formula I with an aryl boronic acid of Formula B17 in which Xa = B (OH) ₃ or with arylcine, phenyltin or naphthylcine derivatives of formula B17, in which Xa = SnMe ₃ , may be accomplished using palladium or palladium metal as a catalyst as outlined in VJ Scott and JE McMury Acc. Chem. Res., 21, 47, 1988, which describes the preparation of tetrahydropiperidines of formula B18, wherein L is a protecting group. Various processes are known for the preparation of enoltriflate-type intermediates of formula B16, phenylboronic or naphthylboronic acids and phenyltin or naphthylcin derivatives as reagents of formula B17 wherein Xa is B (OH) ₃ or SnMe ₃ , these procedures are known in the art known. Removal of the protecting group L can give, for example, piperidine derivatives of formula B19 in which L = H. Hydrogenation of a derivative of formula B18 followed by deprotection of L can be used to prepare saturated derivatives of formula B20. Derivatives of formula B19 can also be converted to compounds of formula B20 by hydrogenation of an olefin in the presence of a platinum or palladium catalyst in a protic solvent such as methanol.

Scheme Bil

Methods for making substituted pyrrolidine, piperidine and hexahydro-1H-azepine derivatives also include the addition of substituted and / or unsubstituted Grignard reagents with an alkyl, cycloalkyl, phenyl or naphthyl group, or lithium-based reagents to form oxopiperidine, oxopyrrolidine, oxopyrrolidine, oxopyrrolidine, oxopyrrolidine, oxopyrrolidine or oxopyrrolidine derivatives. of formula B21 in which L = benzyl, methyl and the like to obtain compounds of formula B22 in which L is benzyl, methyl and the like. Dehydration of the hydroxyl group in these compounds to give derivatives of formula B18 in which L is benzyl, methyl and the like can be accomplished by treatment with a strong acid or elimination reaction on the corresponding mesylate derived from a compound of formula B19 or B20 as described above.

Scheme B12

L • N (CH ₂ ) _n >

M-x

R ³ H (B22)

M.

(CH ₂ ) _n >

M-x

R ³ Y (B19)

The 3,4-disubstituted piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of formula B21 in which X is an electron withdrawing group, for example an ester, ketone, nitrile and the like, can be further subjected to alkylation, hydroxylation or halogenation in a known manner. Also, deprotection of L may be accomplished by known methods.

Ortho-substituted phenylpiperidine derivatives of formula B22a wherein X, Y = H

H .N.

I, i / ^X (B22a) can be prepared from an intermediate of formula phenylpiperidine B23 of the SMN Efande et al, J. Med. Chem., 26, 1278 (1993).

Scheme BI3

(B23)

(B26) < ^B25

As shown in Scheme B13, benzyl alcohol can be oxidized to the aldehyde of Formula B24 by a variety of known procedures. A commonly used process is manganese dioxide in an inert solvent such as chloroform or the Swern method. A variety of functional groups can be attached to the compound of formula B24. For example, by an Emmons reaction with triethylphosphonate in the presence of a base, an alpha, beta-unsaturated ester of formula B25 can be obtained. Simultaneous reduction of the pyridine unit and the olefinic group in the presence of a platinum or palladium catalyst in an alcoholic solvent affords the piperidine of formula B26 in which X, Y = H. The derivative of formula B26 can be further processed to compounds of formula I with ester or acid groups. wherein X and Y are hydrogen using the method of Schemes 1-8. Compound B24 can also be directly converted to the methyl ester of formula B27, wherein X, Y = H by oxidation of the aldehyde group to the ester group by the Corey method (using NaCN, acetic acid) and MnCl 2 in methanol) followed by reduction of pyridine to piperidine using a platinum or palladium catalyst in a protic solvent such as methanol. The piperidine derivative of formula B27 can be further processed to the compounds of formula I using the procedures of Schemes 1-8. The piperidine unit of the compound of formula B27 can be protected using various protecting groups L as known in the art. The ester unit can be hydrolyzed by known methods to give an acid of formula B28 in which X, Y = H. The acid of formula B28 as an intermediate can be used to prepare compounds with a variety of piperidine, further substituted groups, which can then be converted to the resulting compounds. of formula I.

The phenylpiperidine derivatives of formula B22, bearing additional functional groups in which X, Y = H, can be prepared using the synthetic procedures described below.

Scheme B14

L i

N

OH

Urine ² r ² (R ⁶ ) (B30) (B30a)

ABOUT

As shown in Scheme B14, the piperidine derivative of formula B26 may also be a key intermediate for the preparation of various piperidine derivatives of formula B22a in which R ¹⁰ is alkyl- and arylamides, alkyl- and arylacylsulfonamides, alkyl-aryl-ureas, alkyl- and arylcarbamates and the like. The nitrogen atom in the piperidine group of the compound of formula B26 can be protected by a protecting group L, commonly used groups include BOC, CBZ and FMOC, which can be bound by known methods. Then, the ester unit can be hydrolyzed by treatment with sodium or potassium hydroxide in an aqueous or alcoholic medium to give the compound of formula B29. By peptide coupling of a derivative of formula B29 to primary or secondary aliphatic amines, arylamines, appropriately protected amino acids, alkyl- or arylsulfonamides it is possible to obtain amides of formula B30 in which X, Y = H, then deprotecting L. It is also possible to proceed by reacting the acid of formula B29 with carbodiimidazole and then reacting with primary and secondary aliphatic amines, arylamines, suitably protected amino acids, alkyl- or arylsulfonamides in an inert solvent such as tetrahydrofuran or dimethylformamide to form amides of formula B30 in which X, Y = H, the protecting group L is bonded to a nitrogen atom and R and R are as defined above. Urea derivatives of formula B30a in which X, Y = H, L is a nitrogen protecting group and R and R 0 are as defined in formula I can be synthesized from B29 by carrying out a Curtius rearrangement followed by reaction of isocyanate-type intermediates with amines HNR ² R ² or HNR ² R 6. The protecting group L can be removed and the derivatives obtained can be converted to compounds of formula I by one of the procedures outlined in Schemes 1 to 8 above.

Scheme BI5

N-N (B 32) H

The acid intermediate of formula B29 is also a key intermediate for the synthesis of heterocyclic derivatives of formula B32 in which X, Y = H. As shown in Scheme B15, the acid of formula B29 can be converted to a nitrile of formula B31 in which X, Y = H in three steps comprising activating ethyl chloroformate in the presence of a base such as triethylamine, adding aqueous ammonia to obtain the primary amide, and dehydrating the amide to the nitrile by treatment with phosphorus oxychloride in pyridine. The nitrile of formula B31 can be converted to intermediate piperidine of formula B32, wherein X, Y = H and R ¹¹ is ΙΗ-tetrazole by heating with trimethyltin azide in an inert solvent such as toluene, xylenes. The protecting group L can be removed and the derivatives obtained can be processed to the products of formula I according to the procedures outlined in Schemes 1 to 8.

Scheme B16

Other cyclic group-containing piperidine derivatives of formula B32 may also be prepared from intermediates of formula B31 as shown in Scheme B16. Treatment of the nitrile of formula B31 with anhydrous hydrochloric acid in anhydrous ethanol gives the iminoether of formula B33. Addition of the formylhydrazine compound of formula B33, followed by heating the intermediate in an inert solvent such as toluene to give a piperidine of formula B32, wherein X, Y = H, R ¹ is 1,2,4-triazole. It is also possible to attach a carbomethoxyhydrazine group to an iminoether of formula B33 and cyclize the intermediate to give a derivative of formula B32 wherein X, Y = H and R ³ = ^3- are triazoline. Treatment of the derivative of formula B33 with dihydroxyacetone in methanolic ammonia solution at elevated pressure gives a compound of formula B32 wherein X, Y = H and is a hydroxymethylimidazole group. The protecting group L can be removed in a known manner, and the product can then be processed to the compound of formula I using the procedures outlined in Schemes 1-8.

In addition, acids, acid chlorides, nitriles and iminoethers are key intermediates of derivatives substituted with alkyl or phenyl groups, hydroxy groups and amino groups. A number of these processes are disclosed in A. R. Katrizky, Handbook of Heterocyclic Chemistry, Pergamon Press, 1985, New York, N.Y., and can be used to produce a variety of compounds containing heterocyclic groups.

Scheme B17

Still other useful processes for the production of mono- and disubstituted pyrrolidine, piperidine and hexahydro-1H-azepine derivatives of the general formula II in which n = 1 or 2 are known from the literature. For example, J. J. Piati and V. Venner, J. Org. Chem., 14, 543, 1949 describes a process by which a ketoamine of formula B34 can be converted as an intermediate into a derivative of formula B35 wherein n = 1, 2 or 3 under condensation conditions with an aldol. Dehydroxylation of the B35 derivative can be accomplished by a variety of procedures, for example, by catalytic hydrogenation using palladium catalyst in a protic solvent such as methanol.

Removal of the protecting group L from a derivative of formula B36 can be accomplished by a variety of procedures, including the ACE-C1 procedure described by R. Olofson et al., J. Org. Chem., 43, 2795 (1984).

Scheme BI8

(B39)

The 3,4-disubstituted piperidine derivatives of formula 2 in which n = 2 can be readily prepared by literature procedures. One of these general procedures will be described below. G. T. Borrett has shown that it is possible to prepare cis-3,4-disubstituted piperidine derivatives B39 (U.S. Pat. No. 4,861,893) from commercially available ethyl nicotinate.

O The Grignard reagent R MgBr ^J, wherein R · ³ is as defined in formula I. The ester functionality of B38 derivatives can be further modified by conventional means to give the other functional groups of X as defined in formula I. It will be the For example, it is possible to hydrolyze an ester of formula B38 to give the corresponding carboxylic acid of formula B39 (X = CO ₂ H). The derivative of formula B39 can then be converted to the amide (X = CONR ^X R) by a simple reaction to form a peptide bond or even to urea derivatives or carbamates (X = NC (O) NR ² R ² or NC (O) OR ² ) by Curtius rearrangement according to Smith, Org. React., 3, 337, 1946 followed by capture of the isocyanate intermediate with an amine or an alcohol, or it is possible to obtain a hydroxymethyl unit (X = C 6 OR ⁶ ) by reduction with borane. The acid of formula B39 can also be converted to the nitrile and converted to the heterocyclic compounds (X = tetrazolyl, triazolyl, triazolinolyl and the like) shown in Schemes B15 and B16. The carboxylic acid of formula B39 (X = CO ₂ H) can also be converted to a higher homologue of formula B39 (X = CH ₂ CO ₂ H) by Arndt-Eistert reaction, and the products obtained can then be processed to further derivatives by the above procedures.

Scheme BI9

(B38) (B40)

The cis-3,4-disubstituted piperidine derivatives of formula B38 can be converted to the trans-3,4-disubstituted piperidine derivatives of formula B40 by the method of Scheme B19 by treating the derivative of formula B38 with a catalytic amount of a base such as sodium ethoxide in a protic solvent. The ester function of the B40 derivative can be further modified by known methods, including that shown in Scheme B18. The protecting group L can be removed from the compounds of formulas B39 and B41 by conventional methods, and the resulting compounds are then processed to the resulting products of formula I as described above.

Scheme B20

MgBr '

CO ₂ R ^{2 and} CONR ² R ²

As described in Scheme B20, cis-3,4-disubstituted piperidine derivatives of formula B34 can be prepared by addition of compounds of formula B42 to ethylnicotinate according to G.T. Borrett, US 4,861,893. The protecting group on the acetal group can be removed by a variety of known procedures. The resulting aldehyde of formula B44 is a key intermediate for synthesis

3,4-disubstituted piperidines with additional substituents. The aldehyde of formula B44 can be oxidized to the corresponding carboxylic acid of formula B45 and then further processed by coupling other functional groups to amides, urea derivatives, carbamates, acylsulfonamides and the like. Some examples of these transformations were given in connection with the procedures outlined in Scheme BI4.

Scheme B21

L

Compounds of formula B44 can also be converted to α, β-unsaturated esters or nitriles by the Emmons reaction. The resulting unsaturated ester or nitrile can be hydrogenated using a catalytic amount of palladium or platinum in a hydrogen atmosphere. The diester of formula B45 (X = CH 2 Et, E = CC 1 Et), shown in Scheme B21, can be selectively hydrolyzed to the corresponding acid of formula B45 (X = CH 2 Et, E = CO 2 H), which can then be further processed throughout a variety of procedures and linking various functional groups. Compounds of formula B31 (X = CC ^Et, E = CN) can be converted to compounds of formula B32 (X = CC ^Et, Y = H, = ΙΗ-tetrazole) by heating the derivative of formula B31 with trimethylazide in toluene. The nitrile intermediate of formula B31 (e.g., X = CH 2 Et, E = CN) may also be a synthetic precursor for the preparation of compounds of formula B32 with a heterocyclic group (X = CC 1 Et). A number of synthetic procedures for this purpose are disclosed in A.R. Katrizky, Handbook of Heterocyclic Chemistry, Pergamon Press, 1985, New York, N.Y., in connection with Reaction Scheme B16.

The 3,4-disubstituted derivatives of formula 2 obtained by these processes are racemic compounds. The mono- and disubstituted pyrrolidine and hexahydro-1H-azepine derivatives of formula 2 obtained by these processes are also racemic substances. Chiral intermediates of formula 2 are available by a variety of methods including classical racemate resolution. This separation can be achieved, for example, by the formation of diastereomeric salts of racemic amines with optically active acids, for example D- and L-tartaric acid. The determination of absolute stereochemistry can be carried out in a number of ways, for example by crystallography using X-rays and a suitable crystalline derivative, for example a salt with D- or L-tartaric acid. It is also possible to perform an asymmetric synthesis of optically pure substances.

The racemic intermediates of formula 2 can also be converted to derivatives using chiral reagents, the resulting products can be separated chromatographically, and the chiral compounds of formula 2 can then be regenerated by hydrolysis or, as mentioned above, the racemic intermediates can be directly converted to the growth hormone secretion and the diastereomeric mixtures obtained are separated chromatographically to obtain enantiomerically pure substances.

Scheme C9

Hydrogenation a

X (or Y) (C13a)

The 3-monosubstituted piperidine derivatives of formula C13 may be prepared by reduction of pyridine derivatives or their salts by hydrogenation in a suitable organic solvent, for example water, acetic acid, alcohol, for example eta89 nole, or a mixture thereof in the presence of a noble metal catalyst, for example platinum. its oxide on a support, for example on activated carbon, usually at room temperature at atmospheric pressure or at elevated temperature and pressure. The 3-monosubstituted piperidine derivatives can also be prepared by modifying the groups X or Y in the existing 3-monosubstituted piperidines.

Scheme C9A

nBHg / THF

CO ₂ M6

2) Hg / Pd / C

3) HCl / ROH

(C13b)

CO ₂ R

3-Monosubstituted pyrrolidine derivatives are those which are commercially available or can be readily prepared as described in the literature. Scheme C9A provides an example of a suitable process for the preparation of these compounds via a pyrrolidine-3-carboxylic acid ester. This is accomplished by reducing the commercially available methyl 1-benzyl-4-oxo-3-pyrrolidinecarboxylate with borane according to J. Chem. Soc., 24, 1618-1616. Removal of the benzyl group by catalytic hydrogenolysis followed by ester exchange in an appropriate alcohol medium, for example in ethyl alcohol in the presence of an acid, yields the compound of formula C13b. The ester function can be further modified by conventional chemical procedures to other groups X. 3-Monosubstituted pyrrolidines can also be prepared by catalytic hydrogenation of 3-substituted pyrrole derivatives.

Scheme C9B

(13C)

Hexahydro-1H-azepines are commercially available or can be prepared by methods described in the literature. Hexahydro-1H-azepine-3-carboxylic acid, described in Krogsgaard-Larsen P. et al., Acta, Chem. Scand., B32, 327, 1978 is esterified in an alcoholic solvent in the presence of an acid. The ester function can then be further modified by conventional chemical methods to other groups within the meaning of the symbol X.

Scheme CIO (CH ₂ K protection ( _C H ₂ í _ 7_x <C13) (C14) base / activated Y-

CC2)

L cleavage L ΛΨ - (CH ₂ ) n>

x M_

Y (C15)

Scheme C10 depicts a general procedure for the preparation of disubstituted piperidine, pyrrolidine and hexahydro-1H-azepine derivatives. Compounds of formula C13 wherein X is an electron withdrawing group, for example -CN, -CO2R®, wherein R® is alkyl, aryl or alkylaryl having an alkyl moiety of from 1 to 4 carbon atoms, are known or can be prepared by methods for the production of known compounds. The secondary amine function in the compounds of formula C13 can first be protected by an L-protecting group, for example BOC or CBZ, in conventional manner. The introduction of the group Y may be achieved by first reacting the derivative of formula C14 with a strong base, for example lithium bis (trimethylsilyl) amide or lithium diisopropylamide followed by addition of an alkylating or acylating agent, for example alkyl halide, arylalkyl halide, acyl halide, acyl halide, THF at -100 ° C to room temperature. Thioderivatives in which sulfur is bonded directly to an alkyl or aryl group can be prepared in a similar manner by reaction with a disulfide. The halides used are conventionally supplied or known or can be prepared by methods known to produce known substances. The protecting group L in the compound of formula C15 can be removed in a conventional manner to give compounds of formula 2.

Scheme C1

EtO ₂ C

Y (C16) alkylation

EtOgC CN ^ (CH ₂ ) _n (17) θ ^Η 2θ · reduction r

(CH ₂ ) _n

Y _in (C2a)

CO ₂ Et

Compounds of formula 2 can also be obtained by direct ring construction according to Jacoby R. L. et al., J. Med.

Chem., 17, 453-455 (1974). By alkylating cyanacetates of formula C16, available or prepared according to literature procedures, with alkyl dihalides such as 1-bromo-2-chloroethane or 1-bromo-3-chloropropane, the chloride can be obtained. of formula C17. By reduction of nitriles of formula C17 with borane or hydrogenation using Raney nickel as catalyst, the corresponding primary amines can be obtained from which the compounds of formula 2a can then be refluxed in ethanol.

Scheme C12

EtO ₂ C 1 CN Br (CH ₂ ) _n CO ₂ Et

Y or CH ₂ CHCO ₂ Et (C 16) ²

EtO 2 Cl 2 CN / / (CH ₂ ) _n (C 18) CO ₂ Et reduction CN

H (CH ₂ ) _n (C _2a ) Y

CO ₂ Et reduction

H θγΝ (CH ₂ ) _n (C 19) 1 CO ₂ Et

It is also possible to alkylate the cyanoacetates of formula C16 with ethoxycarbonylalkyl bromide or to react with acrylate to form compounds of formula C18. Reduction of the nitriles of formula C18 with borane or hydrogenation using Raney nickel as the catalyst affords the corresponding primary amines, from which the lactams of formula C19 are obtained by refluxing in ethanol. Reduction of the lactam of formula C19 with borane gives compounds of formula C2a

Scheme C13

n 'reduction

reduction _n (H ₂ C)

Y (C2a)

CO ₂ Et

The malonate of formula C20 can also be alkylated with cyanoalkyl bromide or reacted with acrylonitrile to give compounds of formula C21. Reduction of the nitriles of formula C21 with borane or hydrogenation with Raney nickel catalyst gives the corresponding primary amines, from which refluxing in ethanol gives the lactams of formula C22. Reduction of the lactam C22 with borane gives compounds of formula C2a.

Scheme C14

CONR ² R ³ (C 15b) or an ester

Arndt-Eistert reaction

CH ₂ CO ₂ R or amide (C15c)

The functional groups X and Y in the compound of formula C15 can be further converted to groups that cannot be prepared by direct alkylation. For example, in a compound of formula C15 wherein X = CO ₂ Et, the ester group (assuming it is the only ester group in the molecule) can be saponified to a carboxylic acid, which can then be converted to a carboxylic acid, which can then be further converted to amides or other esters. The carboxylic acid can also be converted to the next higher homolog or homologous acid derivative, for example, to an amide or ester by an Arndt-Eistert reaction. It is also possible to directly process the ester to another homolog using the ynolate anions as described by CJ Kowalski and RE Reddy, J. Org. Chem., 57, 7194-7208 (1992). The resulting acid and / or ester can be converted to the next higher homolog and the like. The protecting group L can be removed by conventional means.

Scheme C15

reduction

COgEt C15a

CH ₂ OH Y (C18)

1) MsCl / TEA

2) NaN 3 acylation

CH ₂ O ₂ CR ² (C19)

(C20) Y

L reduction, _de CH ₂ N ₃ - ^(CH 2) n

(C21) Y

CH ₂ NH ₂

The ester in C15a can be reduced to an alcohol of formula C18 in a suitable solvent, for example THF or ether, by treatment with a reducing agent, for example DIBAL-H, the procedure is well at -100 to 0 ° C. The alcohol obtained can be acylated to a compound of formula C19 in a suitable solvent, for example dichloromethane, using an acyl halide or acid anhydride in the presence of a base, for example triethylamine (TEA). The hydroxy group in the compound of formula C18 can also be converted to an easily cleavable group, for example a mesylate, and replaced with a nucleophile, for example a cyanide, thiol or azide residue. Reduction of the azide group in compounds of formula C20 to the amino group in compounds of formula C21 can be accomplished by hydrogenation in the presence of a noble metal such as palladium or its oxides or Raney nickel in a protic solvent such as ethanol. The nitrile group can be reduced to form a homologous amine. The amine of formula C21 can be further converted to amide, urea or sulfonamide derivatives according to the meaning of X, using conventional procedures for this purpose. Also, the protecting group L can be removed by conventional chemical methods.

Scheme C16

Bn __ _(CH2) S (C28) ^1-f-OH (C29) Y (or X), acylation

deprotection (Cf-L)>

OCOR — _ (C2b)

Y (or X) ¹ -f-OCOR (03θΓ ^{or X)}

When the oxygen atom is attached directly to the ring, the addition reaction can be carried out using an activated form of an alkyl, aryl or alkylaryl group such as lithium-based reagents, Grignard reagents and the like, starting from the ketone of formula C28, which is normally supplied. The resulting hydroxy group may be further treated by acylation, sulfonylation, alkylation, and the like to form compounds with different groups as defined above for X or Y. The benzyl protecting group may be removed under conventional conditions to give compounds of formula C2b. In scheme C16, acylation is generally shown.

Scheme C17

(COCI) ₂

2) NaN ₃

3) reflux / toluene (031) Y

(C23)

(C2c) and _H2O

1) BnOH

2) Pd / C

Acylation of L '----- N (CH _{2) n}

NHCOR Deprotection '-

N = C = O amines or alcohol urea derivatives or carbamates nh ₅ (C32)

When the nitrogen-substituted group is directly linked to the ring, a Curtius rearrangement using an acid of formula C23 can be used to obtain an isocyanate of formula C31. Addition of amines or alcohols gives urea derivatives or carbamates which can be deprotected L to give compounds of formula C2. Conversion of the isocyanate to the amine by hydrolysis affords compounds of formula C32. Further derivatization of the resulting amino group by acylation, sulfonylation, alkylation and the like yields compounds with different groups Y and X. The protecting group L can be removed under conventional conditions to give a compound of formula C2a. In Scheme C17, acylation is generally shown.

(C15c)

(C15E)

For compounds that are not readily obtainable by direct alkylation according to C10 Scheme, modifications of readily obtainable compounds of Formula C15 can be made to achieve the desired substitution. For example, compounds in which Y is hydroxybenzyl may be prepared by demethylation of the corresponding compounds in which Y is methoxybenzyl. Similarly, compounds in which Y is aminobenzyl may be prepared by reduction of the corresponding compound in which Y is nitrobenzyl. Scheme C18 shows an example of a process using a nitrile as a starting material and preparing compounds with various substituents. Removal of the protecting group L yields compounds of formula C2 according to Scheme C10.

Compounds of formula (C2) prepared in this manner are racemic when X and Y do not have the same meaning. Separation of the two enantiomers is readily accomplished by conventional crystallization procedures using a chiral acid such as L- or D-tartaric acid or (+) or (-) - 10-camphorsulfonic acid in a suitable solvent such as acetone, water, alcohol, ether, acetate or a mixture of these solvents. Alternatively, the racemic amine of formula C2 can be reacted with a chiral material such as (R) or (S) -O-acetylmandelic acid followed by chromatographic separation of the two diastereomers followed by removal of the chiral auxiliary by hydrolysis. It is also possible to use asymmetric alkylation to prepare optically active intermediates by introducing a removable chiral auxiliary group X or instead of protecting group L, followed by chromatographic separation of the individual diastereomers.

If the molecule contains a sulfide group, it can be oxidized to a sulfoxide group by treatment with oxidizing agents such as sodium periodate, chloroperbenzoic acid or Oxone ® in a solvent such as dichloromethane, alcohol or water or a mixture of these solvents.

The compounds of the invention may also be prepared from a series of substituted natural or synthetic amino acids of formula D6. The preparation of many of these acids has been described in U.S. Pat. The preparation of intermediates in racemic form has been described in Villiams R.

M., Synthesis of Optically Active Alpha-Amino Acids, Pergamon Press: Oxford, 1989, Vol. 7th

H, ^{R r1} 4A every ₂ h (D46)

There are several procedures for dividing (DL) amino acids. One common method for separating protected amino acid or carboxylic acid intermediates is by crystallizing salts derived from optically active acids or amines. It is also possible to link the amino group of the carboxyl-protected intermediates to the optically active acid as described above. Thereafter, the individual diastereomers are separated by chromatography or crystallization followed by hydrolysis of the chiral amide to give the separated amino acids. Similarly, amino protected intermediates can also be converted to a mixture of chiral diastereomeric esters and amides. Separation of the mixture using the above procedures and hydrolysis of the individual diastereomers then yields (D) and (L) -amino acids. Finally, an enzymatic procedure for separating N-acetyl derivatives of (DL) amino acids has also been described in Vhitesides et al., J. Am. Chem. Soc., 1989, 111, 6354-6364.

If it is desired to synthesize said intermediates in optically pure form, one of the following conventional methods may be used: 1) asymmetric electrophilic amination of the enolates according to J. Am. Chem. Soc., 1968, 108, 6394 to 6395, 6395 to 6397 and 6397 to 6399; 2) asymmetric nucleophilic amination of optically active carbonyl derivatives according to J. Am. Chem. Soc., 1992, 114, 1906, Tetrahedron Lett., 1987, 28, 32, (3) diastereselective alkylation of chiral glycineenolate synthons according to J. Am. Chem. Soc., 1991, 113, 9276; J. Org. Chem., 1989, 54, 3916, 4) diastereoselective nucleophilic addition of chiral electrophilic glycinate synthons according to J. Am. Chem. Soc. 1986, 108, 1103.

5) asymmetric hydrogenation of prochiral dehydroamino acid derivatives according to Asymmetric Synthesis, Chiral Catalysis, Mirrison JD, Ed. Academic Press: Orlando, FL, 1985, Vol. 5 and 6) enzymatic synthesis according to Angrew. Chem. Int. Ed. Engl., 1978, 17,176.

100

Scheme D14

2) PdCl ₂ / H ₂

Ph γ * Co ₂ h (D49)

For example, alkylation of diphenyloxazinone enolate of formula D47 according to J. Am. Chem. Soc., 1991, 113, 9276 by treatment with cinamyl bromide in the presence of sodium bis (trimethylsilyl) amide readily proceeds to give the compound of formula D48, which can be converted to the desired (D) -2-amino-5-phenylpentanoic acid of formula D47 by removing N-tert. butyloxycarbonyl group with trifluoroacetic acid and hydrogenation in the presence of PdCl 2 as a catalyst according to Scheme D14.

Scheme D15

HO

H

I

N.

CO ₂ H (D50)

NaH / DMF

_Ar-CH2-X

(D51)

101

Intermediates of formula D46, which are O-benzyl- (D) -serine derivatives of a compound of formula D51, can be readily prepared from suitably substituted benzyl halides and an N-protected (D) -serine of formula D50. The protecting group L is, for example, BOC or CBZ. Benzylation of a compound of Formula D64 can readily accomplish a variety of known procedures including deprotonation by treatment with two equivalents of sodium hydride in an inert solvent such as DMF followed by one equivalent of various benzyl halides according to Synthesis 1989, 36 as shown in Scheme D15.

O-alkyl- (D) -serine derivatives can also be prepared by alkylation. Other processes that can be used to prepare the (D) -serine derivative of formula D51 include acid catalyzed benzylation of the D50-derived carboxy-protected intermediate with reagents of formula ArCH 2 OC (= NH) CCl 2 according to the publication of Yonemitsu and et al., Chem. Pharm. Bull., 1988, 36, 4244. By alkylation of chiral glycinoenolates according to J. Am. Chem. Soc., 1991, 113, 9276 and J. Org. Chem., 1989, 54, 3916 using ArCl 2 OCl 2 X, where X is a leaving group, compounds of formula D51 are obtained. It is also possible to prepare D, L-O-aryl (alkyl) serine derivatives which are then separated by the above procedures.

It will be appreciated that in some cases it will be necessary to change the order of the steps in the individual reaction schemes to facilitate the reaction or to avoid unwanted by-products.

The usefulness of the compounds of the invention as growth hormone secretagogues can be demonstrated by known methods, for example according to Smith et al., Science, 260, 1640-1643, 1993, in particular in connection with FIG. 2 of this publication. All of the compounds of the invention prepared in the following examples were effective as growth hormone secretagogues in the assay. This is evidenced by the efficacy of a whole group of the above-mentioned substances to influence the level of growth hormone in the body.

102

The compounds of formula (I) are useful in vitro as adjuvants for understanding the control of growth hormone secretion at the pituitary. In particular, evaluation of a number of factors known to be affected by growth hormone secretion, such as age, sex, nutrition, blood glucose concentration, the amount of amino acids and fatty acids, as well as satiety or hunger. In addition, the compounds of the invention can also be used to evaluate how other hormones can modify the release of growth hormone. For example, it has already been shown that somastatin can inhibit growth hormone release. Other hormones important in this sense are sex hormones such as testosterone, estradiol and progesterone, adrenal hormones such as cortisol and other corticoids, epinephrine and norepinephrine, pancreatic hormones and other digestive hormones such as insulin, glucagon, gastron, , peptides with activity on blood vessels such as bombesin, neurokinins and thyroid hormones such as thyroxine and triiodothyronine. The compounds of formula (I) may also be used to detect the possible positive or negative feedback of certain pituitary hormones, such as growth hormone and endorphine-type peptides, and which may modify the release of growth hormone from the pituitary. Of particular importance for scientific research is the use of the compounds of the invention to explain the subcellular mechanism of mediating growth hormone release.

The compounds of formula I may be administered to animals, including humans, to release growth hormone in vivo. For example, these substances can be administered to livestock such as pigs, cattle, sheep and the like to accelerate growth and improve feed utilization, as well as to increase milk production. In addition, the compounds can also be administered in vivo to humans for diagnostic purposes to determine if there is any release of growth hormone at all. For example, when the compounds of formula I are administered to children, samples are taken before and after administration of the compounds and the growth hormone concentration is determined. By comparing the amount of growth hormone in the samples, one can then directly conclude on the ability of the pituitary to release growth hormone.

The present invention also relates to pharmaceutical compositions which contain, as an active ingredient, at least one compound of the formula I together with a pharmaceutical carrier or diluent. The active ingredient may contain, in addition to the compounds of formula (I), other agents, for example an anabolic agent or a substance with different efficacy, such as an antibiotic or osteoporosis treatment agent or a corticosteroid compound to minimize catabolic side effects or further pharmaceutical active ingredients. its undesirable side effects.

Growth promoters and anabolic agents include, for example, TRH, diethylstilbestrol, estrogens, beta-agonists, theophylline, anabolic steroids, enkephalins, prosttaglandins of the E series, compounds of US 3,239,345, for example zeranol, compounds of US 4,036,979, for example sulbenox or peptides according to US 4,411,890.

The growth hormone releasing agents of the invention may also be used in combination with other growth hormone secretagogues, such as growth hormone releasing peptides, GHRP-6 or GHRP-1 according to US 4,411,890 and published international patent applications no. . WO 89/07110, WO 89/07111 and B-HT920 as well as hexarelin and the newly discovered GHRP-2, described in published international patent application WO 93/04081. The growth hormone releasing hormone GHRH, also referred to as GRF and its analogs, or growth hormone and its analogs or somatomedins, including IGF-1 and TGF-2 or alpha-androgen agonists such as clonidine or serotonin 5HTID agonists, e.g. sumitriptan or substances that inhibit or release somatostatin, such as physostigmine and pyridostigmine.

104

As is known in the art, the potential use of growth hormone is very diverse and broad. Administration of the compounds of the invention to stimulate the release of endogenous growth hormone may have effects such as growth hormone alone. The use of the compounds according to the invention is therefore also very broad. These may include stimulating growth hormone release in the elderly, treating adults with too low levels of growth hormone, preventing catabolic side effects of glucocorticoids, treating osteoporosis, stimulating the immune system, accelerating wound healing, accelerating healing of bone fractures, treating delayed healing acute or chronic renal failure or insufficiency, o restoring a physiologically small figure, including the case in children whose growth hormone secretion is too low, treating a small figure associated with a chronic disease, treating obesity and delayed growth associated with obesity, treating delayed growth in connection with Prader-Villi syndrome and Turner syndrome, o speeding up recovery and shortening hospital stay after burns or major surgeries such as gastrointestinal tract, o treatment inside uterine delayed growth, bone dyplasia, treatment of peripheral neuropathies, growth hormone replacement in stressed patients, treatment of osteochondrodysplasia, treatment of Noonan syndrome, schizophrenia, depression, Alzheimer's disease, delayed wound healing and psychosocial depression, and psychosocial depression Artificial lung dependence o Reduction of catabolic response after major surgery o Treatment of malabsorption syndromes Cachexia and protein loss in chronic diseases such as cancer or AIDS o Accelerated weight gain in patients with complete parenteral nutrition (TPN) o for the treatment of hyperinsulinemia including non-idioblastosis, for supportive treatment in inducing ovulation and for the prevention and treatment of gastric and duodenal ulcers, furthermore, the compounds of the invention can be used to promote thymus development and prevent premature interruption of function thymus target, auxiliary

105 treatment of patients with chronic hemodialysis, for the treatment of immunocompromised patients and for the promotion of lymphocytes in humans, in particular to increase the T ₄ / Tg cell ratio when this ratio is reduced, for example, after an injury such as head injury or infections such as bacterial or viral infections, especially after HIV infection, to improve muscle strength, mobility, maintain good skin condition and metabolism, maintain renal function in the elderly, stimulate osteoblasts, bone tissue and cartilage growth, stimulate the immune system and treat aging disorders, to accelerate livestock growth, to accelerate wool growth in sheep, to increase feed utilization and to increase dairy production, and to improve meat quality in livestock.

The compounds of the invention are particularly useful for the prevention or treatment of osteoporosis, catabolic diseases, immune system deficiency including reduced T ₄ / Tg cell rate, femoral neck fracture, muscular and bone tissue disorders in the elderly, growth hormone deficiency in both adults and children , for the treatment of obesity, cachexia and protein loss due to chronic diseases, such as AIDS or malignant tumors, and for the treatment of patients recovering from major surgeries, major injuries or major burns.

It is known that a number of substances are currently used to treat these diseases. Combining these known substances with growth hormone secretagogues can in some cases be very advantageous and can produce additional, complementary and often synergistic effects, so that growth acceleration, anabolic and other desirable effects can be better achieved. In optional combinations, the individual active ingredients may independently be present in doses corresponding to one-hundred to two times the effective dose for a single administration.

Combination treatments for inhibiting bone resorption, for preventing osteoporosis, and for accelerating bone fracture healing can be illustrated by the combination of bisphosphonates and compounds of the invention. Use of bisphosphonates for

106 this purpose has been reviewed, for example, in Hamdy N.A.T., Role of Biphosphonate in Metabolic Bone Diseases, Trends in Endocrinol. Metab., 4, 19-25, 1993. Bisphosphonates for use include alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-15, clodronate, pamidronate, and BM-210995. Depending on the efficacy of the individual substances, the daily dose of the bisphosphonate is in the range of 0.1 mg to 5 g and the daily dose of the growth hormone releasing agents of the invention is in the range of 0.01 to 20 mg / kg of weight.

administered orally, intraperitoneally, intraperitoneally,

The compounds of the invention may be parenterally, e.g., intramuscularly, parenterally, e.g. intramuscularly, intravenously, subcutaneously, or in the form of an implant, nasal mucosa, vaginal, rectal, sublingual or topical, depending on the selected dosage form suitable for certain route of administration.

Solid dosage forms for oral administration are, for example, capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is admixed with at least one inert pharmaceutically acceptable carrier, for example sucrose, lactose or starch. The dosage form may contain, as is customary, other substances in addition to inert diluents, for example glidants such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also contain buffers. In addition, tablets and pills may be enteric coated.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. In addition to such inert diluents, the compositions may also contain adjuvants such as wetting, emulsifying and suspending agents as well as sweetening, flavoring and perfuming agents.

Compositions of the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. As examples of non-aqueous solvents or carriers

Examples of the environment include propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. These dosage forms may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents. These compositions can also be sterilized, for example, through a filter, retaining bacteria, by the addition of sterilizing agents, by irradiation or by heating the compositions. The pharmaceutical compositions can also be formulated as sterile compositions intended to be dissolved in sterile water or other sterile injectable medium immediately prior to use.

Formulations for rectal or vaginal administration are preferably suppositories, which may also contain, in addition to the active ingredient, excipients such as cocoa butter or other suppository bases.

Pharmaceutical compositions for nasal or sublingual administration can also be prepared in a known manner using known excipients.

The dose of the active ingredient may vary, but the effective dose should be administered in a suitable dosage form. The actual dose depends on the desired effect, the route of administration and the duration of the treatment. Usually, doses ranging from 0.001 to 100 mg / kg per day are used, this dose being intended for both humans and other animals, particularly mammals, to achieve effective release of growth hormone.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention. The examples and intermediates designated A correspond to the compounds of the first embodiment, the designation B to the compounds according to the second embodiment and the designation C to the third embodiment.

108

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1

Stage A:

To a solution of 25.0 g, 82.2 mmol of commercially available N-t-BOC-D-tryptophan, 10.2 mL, 98.6 mmol of benzyl alcohol and 100 mg of DMAP in 200 mL of dichloromethane at 0 ° C for 1 hour. 17.4 g (90.4 mmol) of EDC are added in portions over several portions. The reaction mixture was stirred at room temperature for 6 hours and then poured into 200 ml of water and the organic layer was separated. The organic solution was washed with a mixture of saturated aqueous sodium chloride solution and 3 N hydrochloric acid, dried over anhydrous magnesium sulfate, filtered and evaporated to a thick oil which solidified on standing.

To a solution of this oil in 30 mL of dichloromethane was added 20 mL of TFA, and the mixture was stirred for 1 hour. The mixture was evaporated, carefully neutralized with saturated aqueous sodium bicarbonate solution and then extracted with 2 x 100 mL dichloromethane. The organic solutions were combined, washed with 100 mL of saturated sodium chloride solution, passed through a short column of silica gel eluting with 5-10% methanol in dichloromethane to give the title amine (23.2 g) as an oil.

109

Stage B:

To a solution of the above product, 10.6 g, 78.8 mmol HOBT and 19 g, 94.5 mmol HOBT and 19 g, 94.5 mmol N-BOC-α-methylalanine in 200 mL dichloromethane was added 19.5 g 0.102 mol of EDC in several portions at 0 ° C. After 5 minutes the clear reaction mixture became milky. The mixture was stirred overnight at room temperature, then poured into 200 ml of water and the organic layer was separated. The organic solution is washed with saturated sodium chloride solution and saturated sodium chloride solution and sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and evaporated to a thick oil which is purified by flash chromatography using a gradient of 10 to 40% ethyl acetate in hexane, to give 28.7 g of the desired product.

1 H NMR (CDCl 3, 200 MHz) δ 8.48 (br.s, 1H), 7.54 (br.d, 1H), 7.38-7.23 (m, 3H), 7.19 (br.d, 2H), 7.15-7.00 (m) 1 H, 6.90 (d, 1 H), 6.86 (d, 1 H),

5.06 (br. S, 2H), 4.95 (ddd, 1 H), 3.30 (2dd, 2 H), 1.40 (s, 15H)

Stage C:

A solution of 28.7 g of the material from Step B in 200 ml of ethanol was stirred at room temperature under a hydrogen atmosphere for 20 minutes in the presence of 2 g of 10% palladium on charcoal. The catalyst was filtered off through a pad of celite and the pad was washed with ethyl acetate. The filtrate was evaporated to give the title acid (23.3 g) as a pink foam.

110

1 H NMR (CD 3 OD, 400 MHz) δ 7.56 (d, J = 8 Hz, 1H), 7.31 (dd, J = 1,8 Hz, 1H), 7.09 (s, 1H), 7.07 (dt, J = 1.7 Hz, 1H), 6.98 (dt, J = 1.7 Hz, 1H), 4.69 (t, J = 6 Hz, 1H), 3.34-3.23 (m, 2H), 1.35 ( s, 3H), 1.34 (s, 9H), 1.29 (s, 3H).

FAB-MS calcd for C ₂₁ H ₂₇ N ₃ O ₅ 389 found 390 (M + H), 290 (M + H-100 (BOC)).

Intermediate 2

Proceed as described for the preparation of intermediate 1, but using N-tert-Boc-O-benzyl-D-serine instead of N-tert-BOC-D-tryptophan to give the intermediate

Second

FAB-MS for C £ gH ₂ g of N ₂ 0 g Calculated 380 Found 381 (M + H), 325 (M + H-56 (tBu)),

281 (M + H-100 (BOC)).

Intermediate 3

Step A: (DL) -N-Acetyl-2-amino-5-phenylpentanoic acid

To a solution of 2.3 g, 0.1 mol of sodium in 60 ml of ethanol was added diethyl acetamidomalonate under nitrogen at room temperature. The mixture was stirred at room temperature for 1 hour and then 1-bromo-3-phenylpropane was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours and then refluxed overnight. After cooling to temperature

At room temperature, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with sodium bicarbonate in water, dried over magnesium sulfate and evaporated to give 32.5 g of an intermediate in 97% yield.

1 H NMR (CDCl 3, 400MHz) 7.26-7.10 (m, 5H); 6.75 (br. S, 1H); 4.19 (q, J = 7Hz, 4H); 2.58 (t, J = 7.9Hz, 2H); 2.39-2.35 (m, 2H); 2.00 (s, 3H); 1.43-1.39 (m, 2H); 1.20 (t, J = 7Hz, 6H).

The above product is suspended in 190 ml

2.5 M sodium hydroxide in water and the mixture was refluxed for 2 hours. The mixture was then cooled to 0 ° C and carefully neutralized by adding 6 M hydrochloric acid to pH 2. The resulting precipitate was collected through a glass sinter funnel and washed with a small amount of cold water and then dried to dryness. The first portion was suspended in 300 ml of water and the mixture was refluxed for 2 hours. The resulting solution was cooled and acidified to pH 1, then the solid was filtered off, yielding 15.3 g of product in 67% yield.

1 H NMR (CD 3 OD, 400MHz) 7.26-7.12 (m, 5H); 4.90-4.37 (m, 1H);

2.65-2.60 (m, 2H); 1.97 (s, 3H); 1.87 -1.82 (m, 1H); 1.73-1.65 (m, 3H). Step B: (D) -N-Acetyl-2-amino-5-phenylpentanoic acid g, 42.5 mmol of the racemic intermediate from the previous step and COCl ₃ .6H ₂ O was dissolved in 21 mL of 2 M KOH and 200 mL of water at temperature The pH of the solution was adjusted to 8 by adding a few drops of 2 M KOH. Acylase I (Aspergillus sp., 0.5 units / mg, 0.9 g, Sigma) is then added with vigorous stirring. The reaction mixture was stirred at 40 ° C for 1 day while maintaining the pH at 8 by adding a few drops of potassium hydroxide. The solid formed is filtered off, the filtrate is acidified with 3 M HCl to pH 2a and then extracted with 4 x 200 ml of ethyl acetate. the organic extracts were combined and evaporated to give 4.64 g (46%) of the title product as a white solid.

1 H NMR (CD 3 OD, 400MHz) 7.26-7.12 (m, 5H); 4.90-4.37 (m, 1H);

2.65-2.60 (m, 2H); 1.97 (s, 3H); 1.87 -1.82 (m, 1H); 1.73-1.65 (m, 3H).

112

Step C: (D) -N-tert-Boc-2-amino-5-phenylpentanoic acid

4.2 g (17.8 mmol) of the intermediate from Step B were suspended in 100 ml of 2 M HCl and the mixture was refluxed for 2 hours. The mixture was then evaporated in vacuo to remove water and hydrochloric acid to give a white solid. To a solution of this material in 50 mL of water was added 3 M NaOH until pH 11 and then 4.66 g (21.4 mmol) of di-tert-butyl dicarbonate was added with vigorous stirring. The mixture was allowed to stand for 4 hours, then acidified to pH 2 by addition of 3 M HCl and extracted with 3 x 100 mL ethyl acetate. The organic extracts were combined and evaporated to give 6.56 g of crude product as a white solid, which was used in the next step without further purification.

1 H NMR (CD 3 OD, 400MHz) 7.26-7.12 (m, 5H); 4.11-4.08 (m, 1H);

2.65-2.60 (m, 2H); 1.83-1.62 (m, 4H); 1.43 (s, 9H).

Stage D:

The procedure for the preparation of intermediate 1 is repeated, but instead of N-tert-BOC-D-tryptophan, (D) tert-Boc-2-amino-5-phenylpentanoic acid is used, yielding intermediate 3.

1 H NMR (CDCl 3, 400MHz) 7.24-7.20 (m, 2H), 7.15-7.04 (m, 3H), 4.604.55 (m, 1 H), 2.62-2.55 (m, 2H), 2.00-1.86 (m, 1 H) 1.78-1.60 (m, 3H), 1.50 (s, 6H), 1.30 (s, 9H).

Example A1:

113

Stage A:

To a solution of 1 g of ethyl (dl) -pipecolinate, 860 mg of HOBT and 2.47 g of intermediate 1 in 80 ml of dichloromethane at 0 ° C was added 2.3 g of EDC. The reaction mixture was stirred overnight at room temperature. The solution was washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to a crude product. This crude product was purified by MPLC eluting with 60% ethyl acetate in hexane to give the title product as a 2.79 g mixture of the two diastereomers. 500 mg of the mixture was separated by MPLC, eluting with 50% ethyl acetate in hexane to give separate individual diastereomers. The diastereomer which was eluted from the column first was designated d ^ (187 mg), the analysis of the stereochemistry of the pipecolinic acid after it has been demonstrated that the diastereomer of the R configuration at the second crop to afford 116 mg of diastereomer _d2 configuration S. In addition, the combined fractions were combined and evaporated to give 190 mg of a mixture of compounds of Example ₂ .

d ^ FAB-MS for C 28 ^Η 40 ^Ν 4θ6 calcd 528, found 529 (M + H) _d2: FAB-MS for C 28 ^ 40 ^ 4θ6 ⁱⁿ yP ° read 528, found 529 (M + H).

Stage B:

N

H

114

A solution of 140 mg of the compound (d) of Step A in 5 mL of ethyl acetate was cooled to 0 ° C. Hydrogen chloride is then bubbled through the mixture with stirring until saturated. The reaction mixture was stirred for 15 minutes, then the solution was evaporated to remove ethyl acetate. The residue was redissolved in dichloromethane and hexane and evaporated in vacuo to give 110 mg of a solid. FAB-MS calcd for C23H32N4O4 428, found 429 (M + H). 1 H-NMR (400 MHz, CD 3 OD): the compound exists as a mixture of two rotamers, approximately 2: 1 ratio.

7.57 (d, 1H), 7.36 & 7.32 (2 d, 1H), 7.14-7.00 (m, 3H), 5.30-5.20 (m), 5.17-5.13 (m), 4.36 (d), 4.21 (q, J = 7Hz), 4.13 (q, J = 7Hz), 4.00 (md), 3.35-3.04 (m), 2.60 (dt), 3.30 (br. d), 2.70 -2.50 (m), 1.57 (s)

1.55 (s), 1.50-1.20 (m), 1.33 (s), 1.25 (t, J = 7Hz), 1.25 (t, J = 7Hz), 1.15-1.10 (m), 0.75 -0.65 (m), 0.30 - 0.20 (m).

Example A2

The product can be obtained according to the procedure of Part B of Example A1 from Intermediate d ₂ of Example A1 using 40 mg of the product of Step A and hydrogen chloride gas in 3 ml of ethyl acetate at 0 ° C. 28 mg of product are obtained.

FAB-MS calcd for 423 found 429 (M + H).

³ H-NMR (400 MHz, CD 3 OD): the resulting product exists as a mixture of two rotamers, approximately 5: 1 ratio:

7.56 (d, J = 8Hz 5 / 6H), 7.50 (d, 1/6H), 7.34 (d, J = 8Hz, 5/6H), 7.31 (d, 1/6H), 7.12 -7.00 (m, 3H), 5.28 (dd, 5 / 6H), 5.15-5.11 (m,

1/6 H), 5.11-5.07 (m, 1 / 6H), 5.02-4.98 (m, 5 / 6H), 4.52-4.45 (m), 4.12 (q, J = 7Hz), 4.25-4.00 (m), 3.65 (m), 3.30-3.05 (m), 2.80-2.70 (m), 2.32-1.25 (m), 1.75-1.65 (m), 1.57 (s), 1.52 (s), 1.51 (s), 1.400.85 (m), 1.22 (t, J = 7Hz), 0.41-0.30 (m).

115

Example A3

Stage A:

To a stirred solution of L-proline benzyl ester hydrochloride (155 mg, 0.64 mmol), intermediate 1 (250 mg, 0.64 mmol), one equivalent HOBT and 0.07 mL, 0.64 mmol NMM in dichloromethane was added 246 mg at 0 ° C. , 1.28 mmol of EDC. The reaction mixture was stirred overnight at 0 ° C and then partitioned between 3 M HCl and ethyl acetate. The organic layer was washed with saturated sodium chloride solution and saturated sodium bicarbonate solution, dried and evaporated. The product was purified by MPLC, eluting with 50% ethyl acetate to give 338 mg of the tripeptide benzyl ester intermediate, yield:

91.5%.

FAB-MS calcd for C32-404-404 576, found 577 (M + H).

Stage B:

The product was prepared A1 from 280 mg of intermediate hydrochloric acid in 10 ml according to the procedure of Step B of the previous step and from ethyl acetate at 0 ° C. The Re116 action lasted 25 minutes to give 218 mg of the product.

FAB-MS calcd for 477, 324, 444, found 477 (M + H). 1 HNMR (400 MHz, CD 3 OD): 8.20 (d), 7.54 (d, J = 7.9Hz, 1H), 7.34-7.00 (m, 9H), 5.11 (dd, J = 4.2Hz, 16.5Hz, 2H), 4.99- 4.94 (m, 1 H), 4.23-4.20 (m, 1 H), 3.58-3.53 (m, 1 H), 3.31-3.13 (m, 2 H), 2.77-2.75 (m, 1 H), 1.711.60 (m, 1 H) 3 H) 1.55 (s, 3 H), 1.51 (s, 3 H), 1.37-1.33 (m, 1H).

Example A4

Step A: (d1) -Pipecolinic acid benzyl ester

A solution of 25 g of (dl) -pipecolinic acid, 38 g of p-toluenesulfonic acid and 84 g of benzyl alcohol in 200 ml of toluene is refluxed under azeotropic conditions for one day. The mixture was cooled to room temperature and the crystals formed were collected to give 52.4 g of the desired product. This product was washed with 3 M NaOH to remove toluenesulfonic acid and then reacted with hydrogen chloride gas in ethyl acetate to convert it to the hydrochloride.

Stage B:

The product can be obtained by the method of Example A, Step A, from 3.5 g of (d1) -pipecolinic acid benzyl ester hydrochloride, 5.00 g of intermediate 1, 1.74 g of HOBT, 1.42 ml of NMM and 3.94 g of EDC. 6.32 g of product are obtained.

117

FAB-MS calc. For C ₃₃ H ₄₂ ^N 4 ^O 6 590, found 591 (M + H).

Stage C:

The product is obtainable by the method of Example B, Step B, from 250 mg of the intermediate of the preceding step and hydrogen chloride gas in ethyl acetate at 0 ° C. 211 g of product are obtained.

FAB-MS calc. 490, found 491 (M + H).

Example A5

Stage A:

A suspension of 5.30 g of the product of Step B, Example A4 and 270 mg of 10% palladium on charcoal in 100 ml of ethanol was stirred for 3 hours under a hydrogen gas flask. The reaction mixture was then filtered through celite and evaporated to give the title acid (4.48 g).

118

Stage B:

The product can be prepared according to the procedure of Example A3, Step A, from 200 mg of the intermediate of the previous step, 27 mg of ethylamine hydrochloride, 54 mg of HOBT, 0.07 ml of NMM and 154 mg of EDC to give a mixture of two diastereomers. , eluting with ethyl acetate. The isomer starting from the first column at 76 mg was designated as d4, in addition 165 mg of the second isomer d2 · d-: FAB-MS was calculated for 527, found 528 (M + H) d ₂ : FAB-MS for C ₄₁ gH ₂ N2Og calcd 527, found 528 (M + H).

Stage C:

The product was obtained according to the procedure of Part D, Example A1, from 60 mg of intermediate d1 from the previous step and hydrogen chloride gas in 5 ml of ethyl acetate at 0 ° C, after a reaction time of 20 minutes, 38 mg of the product was obtained.

FAB-MS calc. 427, found 428 (M + H).

1 HNMR (400 MHz, CD 3 OD): d 7.63-7.00 (m, 5H), 5.33 (t), 5.40, 5.25 (m), 5.11-5.09 (m), 4.32 (br. D), 4.16-4.12 (m) 4.00 (md), 3.35 3.03 (m), 2.96 (q, J = 7Hz), 2.30 (dt), 2.19 (br. D), 1.95-1.40 (m), 1.66 (s), 1.64 (s) 1.40 - 1.20 (m), 1.20 - 1.00 (m), 1.12 (t, J = 7Hz)

Hz), 0.65-0.52 (m), -0.44-0.53 (m).

119

Example A6

The product was obtained as in Step B of Example A1 in 100 mg of the intermediate _d2 from Step B of Example A5 and the gaseous hydrogen chloride in 5 ml of ethyl acetate at 0 DEG C., the reaction lasts 20 minutes, 78 mg of product.

FAB-MS calc. 427, found 428 (M + H).

1 HNMR (400 MHz, CD 3 OD): d 7.54 (d, J = 8Hz, 1H), 7.35 (d, J = 8Hz, 1H), 7.16 (s, 1H), 7.13-7.00 (m, 2) H), 4.98 (dd, J = 6Hz, 10Hz),

4.93 (d, 4Hz), 3.53 (br. D, J = 12Hz, 1H), 3.35-3.22 (m), 3.14-3.09 (m, 1H), 2.85 (dt, J = 3, 13Hz) 1 H (H), 2.02 (br. D, J = 12 Hz), 1.65 (s, 3 H), 1.61 (s, 3 H), 1.10 (t, 7 Hz, 3 H), 1.05- 0.92 (m, 0.72- 0.62 (m, 1H), -0.25-0.30 (m, 1H).

Example A7

Stage A:

The product can be prepared according to the procedure of Example A3 Step A from 115 mg, 0.642 mmol of L-proline ethyl ester hydrochloride, 250 mg, 0.642 mmol of intermediate 1, one equivalent of HOBT, 0.07 mL, 0.642 mmol NMM and 246 mg, 1.28 mmol

120

EDC. 330 mg of product are obtained.

FAB-MS for C 7 H _{4 2} q N ₄ O ₆ Calc'd 514, found 515 (M + H).

Stage B:

The product can be obtained according to step B of Example A1 from 280 mg of the intermediate of the preceding step and 10 ml of hydrogen chloride gas in 10 ml of ethyl acetate at 0 ° C. After a reaction time of 25 minutes 220 mg of product are obtained.

FAB-MS for &lt; 22 &gt; -232 &lt; 32 &gt; (calcd 414, found 415 (M + H). &Lt; 1 &gt; H-NMR (400 MHz, CD3OD): 7.53 (d, J-7.9 Hz, 1H), 7.34 (d, J-8.1 Hz) 1H, 7.14-7.01 (m, 3H), 4.97-4.84 (m, 1 H), 4.15-4.06 (m, 3 H), 3.603.53 (m, 1 H), 3.31-3.13 (m, 2 H), 2.77 -2.72 (m, 1H), 1.72-1.59 (m, 3H),

1.57 (s, 3H), 1.50 (s, 3H), 1.36-1.27 (m, 1 H). 1.23 (t, J = 7.1 Hz, 3H).

Example A8

Step A: 2-cyano-1-hydroxy-4-phenylpiperidine

To a stirred solution of 4-phenylpiperidine (10 g, 0.062 mol) in methanol (30 ml) was added a solution of sodium tungstate dihydrate (0.82 g, 2.48 mmol) in water (7 ml). The mixture was stirred at 0 ° C and simultaneously 30% hydrogen peroxide (13.9 ml, 0.136 mol) was added dropwise. After the addition was complete, the reaction mixture was stirred for 3 hours, then 4.56 g (0.093 mol) of sodium cyanide was added followed by 22 ml (0.088 mol) of 4 M HCl. The reaction mixture was stirred overnight, during which time it was allowed to warm to room temperature. The solid formed is filtered through a glass sinter funnel, the solution is neutralized to pH 7 and then extracted with dichloromethane. The organic extract was combined with the solid, dried (MgSO4) and evaporated. Flash chromatography eluting with 40% ethyl acetate in hexane gave 8.6 g of 2-cyano-1-hydroxy-4-phenylpiperidine.

1 HNMR (400 MHz, CDCl 3): 7.35-7.17 (m, 5H), 6.01 (br. S, 1H), 4.34 (br. S, 1H), 3.31 (td, J = 3,11 Hz, 1H) 13.09 (dt, J = 11.3 Hz, 1H), 2.932.86 (m, 1H), 2.20-2.10 (m, 2H), 1.97-1.80 (m, 2H).

Step B: 2-cyano-4-phenylpiperidine

To a stirred solution of the intermediate from 500 mg in 10 ml of methanol at room temperature was added 3 ml of a 10% solution of titanium tetrachloride in 20 to 30% hydrochloric acid. The mixture was stirred for 15 minutes and then neutralized by addition of 3 M NaOH. The solution was extracted four times with dichloromethane, the organic extracts were combined, dried over magnesium sulfate and evaporated to give 450 mg.

2-cyano-4-phenylpiperidine, this product was used in the next step without further purification.

Stage C:

The method of Example A3, Step A, yielded two compounds using the Me122 intermediate from the previous step after purification by MPLC eluting with 60% ethyl acetate in hexane. First, diastereomer 1 then diastereomer 2 starts from the column.

DJL FAB-MS calcd for C32H39N5O4 557; found 558 (M + H) _d2: FAB-MS for C ^ C ^ HggN calcd 557, found 558 (M + H).

Stage D:

The method of Step B of Example A-is using the product of the previous step and HCl gas in ethyl acetate at 0 ° C gives the title product, C ^ FAB-MS for C ₂₂ H ₂ - £ NGO ₂ Calc'd 457, found 458 (M + H) d ₂ : FAB-MS calcd for C ₂ H 11 N 2 O ₂ 457, found 458 (M + H).

Example A9

Step A: 2-cyano-4-phenylpyridine

To a stirred solution of 4-phenylpyridine-NOxide (25 g, 0.146 mmol) in dichloromethane (200 mL) was added at room temperature.

123

17.4 g of trimethylsilyl cyanide and then a solution of 16.2 ml of dimethylcarbamyl chloride in 50 ml of dichloromethane is added slowly over 30 minutes. The reaction mixture is stirred at room temperature for a further day and then 150 ml of a 10% potassium carbonate solution are slowly added. The mixture was stirred for an additional 30 minutes, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The extracts were combined and dried over magnesium sulfate. Evaporation in vacuo gave 35 g of crude reaction product as a white solid, which was used in the next step without further purification.

FAB-MS calcd for C ^ HHgN 180 180, found 181 (M + H).

1 HNMR (400 MHz, CD 3 OD): 8.71 (dd, 1H), 8.19 (dd, 1H), 7.94 (dd, 1H), 7.81-7.78 (m, 2H), 7.56-7.50 (m, 3H) .

Step B: 4-Phenylpyridine-2-carboxylic acid

A solution of 25 g of the product of the preceding step in 100 ml of 6 M hydrochloric acid was refluxed for one day. The solution was then cooled to room temperature to crystallize. The resulting crystals were collected by filtration to give 27.5 g (87%) of the product.

Step C: Ethyl 4-phenylpyridine-2-carboxylate hydrochloride

To a solution of 5.0 g (21.2 mmol) of the product from the previous step, 2 g of ethanol, 20 mg of DMAP and one equivalent of N-methylmorpholine in dichloromethane was added 1.5 equivalents of EDC. The reaction mixture was then stirred overnight at 0 ° C. The resulting solution was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by MPLC eluting with 40% ethyl acetate in hexane to give 3.71 g of 4-phenylpyridine-2-carboxylate in 77% yield. This material is then converted to the hydrochloride by treatment with hydrogen chloride in ethyl acetate followed by evaporation of the solvent.

Step D: Ethyl 4-phenylpyridine-2-carboxylate

124

A suspension of 200 mg of the product from the previous step and 20 mg of platinum oxide in ethanol was stirred for 3 hours under a hydrogen-filled flask. The reaction mixture was then filtered through a pad of celite and the filtrate was evaporated. The product was used in the next step without further purification.

Stage E:

To a solution of the intermediate prepared in the previous step (200 mg) and 1 equivalent of intermediate 1, 1 equivalent of HOBT and 1 equivalent of NMM in dichloromethane at 0 ° C was added 1.5 equivalents of EDC. The reaction mixture was stirred overnight at 0 C. C. The solution was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Then the product was purified using MPLC eluting with 50% ethyl acetate in hexane to give the product as a mixture of diastereomers.

Grade F:

125

Hydrogen chloride gas was bubbled into the stirred solution of the intermediate from 30 mg in 2 ml of ethyl acetate at 0 ° C until saturated. The reaction mixture is stirred for a further 15 minutes, then evaporated to dryness to give the title product.

FAB-MS calcd 504, found 505 (M + H).

Other products listed in Table A1 were prepared according to Step E and F from Example A9 using intermediate 2 or 3 and intermediate from step D.

Table AI

HCl

Product rl MF FAB-MS (M + 1). 1 Ph (CH2) 3 C29H39N3O4 494 2 PhCH2OCH2- C28H37N3O5 496

The following compounds were prepared according to Example A9 by introducing a 2-cyano group into a series of substituted 4-phenylpyridines by hydrolysis, re-esterification, and hydrogenation of the pyridine ring to give the following intermediates:

126

These products can be reacted with intermediate 1 or 3 to give the following compounds:

CO ₂ Et

CO ₂ Et

127

Step A: 3-benzylpyridine-N-oxide

A solution of 3-benzylpyridine (25 g, 0.148 mol) in 30.1 ml of 30% hydrogen peroxide in 100 ml of acetic acid was refluxed for one day. 3 ml of hydrogen peroxide are then added and the resulting mixture is refluxed overnight. The reaction mixture was evaporated and the residue was partitioned between 3M hydrochloric acid in saturated sodium chloride solution and dichloromethane. The organic layer was separated, dried and evaporated to give 27.6 g (100%) of the desired product.

Step B: 3-Benzyl-2-cyanopyridine

The product was obtained according to the Example A9 Step A, from 27 mg of the intermediate from the previous step. The crude reaction product was then purified by flash column chromatography on silica eluting with 20-40% ethyl acetate in hexane to give 3.0 g of 5-benzyl-2-cyanopyridine in 10% yield and 85% yield. 24.2 g of 3-benzyl-2-cyanopyridine.

Step C: 3-Benzylpyridine-2-carboxylic acid hydrochloride

A solution of 19.1 g of 3-benzyl-2-cyanopyridine in 50 ml of concentrated hydrochloric acid and 50 ml of water is refluxed for two days. The resulting solution was evaporated to give 30.1 g (100%) of a solid product containing the same molar amount of ammonium chloride.

Step D: Ethyl 3-benzylpyridine-2-carboxylate hydrochloride

15.2 g of thionyl chloride are dissolved in 300 ml of ethanol and the resulting solution is added to 20 g of intermediate from the previous step. The mixture was refluxed overnight and then evaporated to give the crude product as the hydrochloride. This product was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution, the organic solution was dried, evaporated and the residue purified on a short silica column to give 18.2 g of the product as the free base. To a solution of this intermediate (16.5 g) in ethyl acetate (80 mL) was added hydrogen chloride by bubbling until saturation. The mixture was evaporated to give 18.9 g of the hydrochloride salt.

129

Step E: Ethyl 3-benzylpiperidine-2-carboxylate hydrochloride

A suspension of 1.0 g of the product of the preceding step and 100 mg of platinum oxide in ethanol was stirred for 5 hours under a hydrogen-filled flask. The reaction mixture is then filtered through a pad of celite and evaporated to give the desired product.

Grade F:

To a solution of 180 mg, 0.634 mmol of intermediate from the previous step, one equivalent of intermediate 1, one equivalent of HOBT and one equivalent of NMM in dichloromethane at 0 ° C was added 1.5 equivalents of EDC. the reaction mixture was stirred overnight at 0 ° C. The solution was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified using MPLC, eluting with 50% ethyl acetate in hexane to give two enantiomerically pure compounds. The compound starting from the first column in 146 mg was designated d d, after which 141 mg of d ₂ was obtained.

d +: FAB-MS calcd for C- ^H ^N ^Og 618, found 619 (M + H) d ₂ : FAB-MS calcd for C- ^H ^N NOg 618, found 619 (M + H) .

G grade:

cis d1

Bn

130

To a stirred solution of intermediate (d) from the previous step (130 mg) in 2 mL of ethyl acetate was added hydrogen chloride gas at 0 ° C by bubbling until saturation. The reaction mixture was stirred for a further 15 minutes, then evaporated to dryness to give 111 mg (95%) of the product.

FAB-MS calc. For C18 H18 N4 O4 518, found 519 (M + H).

Grade H:

The product can be prepared according to the previous step using 130 mg of intermediate d ₂ from step F. 114 mg of product are obtained, yield 98%.

FAB-MS calc. For C18H18N3O4: 518, found 519 (M + H).

Other compounds that can be prepared according to Step F and G from Example A10 using Intermediate 2 or 3 and the intermediate from Step E are listed in Table AII below. No diastereomer separation was observed when purifying the Boe precursor by MPLC.

Table AII

ABOUT

CO ₂ Et cis

C-O

Ò

Bn

131

Product rl MF FAB-MS (M + 1).

Ph (CH 2) 3 - C 30 H 41 N 3 O 4

508

PhCH2OCH2- C29H39N3O5

510

Example All

Step A: Diethylpiperidine-2,3- (cis) dicarboxylate

Hydrogen chloride gas was bubbled through 400 ml of ethanol until the solution absorbed 22 g. 100 g of pyridine-2,3-dicarboxylic acid are then dissolved in the solution and the mixture is refluxed overnight. The mixture is then divided into two portions and each is shaken together with 1.4 g of platinum oxide in a Parr shaker for 8 hours under a hydrogen pressure of 0.28 MPa. Then, the two portions were combined and filtered, and the solid was washed with a large amount of ethanol. Evaporation gave a gray solid which was washed with ethyl acetate and further filtered to give a white solid of 74.8 g.

Stage B:

CO ₂ Et

132

The product can be prepared according to the procedure for Step A from Example A1 using 178 mg of the product of the previous step and intermediate 1. 234 mg of the title compound are obtained.

FAB-MS calc. 600, found 601 (M + H).

Stage C:

The product can be prepared according to the procedure of Example B, Step B, using 230 mg of the intermediate from the previous step. 215 mg of the title compound are obtained.

FAB-MS calc for 500, found 501 (M + H),

523 (M + Na).

Other intermediates listed in Table AIII below were prepared from the corresponding pyridine analogs as described in Example A, Step A above, and the resulting products were prepared according to Step B and C.

Table AIII

Intermediate (QH) Product MF MF FAB-MS (M + 1). FAB-MS (M + 1). 1 U / N CH ₃ C24H34N4O4 443 ^^ CO ₂ Et diastereomeric

mixture

133

2 H C25H36N4O4 457 1 V ^ Cooee diastereomeric ch ₃ mixture 3 ^a | H C25H36N4O4 457 Y 2 ' ^from CO ₂ Et diastereomeric ch ₃ mixture ^and Intermediate was ready epimerization of the cis-isomer by KHMDS in THF.

Example A12

Step A: Diethyl N-Boc-piperidine (cis) -2,3-dicarboxylate

To a stirred solution of Intermediate Example A, Step A (10 g, 37.6 mmol) and triethylamine (6.4 mL) in dichloromethane (50 mL) was added di-tert-butyl dicarbonate (10.7 g) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with a mixture of 3M hydrochloric acid solution and saturated sodium chloride solution. The organic layer was dried, evaporated and purified on a silica gel column eluting with a gradient of 10 to 30% ethyl acetate in hexane to give 9.61 g of the title compound.

134

Stage B:

Boe

N _{x /} CO ₂ Et

Bn

CO ₂ Et

To a stirred solution of 3.79 g, 19 mmol KHMDS in 150 mL of THF at-78 ^and C under argon was added a solution of 5 g, 15.2 mmol diethyl-N-Boc-piperidine (cis) -2,3-dicarboxylate within 30 minutes. The solution was stirred at -78 [deg.] C. for 30 minutes and then benzyl bromide (2.73 g, 15.9 mmol) was added slowly. The reaction mixture was stirred overnight and then allowed to warm to room temperature. The mixture was concentrated, diluted with water and extracted with 100 mL of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate in hexane to give the two diastereomers. First, the compound which is first in the column (1.01 g) is denoted d 6, then 3.75 g of the second compound denoted d _{2 is obtained} . According to the NMR spectrum, the trans-configuration of the ester in the column d 1, the cis configuration corresponds to the compound d ₂ .

Stage C:

Compounds were prepared according to the procedure for Step B of Example A1 using the intermediates from the previous step. By using 850 mg of intermediate d ^ was obtained in a yield of 98% total of 711 mg of D ^, using 3.2 g of intermediate d _2, in 96% yield gave 2.58 g of product d _2> d-£: FAB MS for CigH ^ NC ^ calcd 319, found 320 (M + H) _d2: FAB-MS for C ^ gH ^ THEREOF calcd 319, found 320 (M + H).

135

Stage D:

The compounds were prepared according to the step A of Example A1 from the intermediates from the previous step. From 228 mg of intermediate d-6, a mixture of trans diastereomers (128 mg) was obtained in 30% yield. Using 228 mg of intermediate d ₂ , 164 mg of a mixture of cis-diastereomers was obtained in 30% yield.

Stage E:

Compounds were prepared according to the procedure of Example B, Step B using the intermediates from the previous step. Using 120 mg of intermediate d ^ in a yield of 97%, 106 mg of the product was obtained as a mixture of trans diastereomers d ^. Using 155 mg of intermediate d ₂ , 135 mg of the product as a mixture of cis-diastereomers d ₂ were obtained in 96% yield. d- £ FAB-MS calculated for 590; found 591 (M + H) _d2: FAB-MS for C H N ^ ^ ^ O Calc'd 590, found 591 (M + H).

Other intermediates listed in the following Table AIV were prepared by the above procedures using the N-Boc intermediates of Table AIII as described in steps A, B and C of Example A12, resulting products being

136 prepared as described in steps D and E.

Intermediate (QH) Product MF MF FAB-MS (M + 1). FAB-MS (M + 1).

H dl:

C31H40N4O4

533

I

d2:

C31H40N4O4

533

Oh, ^b

CO.Et mixture of diastereomers

C32H42N4O4

547

The following compounds were also prepared by the method of Example A12 by alkylation with 2-picolyl chloride or 4-bromomethylthiazole to give the following intermediates,

137 which can be reacted with intermediates 1 or 2 to give the following end products.

Example A13

NH _? HCl

C = 0 0

Δ H CONH (CH ₂ ) ₂ OH

Stage A:

138

To a stirred solution of 100 mg, 1.16 mg of dl-2-pipecolamidoethanol, 78.38 mg, 1.16 mmol of HOBT and 226.12 mg, 1.16 mmol of intermediate 1 in 3 mL of dichloromethane was added 63.8 mL at room temperature. ml, 1.16 mmol of 4-methylmorpholine. The mixture was cooled to 0 ° C and EDC 222.3 mg, 2.32 mmol was added. The reaction mixture was stirred at room temperature for 16 hours. After evaporation, the residue was partitioned between ethyl acetate and 1M hydrochloric acid. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to an oily foam which was purified by thin layer chromatography using acetone: chloroform 3: 7 to give 91 mg. product with Rf = 0.45.

CI-MS: calcd. 1 H NMR (400 MHz, CDCl 3): δ 8.35 (br.s, 1H), 7.57 & 7.55 (2s,

1 H, 7.35, 7.33, (2s, 2H), 7.17 (t, J = 6.95Hz, 1 H), 7.15-7.07 (m, 3H), 7.03 (distors, J = 4.95Hz, 1 H), 5.16 (d, J = 4.68 Hz, 1 H), 4.94 (m, 2 H), 3.65 (m, 2 H), 3.55-3.10 (m, 5 H), 2.9-2.62 (m, 4 H), 2.3-2.2 (m, 1 H), 1.43 , 1.46 a. 1.41 (3s, total 15H), 1.00 (m, 1 H), 0.83 (m, 1 H).

Stage B:

The compound was prepared according to the procedure for Step B of Example A1 using the product from the previous step and hydrogen chloride gas in ethyl acetate at 0 ° C.

CI-MS: calcd for C-23H33N5O4 443, found 444 (M + H). 1 H NMR (400 MHz, CD 3 OD): d δ 7.54 (d, J = 7.7Hz, 1H), 7.36 (d, J = 8.1Hz), 7.12 (dist: t, J = 7.5Hz, 1H), 7.03 ( dist, t, J = 7.5 Hz, 1H), 4.97-4.92 (m, 1 H), 3.63 (m, 1 H), 3.75 (br. d, 1 H), 2.82 (br. t, J = 2.3 Hz,

1H), 2.07 (br. D, J = 2.3Hz, 1H), 1.66-1.57 (m, 6H), 1.55-0.88 (m, 4H), 0.70-0.55 (m, 1H).

139

The other compounds listed in Table AV were prepared according to Steps A and B using Intermediate 1. The piperidine intermediates are commercially available or can be prepared by any of the above procedures or literature procedures.

W Molecular FAB (orCI) -MS ^formula (M + 1)

1 -CO2CH3 C22H30N4O4 415 2 -CONH (CH 2) 2 OH C23H33N5O4 444 3 -CONHCH2C (CH 3) 2 OH C25H37N5O4 472 4 -CONHCH2CH (OH) CH 3 C24H35N5Ô4 458 5 -CO2NH2 C21H29N5O3 399 (EI, M +) 6 -CH2COCH3 C23H32N3O4 413 7 CH (OH) Ph-p-Cl C27H33N4O3C1 497 8 -CH (OH) CH2CH3 C23H34N4O3 415 9 -CONHBn C28H35N5O3 490 10 CONH (CH2) 2CH3 C24H35N5O3 442 11 H N ~ C25H37N5O3 456 12 -CONHPh C27H33N5O3 476 13 NN H ch ₃ C21H28N8O2 425 14 C23H30N6O3 439

140

The other compounds listed in the following Table AV were prepared according to Steps A and B using Intermediate 3 and some of the intermediates listed in the above Table.

Table AVa

w molecular formula FAB (or CI) -MS (M + 1). 1 -CO2CH2CH3 C23H35N3O4 418 2 -CONHCH2C (CH 3) 2 OH C25H40N4Q4 461 3 -CONH (CH 3) 2 C23H33N5O3 428 4 CH (OH) Ph-p-Cl C27H36N3O3C1 486

Example BI

141

Stage A:

To 7.0 g of 2-bromobenzyl alcohol in 7.0 g of dihydropyran at room temperature were added two drops of concentrated hydrochloric acid and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ether (150 ml) and washed with saturated sodium bicarbonate (2 x 100 ml), brine (150 ml), dried (MgSO4) and evaporated to a thick oily material. This material was purified by flash chromatography eluting with hexane / ethyl acetate to give 10 g of tetrahydropyranyl ether.

To 260 ml of anhydrous ether was added at -78 ° C

23.6 ml of a 1.6 M solution of mBuLi in hexanes. To the solution was added a solution of 7.5 g of THP in 100 mL of ether, and the mixture was stirred at -78 ° C for 30 minutes and then at -40 ° C for 30 minutes. The resulting solution was then added dropwise to a mixture of 2.16 g of pyridine and 6.3 ml of tert-butyldimethylsilyl triflate in 200 ml of ether at -78 ° C. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The mixture is then mixed with 75 ml of water and oxygen gas is bubbled through the mixture for 3 hours. Then the reaction mixture was diluted with ether and 3M HCl was added until pH 1, then the organic layer was separated, then the aqueous layer was basified with 20% NaOH until pH 8-9, then extracted with 3 x 100 mL chloroform. The organic layer was then washed with water, 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated.

To 3.42 g of the title compound in 100 ml of chloroform was added 30 g of activated manganese dioxide and the mixture was stirred overnight. The solid was filtered through a pad of celite and the filtrate was evaporated.

To 2.4 ml of triethylphosphonacetate in 30 ml of anhydrous THF at 0 ° C was added 16.3 ml of a solution of sodium hexamethyldisilazide in THF and the mixture was stirred for a further 30 minutes. A solution of the above aldehyde intermediate in 10 mL of THF was then added and the mixture was stirred for an additional 30 minutes. The reaction is quenched by the addition of 25 ml of saturated ammonium chloride solution and the mixture is extracted with 3 x 25 ml of ethyl acetate. The organics were combined, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. Flash chromatography of the residue with hexane / ethyl acetate (4: 1) as eluent gave 1.5 g of the desired product as a pale yellow solid.

1 H NMR (CDCl 3, 400MHz) d 8.63 (d, 2H), 7.68 (dd, 1 H), 7.60 (d, 1 H),

Stage B:

HHCI

N

'0

To 1.5 g of the above intermediate in 25 ml of methanol was added 5 ml of 4 M HCl in ethyl acetate and the mixture was evaporated to dryness. The solid was dissolved in 30 ml of methanol, 0.50 g of platinum oxide was added, and the mixture was hydrogenated at 50 psi for 5 hours. The catalyst was filtered off through a pad of celite and the filtrate was evaporated to give the desired product. ³ H-NMR showed this material to contain approximately 5% cyclohexylpiperidine.

1 H NMR (CD 3 OD, 400MHz) d 7.40-7.20 (m, 4H), 4.08 (q, 2H), 3.50 (m, 2H), 3.25-3.10 (m, 3H), 3.00 (t, 2H), 2.60 (t 2.03-1.90 (m, 4H).

1.20 (t, 3 H).

143

Stage C:

To a mixture of the above intermediate in 30 mL of methylene chloride was added 0.82 mL of triethylamine, 1.2 mL of NMM, 0.90 g of HOBT, 2.13 g of (2R) -N-tB0C-5-phenylpentanoic acid (prepared according to HK publication) Chenault et al., J. Am. Chem. Soc., 111, 6354-6364 (1989) and finally 1.7 g of EDC and stirred at room temperature for 18 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic extracts were combined, washed with 0.1 M HCl, saturated brine, dried over sodium sulfate and evaporated.

The above crude product was dissolved in 30 ml of methylene chloride, 10 µl of TFA was added and the mixture was stirred at room temperature for 1 hour. Then the solvent is evaporated to dryness and the residue is neutralized with aqueous sodium carbonate solution, dried over potassium carbonate and evaporated. To a solution of the intermediate in 30 mL of methylene chloride was added 1.04 g of HOBT,

1.56 g of N-tBOC-.alpha.-methylalanine and 1.8 g of EDC were stirred at room temperature for 4 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic extracts were combined, washed with 0.1 M HCl and saturated brine, dried (MgSO 4) and evaporated. Flash chromatography of the oily residue using a 6: 1: 1 mixture of methylene chloride, acetone and ether gave the title compound as a white solid, m.p.

144 obtains the desired product.

1 H NMR (CDCl 3, 400MHz) d 7.30-6.98 (m, 9H), 5.00-4.85 (m, 2H), 4.72-4.64 (m, 1H), 4.13 (2q, 2H), 4.00-3.82 (m, 1H) . 3.14-2.85 (m. 4H);

2.7-2.50 (m, 5H); 1.83-1.50 (m, 5H); 1.50 (s, 3H); 1.46 (s. 1.5H); 1.44 (s. 1.5H); 1.40 (s. 9H); 1.28 (m, 1 H), 1.23 (2t, 3H).

Stage D:

To 1.70 g of the intermediate from step C in 30 ml of methylene chloride was added 10 ml of TFA and the mixture was stirred at room temperature for 1 hour. Then the reaction mixture was evaporated to dryness, basified with aqueous sodium carbonate solution and extracted with methylene chloride. The extracts were combined, washed with saturated sodium chloride solution, dried over potassium carbonate, filtered and evaporated to the free base as a thick oil. This material was dissolved at 0 ° C in 5 mL of ether and 0.50 mL of 4 M HCl in ethyl acetate was added. The precipitate was filtered off under nitrogen and dried to give the product.

1 H NMR (CD 3 OD, 400MHz) d 7.30-6.98 (m, 9H), 5.00-4.85 (m, 2H), 4.72-4.64 (m, 1 H), 4.13 (2q, 2H), 4.00-3.82 (m, 1 H) 3.14-2.85 (m. 4H),

2.7-2.50 (m, 5H); 1.83-1.50 (m, 5H); 1.50 (s, 3H); 1.46 (s. 1.5H); 1.44 (s. 1.5H); 1.40-1.28 (m, 1H). 1.23 (2t, 3 H).

145

Example B2

Stage A:

To a solution of 0.20 g of the intermediate of Example B1, Step C, in 5 mL of anhydrous THF was added 46 mg of potassium trimethylsilanoate. After 2 hours, 46 mg of the same and 2 ml of THF were added and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with 10 mL of water and washed with 2 x 10 mL of ether. The aqueous layer was acidified by addition of 0.1 M HCl to pH 2 and then extracted with 2 x 15 mL of methylene chloride. The organic extracts were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. Flash chromatography of the residue with chloroform: methanol: ammonia (85: 15: 1) gave 56 mg of the desired product.

1 H NMR (CDCl 3, 400MHz) d 7.32-7.20 (m, 4H), 7.20-6.98 (m, 5H),

5.10 (bs, 1 H), 5.00-4.90 (m, 1 H), 4.65 (bt, 1 H), 4.90 (dd, 1 H), 3.10-2.85 (m, 4 H), 2.70-2.50 (m, 5 H), 1.80-1.50 (m, 5H), 1.50 (s, 4H), 1.46 (s, 1H), 1.42 (s, 1H), 1.38 (s, 9H), 1.35-1.20 (m, 1H).

146

Stage B:

To the above intermediate was added 2 mL of 4 M HCl in ethyl acetate at room temperature and the mixture was kept at room temperature for 2 hours. The mixture was evaporated to dryness and the residue was triturated with ether to give the title product as a white solid.

1 H NMR (CD 3 OD, 400MHz) d 8.15 (t, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1 H), 4.60 (bd, 1 H), 4.05 (d, 1 / 2H), 3.95 (d) 3.25-3.05 (m, 2H).

3.00 (dt, 2H), 2.80-2.50 (m, 5H), 1.85-1.63 (m, 6H), 1.63 (s, 2H), 1.60 (s, 4H), 1.60-1.20 (m, 2H).

Example B3

The resulting product was prepared in a similar manner to that described in steps C and D of Example B1, but the commercially available N-t-BOCO-benzyl-D-serine was used in place of (R) -2N-t-BOC-5-phenylpentanoic acid.

147 1H NMR (CD3OD, 400MHz) d 8.30 (d, 1 / 2H), 8.23 (d, 1 / 2H), 7.40-7.25 (m, 5H), 7.20-7.05 (m, 3.5H), 6.88 (d, 1 / 2H), 5.20 (m, 1H), 4.70-4.50 (m, 3H), 4.20-4.05 (m, 3H), 3.84-3.65 (m, 2H), 3.28-2.95 (9m, 4H), 2.75 (q) 1H, 2.58 (dt, 2H), 1.85-1.70 (m, 2H), 1.64 (s, 2H), 1.61 (s, 4H), 1.551.40 (m, 2H), 1.20 (2t, 3H).

Example B4

To 54 mg of the compound of Example B3 was added 2 mL of a 2 M aqueous HCl solution and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuo to give the desired product. 1 H NMR (CD 3 OD, 400MHz) d 8.30 (d, 1 / 2H), 8.23 (d, 1 / 2H), 7.40-7.25 (m, 5H), 7.20-7.05 (m, 3.5H), 6.88 (d, 1) (2H), 5.20 (m, 1 H), 4.70-4.50 (m, 3 H), 4.20-4.05 (m, 1 H), 3.84-3.65 (m, 2 H). 3.28-2.95 (m. 4H); 2.75 (q,

1H), 2.58 (dt, 2H), 1.85-1.70 (m, 2H), 1.64 (s, 2H), 1.61 (s, 4H), 1.551.40 (m, 2H).

Example B5

148

To a solution of 0.109 g of the intermediate obtained in Step A of Example B2 in 3 ml of methylene chloride was added 0.017 ml of ethanolamine, 34 mg of HOBT and 58 mg of EDC, and the mixture was stirred overnight at room temperature. The reaction mixture was then diluted with 10 mL of methylene chloride and washed with 5 mL of 0.1 M HCl, 5 mL of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography using 3: 2 methylene chloride / acetone as eluent to give the desired product.

As above, the material was treated with methylene chloride solution TFA for 30 minutes at room temperature, then the mixture was evaporated to dryness and triturated with ether to give the title product as a pale yellow solid.

1 H NMR (CD 3 OD, 400MHz) d 8.15 (t, 1H), 7.30-7.00 (m, 9H), 4.95 (m, 1 H), 4.60 (bd, 1 H), 4.40 (bs, 1 H), 4.00 (bdd, 1 H) ). 3.60-3.50 (m, 2 H). 3.40-3.10 (m, 4H), 3.05-2.90 (m, 2H), 2.85-2.60 (m, 5H), 2.52-2.40 (m,

4H), 1.90-1.65 (m, 6H). 1.63 (s, 2H); 1.60 (s, 4H); 1.60-1.20 (m, 2H).

Example B6

Stage A:

OH

149

To 9.0 g of 2-bromophenethyl alcohol in 6.12 ml of dihydropyran at room temperature were added two drops of concentrated hydrochloric acid and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ether (150 ml), washed with saturated sodium bicarbonate (2 x 100 ml), brine (150 ml), dried (MgSO4) and evaporated to a thick oil. This oil was then purified by flash chromatography using hexane / ethyl acetate as eluent to give 10 g of the resulting ether.

To 200 ml of anhydrous ether was added at -78 ° C

17.7 ml of a 1.6 M nBuLi solution in hexanes. A solution of 8.0 g of the ether intermediate in 100 ml of tetrahydropyranyl ether is then added to the obtained solution and the mixture is stirred for 30 minutes at -78 ° C and then for a further 30 minutes at -40 ° C. The solution was then added dropwise to a mixture of 2.16 g of pyridine and 6.3 ml of tert-butyldimethylsilyl triflate in 200 ml of ether at -78 ° C. The reaction mixture was then allowed to warm to room temperature and stirred at room temperature overnight. The reaction is then quenched by the addition of 75 ml of water and oxygen gas is bubbled through the mixture for 3 hours. Then the reaction mixture was diluted with ether and 3M HCl solution was added until pH 1, then the organic layer was separated. The aqueous layer was basified with 20% NaOH until pH 8-9 and then extracted with 3 x 100 mL chloroform. The organic layer was washed with water and 200 mL of saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The product was purified by flash chromatography eluting with hexane / ethyl acetate 1: 1 to give the desired product.

Approximately 0.90 g of the phenylpyridine intermediate prepared as described above was converted to the hydrochloride by treatment with 4M hydrochloric acid in ethyl acetate.

1 H NMR (CDCl 3, 400MHz) d 8.90 (d, 2H), 8.20 (dd, 1H), 7.73-7.35 (m,

4H), 3.70 (t, 2 H), 2.83 (t, 2 H).

150

Stage B:

TFA

To 0.90 g of the above intermediate in 25 ml of methanol was added 0.10 g of platinum oxide and the mixture was hydrogenated with hydrogen at 50 psi for 5 hours. Then the catalyst is filtered off and the filtrate is evaporated. The residue is treated with 1.4 g of di-tert-butyl carbonate in a mixture of 3 ml of dioxane, 1 ml of water and 1 ml of triethylamine for a total of 18 hours. The protected piperidine is separated by flash chromatography using a 10: 1 mixture of methylene chloride and acetone as eluent.

To 0.25 g of the protected piperidine intermediate prepared as above was added 2 mL of methylene chloride and 0.50 mL of TFA, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then evaporated to dryness and azeotroped with toluene.

To a solution of the obtained residue in 2 ml of methylene chloride was added 0.079 g of HOBT, 0.14 g of intermediate 2, 0.070 ml of NMM and 0.090 g of EDC, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic extracts were combined, washed with 0.5 M hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Flash chromatography of the residue with methylene chloride: acetone (9: 1) as eluent gave the bound product.

Removal of the N-tert-butoxycarbonyl protecting group from the intermediate was carried out by treatment with 1 ml of methylene chloride for 2 hours, then the reaction mixture was evaporated, the residue triturated with ether and dried in vacuo to give the title product as a colorless solid.

1 H NMR (CD 3 OD, 400MHz) d 7.40-6.88 (m, 9H), 5.17 (bs, 1 H), 4.774.50 (m, 3 H), 4.18 (bd, 1 H), 3.80-3.65 (m, 4 H), 3.30 -3.05 (m, 4H), 2.952.70 (m, 2H), 1.85-1.60 (m, 2H), 1.60 (s, 2H), 1.58 (s, 4H), 1.70-1.45 (m, 2H).

Example B7

Stage A:

Reduction of the phenylpiperidine intermediate from Step A of Example B1 by treatment. The platinum oxide is carried out in various solvents, for example ethanol and methanol, in the presence and absence of concentrated hydrochloric acid. Both trans-esterification and non-selective reduction of pyridine were observed. Several reaction mixtures were combined and the material was treated with excess di-tert-butyl carbonate in a mixture of methylene chloride and triethylamine. about 5.0 g of the crude material obtained after

The 152 acid treatments were further treated with 100 ml of methanol and 10 ml of water containing 1.6 g of sodium hydroxide for a total of 2 hours. The reaction mixture was diluted with water and washed with ether. The aqueous layer was acidified by addition of 0.5 M HCl until acidic pH and then extracted with chloroform. the organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. To 4.0 g of this piperidine-derived acid in 150 ml of methylene chloride was added 1.86 ml of benzyl alcohol, 1.90 g of HOBT, 3.45 g of EDC and a catalytic amount of DMAP at room temperature, and the mixture was stirred overnight at room temperature. . Then the reaction mixture was washed with saturated sodium bicarbonate solution, 0.5 M HCl, saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. Purification by flash chromatography gave the desired product.

1 H NMR (CDCl 3, 400MHz) d 7.40-7.28 (m, 5H), 7.22-7.10 (m, 4H),

5.12 (s, 2 H), 4.25 (bs, 2 H), 3.04 (t, 2 H), 2.94-2.70 (m, 3 H), 2.67 9t, 2 H, 1.75-1.60 (m, 3 H), 1.53 (s, 9 H) 1.33-1.20 (m, 1H).

Stage B:

To a solution of 0.70 g of the above intermediate in 2.5 ml of methylene chloride was added 1 ml of TFA and the reaction mixture was stirred at room temperature for 1 hour. The mixture was then evaporated to dryness and dissolved in saturated aqueous bicarbonate with methylene chloride. Organic saturated potassium chloride solution and evaporated. Subtracted sodium and extracted extracts are combined, washed with sodium, dried with carbonate and treated with intermediate 1 according to step B of Example B6. Flash chromatography of the residue with hexane: acetone: ether 6: 1: 1 gave 0.47 g of the desired product.

Stage C:

Hydrogen chloride gas was bubbled into the solution of 0.20 g of the above intermediate in ethyl acetate at 0 ° C over 10 seconds. The reaction mixture was then sealed and stirred for 30 minutes. Ether was added and the resulting precipitate was filtered under nitrogen to give 0.195 g of the title compound as a white solid.

According to NMR, this is a 2: 1 mixture of rotamers. 1 H-NMR (CD 3 OD, 400MHz) d 8.30 and 8.20 (2d, 1H), 7.53 and 7.45 (2d, 1H),

7.40 and 7.35 (2d, 1 H), 7.30-7.00 (m, 11 and 1/3), 6.54 (d, 2 / 3H), 5,305.18 (m, 1 H), 5.09 and 5.05 (2s, 2H), 4.60 and 4.55 (2d, 1 H), 3.90 (2d,

1H), 3.35 (dd, 1 H), 3.20 (dd, 1 H), 3.00-2.85 (m, 3H), 2.75-2.40 (4H),

1.64 (d, 2 / 3H), 1.64 (d, 2 / 3H), 0.73 (dt, 1 / 3H), -0.03 (dt, 2 / 3H)

1 / 3H).

154

Example B8

To a solution of 0.19 g of the intermediate from Step C of Example B7 in 3 ml of dioxane was added 50 mg of 10% palladium on charcoal and the mixture was hydrogenated under a hydrogen-filled flask for 3 hours. The reaction was slow, so 50 mg of 20% palladium hydroxide on charcoal was added and the mixture was hydrogenated overnight. The catalyst was filtered through a pad of celite and washed with dioxane. Evaporation of the filtrate gave the title product as a pink solid.

According to NMR, this is a 2: 1 mixture of rotamers. 1 H-NMR (CD 3 OD, 400MHz) d 8.30 and 8.20 (2d, 1H), 7.53 and 7.45 (2d, 1H), 7.40 and 7.35 (2d, 1H), 7.20-7.00 (m, 6 and 1/3), 6.54 (d, 2 / 3H); 5.305.18 (m, 1H); 4.60 and 4.55 (2d, 1H). 3.90 (2d, 1 H), 3.35 (dd, 1 H), 3.20 (dd, 1 H), 3.00-2.85 (m, 3 H), 2.75-2.40 (4 H), 1.64 (s, 6 H), 1.40 (d, 2 H) 3H), 1.06 (d, 2 / 3H), 0.73 (dt, 1 / 3H), -0.03 (dt, 1 / 3H).

Example B9

155

To 0.20 g of the benzyl alcohol-pyridine intermediate from Example A, Step A, 2 ml of anhydrous acetone and 0.10 ml of benzyl bromide were added, and the mixture was stirred at room temperature for 1 hour. The volatiles were removed on a rotary evaporator and the residue was azeotroped with toluene. The residue was then dissolved in methanol and treated with 0.10 g of sodium borohydride for 1 hour. The reaction mixture was diluted with water and extracted with methylene chloride. The organic extracts were combined, washed with saturated brine, dried over magnesium sulfate, filtered and evaporated. A mixture of N-benzyltetrahydropyridines is obtained, which is hydrogenated in ethanol for a total of 5 hours using 10% palladium on charcoal as catalyst. Then the catalyst is filtered off and the filtrate is evaporated. The residue was purified by chromatography using methylene chloride / methanol 90:10 as eluent to give 70 mg of a mixture of tetrahydro- and hexahydropyridines. To a solution of 70 mg of this mixture in 5 mL of methylene chloride was added 0.10 g of intermediate 3, 0.040 g of HOBT and 0.070 g of EDC, and the mixture was stirred overnight at room temperature. The reaction mixture was then poured into saturated aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were combined, washed with saturated brine, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography using 4: 1 hexane: ethyl acetate as the eluent to give 0.090 g of the product as a mixture of diastereomers.

The product obtained above is hydrogenated in ethanol in the presence of 10% palladium on activated carbon catalyst for 18 hours. The catalyst was filtered off through a pad of celite and the filtrate was evaporated. Flash chromatography of the residue using 6: 1 methylene chloride: ether gave 90 mg of the desired product.

Removal of the protecting group is carried out in 2 ml of methanol in the presence of 1 ml of concentrated HCl for 5 hours, the reaction mixture is evaporated to dryness and the residue triturated with ether to give a solid which is purified using MPLC on LH2Q column as eluent using methanol,

156 to give 34 mg of the product as a white solid. 1 H NMR (CD 3 OD, 400MHz) d 7.35-7.04 (m, 9H), 4.95 (m, 1H), 4.69 (d, 2H), 4.60 (d, 1H), 3.97 (dd, 1H), 3.30-3.10 9m, 3H), 2.82-2.60 (9m, 4H), 1.90-1.70 (m, 5H), 1.63 (s, 2H), 1.60 (s, 4H), 1.55-1.40 (m, 1H).

930 mg of the intermediate from Example B12, Step B, as a mixture of two diastereomers, was dissolved in methanol and hydrogenated using palladium hydroxide and 10 psi for a total of 12 hours. The mixture was then filtered through celite and the filtrate evaporated in vacuo to give 700 mg of deprotected product. To 5.5 mg of the product in 0.5 ml of methylene chloride was added 4.9 mg of N-BOC- (D) -alanine, 6.0 mg of EDC and 3.5 mg of HOBT. The mixture was stirred overnight, then poured into water, extracted with methylene chloride and washed with saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by PLC using 1: 1 hexanes and ethyl acetate to give the desired product. Deprotection can be carried out according to the procedure of Example B9, Step B, whereby 7.8 mg of the desired product is obtained.

1 H-NMR (400 MHz, CD 3 OD, mixture of diastereomers and rotamers):

7.59 (m, 1H), 7.39-7.01 (m, 9H), 5.37 (m, 1 H), 5.18 (m, 1 H), 4.61 (m, 1 H), 4.30 (m, 4.02-3.61 (m, 3 H), 3.35-2.35 (m, 7 1/2 H),

1.60 (m, 1H), 1.56 (d, 7 Hz 3 / 2H), 1.50 (m, 3 / 2H), 0.95 (m, 3/2 H), 0.88 (m, 3/2 H). FAB-MS: 491.0 (M + 1).

157

Example Bil

To a solution of 0.10 g of Example B15 Step A compound in 2 ml of chloroform at 0 ° C was added 0.018 g of 5-aminomethyltetrazole, 0.027 g of HOBT, 0.65 ml of triethylamine and 0.048 g of EDC and stirred at 0 ° C for 10 min. C. 1 ml of DMF is then added to the suspension and the mixture is stirred overnight. The reaction mixture was evaporated and the residue was separated by preparative thin layer chromatography (1 mm thick plate) using 90: 10: 1 chloroform: methanol: ammonia to give the desired product.

FAB-MS m / e calcd for C C HH ^ gNgO ^ 646.36 found 647.2 (m + 1)

To a cooled solution of 0.025 g of this product in 1 mL of ethyl acetate was added hydrogen chloride gas by bubbling until saturation, and the mixture was allowed to stand at room temperature for 30 minutes. Then the mixture is evaporated to give the desired product.

· * · Η-ΝΜΙΪ. (200 MHz, CD 4 OD) for the mixture of rotamers: 7.91 (d,

J = 8Hz); 7.35-7.06 (m); 5.14 (bs); 4.65-4.48 (m); 3.92 (bt, J = 13); 3,723.04 (m); 2.76-2.58 (m); 1.95-1.68 (m); 1.61 (s); 1.28 (s).

FAB-MS calcd for C- ^H ^ gNgOg 546.31 found 547.1 (m + 1).

158

Stage A1:

Example B12

To a solution of 3-ethoxycarbonyl-4-piperidine hydrochloride (11.4 g, 54.9 mmol) in 1 M sodium hydroxide solution (82 mL) was added di-tert-butyl dicarbonate (12.2 g, 56.0 mmol) in dioxane (82 mL) at room temperature. . After 12 hours, the mixture is diluted with ethyl acetate and washed with 0.5 M hydrochloric acid and saturated sodium chloride solution. The organic layer was dried (MgSO4), filtered and evaporated. 14.3 ml of methylene chloride are added to the residue after dissolution in 200 ml of methylene chloride.

82.3 mmol of diisopropylethylamine and 10.1 ml, 60.4 mmol of trifluoroacetic anhydride at -78 ° C. After half an hour, the mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer was washed with 1M hydrochloric acid, saturated sodium chloride solution and then dried over magnesium sulfate. The organic layer was evaporated to give 21.0 g of vinyltrifluoroacetate in 95% yield. To a solution of 1-methyl-2-pyrrolidinone (4.76 g, 11.6 mL) was added phenyltrimethyltin (2.1 mL, 11.6 mmol) and palladium (II) acetate (0.13 g, 0.58 mmol) at temperature.

159 rooms. After 2 hours, the reaction mixture is poured into water and extracted three times with ether. The organics were combined, washed three times with water, then washed with saturated sodium chloride solution and dried over magnesium sulfate. Evaporation and purification by MPLC using 10: 1 hexanes / ethyl acetate gave the title compound (3.2 g, 83%).

The resulting product was prepared from 3.2 g (9.60 mmol) of the intermediate obtained in Step A1. The intermediate is dissolved in 100 ml of methanol, hydrogenated in the presence of platinum oxide at 1 bar for 2 hours (the reaction proceeds very slowly), then palladium on charcoal is added under a hydrogen atmosphere. The mixture was stirred for 72 hours and then filtered through a pad of celite. The filtrate was evaporated in vacuo. The residue was purified by MPLC with 10: 1 hexanes / ethyl acetate to give 1.9 g of the cis product.

Grade B

Or? ⁰ * ®

160

To 200 mg, 0.6 mmol of the intermediate from Step A was added 2 mL of TFA. After 10 minutes, the mixture was evaporated and the residue was azeotroped with toluene, distilled three times. The residue was dissolved in ethyl acetate and the solution was washed with sodium bicarbonate solution. The organic layer was evaporated. The residue was dissolved in 10 mL of methylene chloride and 223 mg, 0.66 mmol of N-CBZ-D-tryptophan, 138 mg, 0.72 mmol of EDC and 89 mg, 0.66 mmol of HOBT were added to the solution. After 2 hours, the reaction mixture was poured into water and extracted with methylene chloride, dried over sodium sulfate, filtered and evaporated. The residue was purified by MPLC eluting with hexanes / ethyl acetate to give the two diastereomers in a total yield of 66%. To give 82 mg of the less polar diastereomer of D ^ and 138 mg of the polar diastereomer d _second

Stage C:

mg of the less polar diastereomer of Step B was dissolved in 5 ml of methanol and hydrogenated using palladium on charcoal at 1 bar for 2 hours, monitored by TLC. The mixture was then filtered through celite and the filtrate evaporated in vacuo. 38 mg of N-CBZ-α-methylalanine, 31 mg of EDC and 21 mg of HOBT are added to the residue in 5 ml of chloroform. After stirring at room temperature for 3 hours, the mixture is poured into water, then the mixture is extracted with methylene chloride and the extract is washed with saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography using 1: 1 hexanes / ethyl acetate to give a total of 60 mg of the desired product in 69% yield.

Stage D:

nh ₂ hci

The intermediate obtained in the previous step C is dissolved in 3 ml of methanol and hydrogenated using palladium hydroxide on charcoal at 1 atm for 1 hour (reaction progress is monitored by TLC). The mixture was then filtered through celite and the filtrate evaporated in vacuo. The residue was acidified with hydrochloric acid in ether to give 40 mg of d1 as a white precipitate.

1 H-NMR (400 MHz, CD-iodo) for the mixture of rotamers: 7.64 (d, 8 Hz, 1/2 H),

7.57 (d, 8Hz, 1/2H), 7.37-7.01 (m, 9H), 5.28 (dd, 8.5Hz, 1/2H), 5.18 (t, 7Hz, 1/2H) 4.76 (m, 1 H), 4.30 (m, 1 H), 4.15 (m, 1 H), 3.81 (m, 2 H), 3.35 (m, 1 H), 3.16 (m, 1/2 H), 3.02 (m, 1/2 H), 2.98 (m, 1/2 H), 2.45 (m, 1H), 2.25 (m, 1/2 H), 1.74 (m, 1 H), 1.63 (m, 1 H),

1.57 (s, 3 / 2H); 1.52 (s, 3 / 2H); 1.49 (s, 3 / 2H); 1.34 (s, 3 / 2H); 0.98 (t, 7 Hz, 3/2 H); 0.90 (t, 7 Hz, 3/2 H).

FAB-MS: found 505.6 (M + 1).

162

Example B13 (cis, d ₂ )

The compound was prepared from the intermediate obtained from 93 mg of the more polar diastereomer of Step B of Example B12 as described in steps C and D of Example B12 to give 56 mg of the final product d ₂ .

1 H-NMR (400 MHz, CD 3 OD) for rotamer mixture: 7.57 (m, 1H), 7.356.94 (m, 9H), 5.37 (t, 7 Hz, 2/3 H), 5.17 (m (1/3 H), 4.61 (m, 1 H), 4.28 (m, 1/3 H), 4.06 (m, 2/3 H), 3.84-3.53 (m, 2 H), 3.28-2.80 (M) 1 H, 2.53 (M, 1 H), 1.61 (S, 2 H), 1.51 (S, 1 H), 1.47 (S, 2 H), 1.29 (S, 1 H), 0.95 (t, 7 H) Hz, 2 H), 0.80 (t, 7 Hz, 1 H). FAB-MS: 505.7.

Example B14 (trans, d 1 + d ₂ )

163

Stage A:

A small piece of sodium is taken up in 2.5 ml of anhydrous ethanol. After dissolution of sodium, 40 mg of the intermediate from Step A of Example B12 were added to the mixture and placed in an oil bath at 80 ° C for 2 hours. The mixture was poured into 0.1 M HCl and extracted with ether. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified using PLC and 5: 1 hexanes / ethyl acetate to give 26 mg of the trans isomers.

Stage B:

The product was prepared from 24 mg of intermediate from step A and intermediate 1 in the manner described in steps B and C of Example B7 to give 5.4 mg of the product as the hydrochloride.

1 H-NMR (400 MHz, CD 3 OD, mixture of diastereomers and rotamers): 7.63-7.35 (m, 2H), 7.24-6.75 (m, 8H), 5.01 (m, 1H), 4.60 (m) , 1 H),

4.08-3.68 (m, 3/3 H), 3.39-2.41 (m, 5 2/3 H), 1.78-0.96 (1 1/3 H), 1.62 (s, 3 H), 1.61 (s, 3 H) H), 0.86 (m, 3 H), 0.66 (m, 1/3 H), -0.10 (m, 1/3 H). FAB-MS: 505.6 (M + 1);

164

Example B15

Stage A:

About 0.250 g of the piperidine intermediate from Step A of Example B44 was treated with 0.39 g of intermediate 3, 0.152 g of HOBT, 0.17 ml of N-methylmorpholine and 0.225 g of EDC in 15 ml of chloroform for 18 hours. The reaction mixture was washed with 10 mL 0.5 M HCl, 10 mL saturated aqueous sodium bicarbonate, dried (MgSO 4) and evaporated. The crude product was purified by flash chromatography using 4: 1 hexane / ethyl acetate as eluent.

To 0.136 g of this material in 10 mL of 1: 1 methanol / water was added 25 mg of lithium hydroxide and the mixture was stirred overnight. The reaction mixture was then diluted with 10 mL of water and washed with water, the aqueous layer was acidified to pH 2 by addition of 0.5 M HCl and then extracted with 3 x 10 mL of ether. organic

The 165 extracts were combined, washed with saturated brine, dried (MgSO 4) and evaporated to give the desired material as a white solid.

Stage B:

The product was prepared from the compound of Step A by treatment with a saturated solution of hydrogen chloride gas in ethyl acetate for 30 minutes at room temperature. After addition of ether, the precipitate formed is filtered off and dried:

@ ³ H-NMR (400 MHz, CD3 OD) for a mixture of rotamers: 8.10 (t, 1 H), 7.78 (dd, 1 H), 7.50-7.00 (m, 8 H), 4.90 (m, 1 H), 4.55 (d, 1 H, 3.94 and 3.90 (2 doublets, 1 H), 3.80-3.60 (m, 1 H), 3.05 (dt, 1 H), 2.70-2.50 (m, 4 H), 1.901.50 (m, 6 H), 1.55 (s) 3H), 1.50 (s, 3H), 1.40 (m, 1 H).

Example 16

166

Stage A:

To a solution of 89 mg, 0.267 mmol of the intermediate from Step A of Example B12 in 2 mL of THF was added 800 mL of a 0.5 M solution of potassium bis (trimethylsilyl) amide (0.4 mmol) at -78 ° C. of methyl iodide (22 mL, 0.34 mmol) was added. The reaction mixture was allowed to warm slowly to room temperature and stirred at this temperature for a further 12 hours, then poured into water and extracted with ether. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography using hexanes / ethyl acetate 1: 1 to give 91 mg (98%) of the product.

Stage B:

The title compound was prepared from 91 mg of Step A intermediate as described in Step B, C and D of Example B12.

1 H-NMR (400 MHz, CD 6 OD, mixture of diastereomers and rotamers):

7.58 (m, 1H), 7.37-7.00 (m, 9H), 5.40-5.23 (m, 1H), 4.60 (m, 1H), 4.20-3.73 (m, 3H), 3.40 (m, 3.15 (m, 2H), 2.82 (m, 1H), 2.612.30 (m, 2H). 1.72 (m, 1 H), 1.63-1.29 (m, 6 H), 1.13-0.84 (m, 6 H). EI-MS: 518.2 (M).

167

Example B17 (cis, d-^ + d ₂ )

To a stirred solution of the intermediate from Step A1 of Example B12 (1.0 g, 3.02 mmol) in 4 mL of ethanol was added 4 mL of 4 M sodium hydroxide solution. The reaction mixture was stirred at room temperature for 16 hours and then evaporated in vacuo. The residue was diluted with water and acidified to 0.5 M hydrochloric acid and extracted with ether. The organic extract was dried over sodium sulfate, filtered and evaporated. The crude residue was dissolved in methanol and hydrogenated in the presence of palladium hydroxide at 100 psi for a total of 16 hours. The mixture was then filtered through celite and the filtrate evaporated in vacuo. To the crude acid in 10 mL of chloroform was added 341 mL of benzyl alcohol, 750 mg of EDC, and a catalytic amount of DMAP. After 16 hours, the mixture was diluted with methylene chloride and then washed with water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by MPLC and 5: 1 hexanes in ethyl acetate to give 459 mg of the title product in 38% yield.

Stage B:

/ BOC

The intermediate from Step A (459 mg, 1.16 mmol) was treated with TFA (2 mL) at room temperature. After 10 minutes, the reaction mixture was evaporated and azeotroped with toluene three times. 433 mg of intermediate 1, 265 mg of EDC, 172 mg of HOBT and 194 ml of triethylamine were added to the residue in 10 ml of chloroform. The reaction mixture was stirred at room temperature for 3 hours and then poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Evaporation and purification of the residue by MPLC using hexanes / ethyl acetate (1.5: 1) yielded 574 mg (65%).

Stage C:

169

To 10 mg of the intermediate of Step B was added TFA at room temperature. After 10 minutes the mixture was evaporated to give 3 mg of the desired product.

1 H-NMR (400 MHz, CD 3 OD, mixture of diastereomers and rotamers): 7.62 (m, 1H), 7.37-6.81 (m, 14H), 5.42-5.15 (m, 1H), 4.79 (m, 2H) H).

4.65 (m, 1H), 4.32 (m, 1/2 H), 4.12 (m, 1/2 H), 3.27-2.85 (m, 5 1/2 H), 2.55-2.27 (m, 1 1 / 2 H), 1.74 (m, 1H), 1.60-1.29 (m, 6H). FAB-MS:

567.0 (M + 1).

Example B18 (cis, d ^ + d ₂ )

Stage A:

The product was prepared from 20 mg of the intermediate obtained in Step B of Example B17 as described in Example 170 de B8.

Stage B:

Using the intermediate obtained in Step A and following the procedure described in Step C of Example B17, 10 mg of the desired product is obtained.

1 H-NMR (400 MHz, CD 3 OD, mixture of diastereomers and rotamers): 7.62 (m, 1H), 7.37-6.98 (m, 9H). 5.36-5.21 (m 1 H), 4.69 (m. 1/2 H),

4.58 (m, 1/2 H). 4.27-3.91 (m, 2H), 3.27-2.75 (m, 5H), 2.51-2.34 (m, 2H), 1.72 (m, 1H), 1.58-1.21 (m, 6H). FAB-MS: 576.9 (M + 1);

Example B19 (cis, d ^ + d ₂ )

171

Stage A:

To 142 mg of the intermediate from Example B18 Step A in 3 ml of methylene chloride was added 22 ml of 2- (methylthio) ethanol, 57 mg of EDC and a catalytic amount of DMAP. After 3 hours the mixture was diluted with methylene chloride and then washed with water and saturated sodium chloride solution. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified using PLC and 1: 1 hexanes / ethyl acetate to give 69 mg (43%) of the product.

Stage B:

Hydrogen chloride gas was bubbled through a solution of 50 mg of the intermediate from Step A in 2 mL of ether at 0 ° C. After

The mixture was evaporated for 172 seconds to give the title compound (41 mg).

¹ H-NMR (400 MHz, CD 3 OD, mixture of diastereomers and rotamers):

7.61 (m, 1H), 7.37-6.97 (m, 9H), 5.38-5.18 (m, 1H), 4.83-4.54 (m, 1H), 4.37-3.77 (m, 3H), 3.57-2.83 (m, 6H), 2.55-2.21 (m, 3H), 2.14-1.84 (m,

H, 1.72 (m, 1H), 1.61-1.29 (m, 6H). FAB-MS: 551.0 (M + 1).

Example B20 (cis, d-^ + d ₂ )

To a solution of 52 mg of the intermediate from Example B18 Step A in 3 mL of methylene chloride was added 9 mg of ethylamine hydrochloride, 21 mg of EDC, 15 mL of triethylamine and a catalytic amount of DMAP. After 3 hours the mixture was diluted with methylene chloride and then washed with water and saturated sodium chloride solution. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified using PLC and 20: 1 methylene chloride / methanol to give 25 mg of product. This intermediate was subjected to Step C, Example B17, to give 25 mg of product.

@ 1 H-NMR (400 MHz, CDCl3 OD, mixture of diastereomers and rotamers): 7.68-6.93 (m, 10H), 5.34-5.12 (m, 1H), 4.75-4.30 (m, 2H), 3.50-2.60 (m, 8H), 1.72-1.17 (m, 8H), 0.83-0.68 (m, 3H). FAB-MS: 504.0 (M + 1).

173

Example B21 (cis, d ^ + d ₂ )

Stage A:

[BOC f \ L

OH

To a solution of 950 mg, 2.87 of Example B12 in 10 mL of THF, the mmol of the intermediate from Step A1 was added 8 mL of a 1.0 N solution of diisobutylaluminum hydride in methylene chloride (8.0 mmol) at -78 ° C. The mixture was stirred at 0 ° C for 1 hour and then warmed slowly to room temperature. The reaction is quenched by addition of 1 M sodium hydroxide and extracted 3 times with ether. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by MPLC using 2: 1 hexanes / ethyl acetate to give 617 mg of the reduced product.

Stage B:

[BOC

N

A 1 OH cis

174 mg of the intermediate obtained in Step A was hydrogenated under the conditions described in Step A of Example B12 to give 13 mg of the product.

Stage C:

mg of the intermediate obtained in step B was treated as in steps B and C of Example B17 to give 12 mg of the desired product.

@ ³ H-NMR (400 MHz, CD3OD, mixture of diastereomers and rotamers):

7.74-6.80 (m, 10H), 5.55 (m 1/2 H), 5.20 (m, 1 H), 4.66 (m, 1 H), 4.11 (m, 1 H). 3.93 (m, 2 H), 3.20 (m, 3 H), 3.00-2.82 (m, 2 1/2 H), 2.692.45 (m, 2 1/2 H), 2.05-1.84 (m, 1 H), 1.68 (s, 3/2 H), 1.61 (p. 3/2 H),

1.60 (p. 3/2 H). 1.47 (p. 3/2 H). 0.90 (m, 1 H), 0.17 (m, 1 H). FABMS: 463.0 (M + 1).

Example B22 (cis, d ^ + d ₂ )

175

Stage A:

OAC

To 330 mg, 1.14 mmol of the intermediate from Step A of Example B21 in 10 mL of methylene chloride was added 130 mL of acetic anhydride, 240 mL of triethylamine and a catalytic amount of DMAP at 0 ° C. After one hour, water was added and the mixture was stirred at room temperature for one hour. The mixture was then extracted with methylene chloride and washed successively with 1 M sodium hydroxide solution and saturated sodium chloride solution. The organic layer was dried (MgSO4), filtered and evaporated. The residue is hydrogenated according to Example B12, Step A to give the desired product.

Stage B:

mg of the intermediate of Step A was processed as in Step B of Example B177 and Step B of Example B19 to give 23 mg of the title product.

@ 1 H-NMR (400 MHz, CDCl3, mixture of diastereomers and rotamers): 7.74-6.87 (m, 10H), 5.55-5.16 (m, 1H), 4.65 (m, 1H), 3.96 (m, 1H) .

3.81 (m, 1H), 3.20 (m, 1H), 2.86 (m, 1H), 2.61 (m, 1H), 2.46 (m, 1/2)

176

Η), 2.27 (m, Η), 2.13 (m, 1 Η), 1.98 (s, 1 Η), 1.93 (s, 1 Η), 1.90 (s,

Η), 1.85 (s, 1/2 Η), 1.73-1.30 (m, 7 1/2 Η), 0.85 (m, 1/2 Η), 0.12 (m, 1/2 Η). FAB-MS: 505.3 (M + 1);

Example Β23 (cis, d ^)

Stage A:

To 87 mg of the intermediate from Step A of Example B12 was added 1 mL of TFA. After 10 minutes, the mixture was concentrated and azeotroped three times with toluene. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate solution. The organic layer was evaporated. 70 mg of N-BOC- (2R) -amino-5-phenylpentanoic acid, 55 mg of EDC and 35 mg of HOBT are added to the residue in 3 ml of methylene chloride. After 2 hours, the reaction mixture is poured into water and extracted with methylene chloride, dried over sodium sulfate, filtered and evaporated.

177

To the intermediate of Step A was added 1 mL of TFA. After 10 minutes, the mixture was evaporated and azeotroped with toluene three times. To the residue in 3 mL of methylene chloride was added BOC-α-methylalanine, EDC, HOBT and triethylamine. After 2 hours the reaction mixture was poured into water and extracted with methylene chloride, dried over MPLC and 2: 1 hexanes / ethyl acetate to give two diastereomers in 75% yield. 54 mg of the less polar diastereomer d 2 and 53 mg of the more polar diastereomer d _{2 are obtained} .

Stage C:

178

To 54 mg of the less polar diastereomer of Step B was added 1 mL of TFA. After 10 minutes, the mixture was evaporated and azeotroped with toluene three times. The residue was dissolved in ethyl acetate and washed with sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in ether containing hydrogen chloride to give 40 mg of diastereomers d 'as a white solid.

@ ³ H-NMR (400 MHz, CDCl3 OD, mixture of rotamers): 7.23 (m, 10H), 5.08 (m, 1H), 4.76 (m, 1H), 4.21 (m, 1H) 3.80 (m, 2 H), 3.47 (m, 1 H), 3.26-2.99 (m, 4 H), 2.86 (m, 1 H), 2.63 (m, 2 H), 2.40 (m, 1/2 H)

1.75 (m, 4H), 1.63 (s, 2H), 1.60 (s, 2H), 1.57 (s, 2H), 0.95 (t, 7Hz, 2H), 0.87 (t, 7Hz, 1 H). FAB-MS: 494.1 (M + 1);

Example B24 (cis, d ₂ )

d mg of the desired product _2, from 53 mg of the polar diastereomer obtained in Step B of Example B23, Step C as in Example B23.

1 H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 7.23 (m, 10H), 4.91 (m, 1H), 4.75 (m, 1H), 4.03 (m, 1H) ), 3.81 (m, 2H), 3.45 (m, 1H), 3.26-2.96 (m, 2H), 2.71 (m, 2H), 2.40 (m, 1H), 1.90 -1.64 (m, 4H), 1.63 (s, 2H), 1.61 (s, 3H), 1.59 (s, 3H), 0.93 (t, 7 Hz, 3H). FAB-MS:

494.3 (M + 1).

179

Example B25 (cis, d- + d ₂ )

Stage A:

To the stirred intermediate prepared according to Step A1 of Example B12 was added 4 mL of 4 M sodium hydroxide in 4 mL of ethanol. The reaction mixture was stirred at room temperature for 16 hours and then evaporated in vacuo. The residue was diluted with water and acidified with 0.5 M hydrochloric acid, then extracted with ether. The organic layer was dried over sodium sulfate, filtered and evaporated. 100 mg of the residue in 3 ml of methylene chloride are mixed with 74 mg of ethylamine hydrochloride, 115 mg of EDC, 49 mg of HOBT and 83 ml of triethylamine. After 2 hours, the reaction mixture is poured into water and the resulting mixture is extracted with methylene chloride, dried over sodium sulfate, filtered and evaporated. The residue was purified by MPLC using 1: 1 ethylhexanes / ethyl acetate to give 74 mg of product.

180

Grade B

mg of the title compound was obtained using 74 mg of the intermediate of Step A according to the procedure of Example B12, Step A.

Stage C:

mg of the intermediate of step B was treated as in steps A, B and C of Example B23 to give 15 mg of the desired product.

1 H-NMR (400 MHz, CD 3 OD, mixture of diastereomers and rotamers):

7.27 (m, 10H), 4.91 (m, 1H), 4.67 (m, 1H), 3.96 (m, 1H), 3.42 (m, 1 H), 3.26-2.59 (m, 9 1) (2 H), 1.90-1.64 (m, 4 H), 1.64-1.57 (m, 6 H), 0.79 (t, 7 Hz, 3/2 H), 0.77 (t, 7 Hz, 3/2 H) . FAB-MS: 493.3 (M + 1);

181

Intermediate 4

NHtBoc

..JJ CO O

N i

H M

OH

To a solution of 0.80 g of the product of Step B of Example B7 in 20 mL of ethanol was added 0.080 g of 20% palladium hydroxide on charcoal and hydrogenated at atmospheric pressure for 3 hours. The catalyst was then filtered through a pad of Celite and the filtrate was evaporated to give the title product.

Examples B26, B27, B28, B29

The compounds listed in the following Table B1 were prepared from intermediate 4 in two steps. The acidic intermediate was coupled to alcohols or amines in methylene chloride solution in the presence of EDC and DMAP at room temperature and the resulting intermediate was purified and treated with hydrogen chloride gas in ethyl acetate to give the products listed in Table BI.

Table BI

R

NH ₂ HCl

182

Example R

no.

Molecular formula

FAB MS m / e found m / e calc. (M + 1)

B26 OCH _{(CH3) 2} C31H42N4O4 569 570.2 B27 O (CH ₂ ) ₃ CH ₃ C33H44N4O4 560 561.1 B28 ^Nd / ° C33H43N5O4 573.33 574.1 B29 NHCH ₂ CH ₃ C31H41N5O3 531 532.3

Example B30

Stage A:

183

To a solution of 1.1 g of the piperidine intermediate from Step A of Example B7 in 5 mL of ethyl acetate was added hydrogen chloride gas by bubbling for 10 seconds at room temperature, followed by stirring for 30 minutes. The solvent was evaporated and the oily residue was basified with aqueous sodium bicarbonate solution and then extracted with methylene chloride. The organic extracts were combined, washed with saturated brine, dried over potassium carbonate, filtered and evaporated to give 0.90 g of the amine as a thick oil. To a solution of this intermediate in 20 mL of methylene chloride was added 0.97 g of (2R) -N-t-BOC-5-phenylpentanoic acid, 0.45 g of HOBT and 0.80 g of EDC, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with methylene chloride. The organic extracts were combined, washed with 0.5 M hydrochloric acid solution, saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography using 5: 1 hexane: acetone as eluent to give 2 g of product.

To this intermediate was added 2 mL of trifluoroacetic acid in 20 mL of methylene chloride and the mixture was allowed to stand at room temperature for 1 hour. The volatiles were removed on a rotary evaporator and the residue was basified with aqueous sodium bicarbonate solution and extracted with methylene chloride. The organics were combined, dried over potassium carbonate, filtered and evaporated. The residue was dissolved in methylene chloride and treated with 0.60 g of N-t-BOC-α-methylalanine in the presence of 0.40 g of HOBT and 0.70 g of EDC. the reaction mixture was stirred overnight and then worked up as above. The residue was purified by flash chromatography using 5: 1 hexane: acetone as eluent to give the product as a colorless foam.

@ 1 H-NMR (400 MHz, CDCl3 OD, mixture of rotamers): 7.40-6.85 (m, 14H),

5.10 (s, 2H), 5.05-4.88 (m, 2H), 4.70-4.60 (m, 1 H), 3.93 (d, 1 / 2H), 3.85 (d, 1 / 2H), 3.10-2.85 (m, 4H) 2.70-2.50 (m, 5H), 1.85-1.60 (m, 7H), 1.50 (s, 3H), 1.48 and 1.47 (2s, 3H), 1.42 (s, 9H), 1.40-1.20 (m, 1H).

184

Stage B:

Approximately 0.050 g of the intermediate from Step A was dissolved in 1 ml of ethyl acetate, 1 ml of ethyl acetate, saturated with hydrogen chloride gas was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0 ° C, ether was added and the solvent was evaporated to give the product as a foam.

1 H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 7.40-7.00 (m, 14H), 5.10 (s, 2H), 4.90 (m, 1H), 4.58 (d, 1H), 3.95 and 3.90 (2-doublets, 1H), 3.20-2.95 (m, 4H), 2.80-2.60 (m, 5H), 1.85-1.60 (m, 9H), 1.62 (s, 3H),

1.60 (s, 1 H). 1.40 (m, IH).

Example B31

N.

NH ₃ Cl nh ₂

185

Stage A:

To 0.90 g of the intermediate from Example B30 Step A in 5 ml of methanol was added 0.10 g of 20% palladium hydroxide and the mixture was hydrogenated overnight at atmospheric pressure. The catalyst was filtered through a pad of celite and washed with methanol. The filtrate was evaporated and the residue was dried in vacuo to give the resulting acid as a colorless foam. This product was used without further purification.

Stage B:

To a solution of 0.30 g of the acid intermediate from Step A in 10 mL of anhydrous THF was added 0.14 mL of triethylamine and 0.07 mL of ethyl chloroformate, and the mixture was stirred for 1 hour. The reaction was quenched by the addition of 2 mL of aqueous ammonium hydroxide solution and extracted with methylene chloride. The organic portions were combined, washed with 0.5 M hydrochloric acid, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography using a 95: 5 mixture of chloroform and methanol to give a solid which was deprotected with hydrochloric acid and ethyl acetate as described above to give the title product as a white solid. material.

¹ H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 8.15 (t, 1H), 7.307.00 (m, 9H), 4.90 (m, 1H), 4.70 (d, 1H), 4.05 and 3.95 ( 2 doublets, 1 H), 3.30-2.95 (m, 4H), 2.90-2.60 (m, 3H), 2.50 (bs, 2H), 1.90-1.65 (m, 7H), 1.60 (2 singlets, 6H), 1.48 ( m, 1H).

Examples 32 to 35 and 49

The compounds listed in Table B2 were prepared from the intermediate of Example B31, Step A using a procedure to produce the resulting product of Example B5. Instead of ethanolamine, amines were used as described below and deprotection was carried out in ethyl acetate by treatment with anhydrous hydrogen chloride. Ether was used to precipitate the hydrochloride.

Table B2

187

Molecular formula

Example R

FAB MS m / e found m / e calc. (M + l)

B32 N _{(CH3) 2} C31H44N4O3 520 521.2 B33 NHtBu C33H48N4O3 548 549.2 B34 / - \ _WITH C33H46N4O3S 578 579.2 B49 NHCH ₂ CH ₃ C31H44N4O3 520 521.2

Example B35

To a solution of 0.50 A of Example B31 in 5 mL of the acidic intermediate of step

1,26-dichloroethane was added 0.16 g of carbonyldiimidazole and the mixture was stirred at 60 ° C for 30 minutes. The reaction mixture was then cooled to room temperature and 0.12 g of 2-aminopyrazole was added to half of the reaction mixture and the mixture was heated to 60 ° C for 1 hour, then cooled to room temperature and stirred for a further two days. The reaction mixture was poured into 0.5 M aqueous hydrochloric acid solution and extracted with methylene chloride. The organic extracts were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, evaporated and the residue purified by flash chromatography using hexane

188 and acetone 1: 1 as eluent. The purified material was deprotected by treatment with a mixture of hydrochloric acid and ethyl acetate as described above to give the title product as a white solid.

FAB-MS calc. For 32 32 ^ ^ ^ ^ ^ ^ ^ 03 m 03: m / e calcd 558 found 559.2 (m + 1).

Example B36

The resulting product was prepared according to the procedure of Example B5 except that morpholine was used instead of ethanolamine.

^X H-NMR (400 MHz, CD 3 OD mixture of rotamers): 7.30-6.95 (m, 9H);

4.95 (m, 1 H), 4.68 (d, 1 H), 4.00 and 3.95 (2 doublets, 1 H), 3.59 (m, 4 H), 3.35 (m, 4 H), 3.25-2.90 (m, 4 H), 2.80 50 ( m, 5H), 1.90-1.65 (m, 7H);

1.63 (s, 3H), 1.60 (s, 3H), 1.47 (m, 1 H).

Example B37

NHSO ₂ Ph

189

Stage A:

OH

5 ml of triethylamine and 2.8 ml of CBZ-C1 are added to a stirred solution of 5.0 g of the piperidine intermediate prepared in Step B of Example BI at 0 ° C. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The mixture was poured into aqueous ammonium chloride solution and extracted with methylene chloride. The organic layer was washed with 0.5 M hydrochloric acid solution, dried over magnesium sulfate and evaporated. The crude residue was dissolved in 25 mL of methanol / water, 3 equivalents of sodium hydroxide were added and the mixture was stirred for 2 hours. Then the reaction mixture was acidified to pH 2 by addition of 2 M HCl and extracted with ethyl acetate. The organics were combined, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to give the resulting acid as a foam.

Stage B:

NHSO ₂ Ph

190

To a solution of 0.225 g of the above acidic intermediate in 10 ml of methylene chloride was added 0.12 g of benzenesulfonamide, 0.093 g of DNAP and 0.164 g of EDC, and the mixture was stirred overnight. The reaction mixture was washed with 2 x 10 mL 0.5 M HCl, dried over sodium sulfate and evaporated. The crude residue was dissolved in 10 ml of methanol, 0.10 g of 10% palladium on charcoal was added, and the mixture was hydrogenated at 50 psi overnight. The catalyst was filtered off through a pad of celite and the filtrate was evaporated to give the piperidine derivative, which was used in the next step without further purification.

The piperidine intermediate is bound to intermediate 3 and the protecting groups are removed by treatment with hydrochloric acid in ethyl acetate as described above to give the title product as a white solid.

FAB-MS for C35H ₄₄ N ₄ 0gS m / e calc 633.1 found 632 (M + 1).

Example B38

Stage A:

COOH

191

Said intermediate was prepared as described in Example B37, Step A except that di-tert-butyl carbonate was used in place of CBZ-C1.

Stage B:

To a stirred solution of 2.90 g of the acid prepared in Step A in 30 ml of anhydrous THF was added 2.5 ml of triethylamine and 1.25 ml of ethyl chloroformate, and the mixture was stirred for 30 minutes. 10 ml of the reaction mixture were separated and 20 ml of aqueous ammonium hydroxide solution was added to the remaining mixture, stirred for 30 minutes and then extracted with ethyl acetate. The organic extracts were combined, washed with 0.5 M HCl, then saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and evaporated to an oily residue. This material was dissolved at 0 ° C in a mixture of 20 mL of methylene chloride and 20 mL of pyridine, 1.1 mL of POCl ₃ was added, and the mixture was stirred for 30 minutes. The reaction mixture was poured into saturated aqueous sodium chloride solution, washed with 0.5 M hydrochloric acid solution, saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over sodium sulfate and evaporated. Flash chromatography of the residue using hexane: ethyl acetate (5: 1) as eluent gave the title compound.

192

Stage C:

To a solution of 1.0 g of the nitrile intermediate prepared in Step B in 20 ml of toluene was added 1.96 g of trimethyltin azide and the mixture was heated under reflux for 18 hours. The excess azide which precipitated upon cooling to room temperature was filtered off. The filtrate was evaporated and partitioned in half. To the half was added 10 mL of ethyl acetate and a trace of methanol, and hydrogen chloride gas was bubbled through the mixture for 5 minutes, then the mixture was stirred for 1 hour. After this time, ethyl ether was added and the mixture was evaporated to a gummy material which was washed with ethyl ether and dried in vacuo to give a brownish solid. 400 MHz NMR (CDCl 3) showed the desired tetrazole intermediate.

To 0.30 g of piperidine hydrochloride obtained above in 0.4 ml of chloroform was added 0.47 g of intermediate 3, 0.16 g of HOBT, 0.45 ml of N-methylmorpholine and 0.29 g of EDC, and the mixture was stirred overnight. The mixture was poured into 0.5 M HCl solution and extracted with chloroform. The organic extracts were combined, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to a gummy residue which was purified by flash chromatography eluting with chloroform, methanol and ammonia (85: 15: 1) to give 0. 15 g of the desired product.

193

Stage D:

This material was prepared from the intermediate obtained in Step C by treatment with hydrochloric acid in ethyl acetate as described above.

¹ H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 8.15 (t, 1H), 7.60

7.05 (m, 9H); 4.90 (m, 1H); 4.60 (d, 1H); 4.05 and 3.95 (2 doublets, 1H); 3.30-3.10 (m, 4H); 3.10-2.60 (m. 5H); 1.90 -1.65 (m. 9H); 1.60 (s. 6H);

1.50 (m, IH).

Example B39

To a solution of 0.030 g of the intermediate prepared in Step C of Example B38 in 2 ml of anhydrous acetone was added 13 mg of powdered potassium carbonate and 0.006 ml of methyl iodide, and the mixture was stirred overnight at room temperature. The reaction mixture was then poured into saturated sodium chloride solution and extracted with chloroform. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to give an alkyl product which was deprotected with hydrochloric acid in ethyl acetate and then used without further purification. The title compound (0.006 g) is obtained as a mixture of isomers.

FAB-MS calculated for m / e 531

Example B40

Stage A:

The intermediate was prepared by BOC-material prepared in a step analogous to Method B of Example B38.

than

195

Stage B:

Hydrogen chloride gas was bubbled into the stirred solution of the nitrile from Step A (1.0 g) in anhydrous ethanol (10 mL) at 0 ° C for 1 h. The reaction mixture was then sealed and stored in a freezer overnight. Thereafter, excess hydrogen chloride gas is removed by bubbling nitrogen for 1 hour, then ethyl ether is added to precipitate the imino ether intermediate, but only an oily material is formed. The solvent was evaporated on a rotary evaporator and the gummy residue was dissolved in methylene chloride and evaporated, repeated once more. Ethyl ether is then added again to give the iminoether hydrochloride as a foam.

To 0.20 g of this intermediate in 5 ml of dichloromethane was added 0.073 ml of diisopropylethylamine and 0.030 g of formylhydrazine, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with methylene chloride. The organic extracts were combined, washed with saturated brine, dried over sodium sulfate and evaporated. The residue obtained is dissolved in 5 ml of xylenes and the solution is refluxed for several hours. The reaction mixture was cooled to room temperature and the xylenes were evaporated. The residue was hydrogenated in 2 ml of methanol containing 40 mg of 20% palladium hydroxide catalyst for 2 hours. The piperidine intermediate thus obtained was coupled to intermediate 3 under standard conditions in the presence of EDC / HOBT as previously described. The crude product was purified by flash chromatography using a 95: 5: 1 mixture of methylene chloride, methanol and ammonia as the eluent. Removal of the BOC protecting group by treatment with hydrochloric acid in ethyl acetate affords the title product as a white solid.

¹ H-NMR (400 MHz, CD 3 OD, mixture of rotamers): 9.15 (s, 1H), 8.16 (bs, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.60 ( bs, 1H), 4.10 and 3.95 (2 doublets, 1H), 3.30-3.00 (m, 4H), 3.00-2.60 (m, 5H), 1.90-1.60 (m, 9H), 1.62 (s, 3H), 1.60 (s, 3H), 1.40 (m, IH).

Example B41

The resulting product in Example B40, but prepared in an analogous manner to using N-carboxymethylhydrazine instead of N-formylhydrazine.

¹ H-NMR (400 MHz, CD ₃ OD, mixture of rotamers): 7.30-7.02 (m, 9H), 4.90 (m, 1H), 4.60 (d, 1H), 4.05 and 3.95 (2 duplicates, m), 3.30-2.95 (m, 5 H), 2.80-2.60 (m, 4 H), 1.90-1.70 (m, 9 H), 1.60 (s, 3 H), 1.59 (s, 3 H),

1.39 (m, IH).

Example B42

ABOUT

NH ₃ Cl

ABOUT

197

Stage A:

To a solution of 3.0 g of the acid intermediate prepared in Step A of Example B37, 0.70 ml of oxalyl chloride and three drops of DMF were added in 50 ml of benzene, and the mixture was stirred at room temperature for 2 hours. Then the benzene was evaporated and the residue was dissolved in acetone at 0 ° C. The solution is then added

1.59 g of sodium azide in 5 ml of water and the mixture was stirred at 0 ° C for 1 hour. The reaction mixture was diluted with ether and water and the organic layer was separated. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to an oily residue. This material was dissolved in anhydrous toluene and the solution was refluxed for 4 hours. The reaction mixture is then evaporated and the isocyanate obtained is stored in a freezer.

To 0.40 g of the isocyanate thus obtained was added 0.80 ml of triethylamine and 0.20 g of methylamine hydrochloride in toluene and stirred overnight. The reaction mixture was poured into aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were combined, washed with saturated brine, dried (MgSO 4) and evaporated to give methyl urea which was used without further purification.

Stage B:

198

The piperidine intermediate prepared in Step A is hydrogenated in the presence of palladium hydroxide in methanol to remove the CBZ protecting group, then bound to intermediate 3, purified and deprotected with hydrochloric acid in ethyl acetate to afford the title product.

1 H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 8.10 (m, 1H), 7.40 7.00 (m, 9H), 4.95 (m, 1H), 4.63 (d, 1H), 4.10 and 4.00 (2 doublets, 1 H), 3.40-3.10 (m, 4 H), 2.85-2.90 (m, 2 H), 2.70 (s, 3 H), 2.80-2.60 (m, 3 H), 1.90-1.62 (m, 7 H) 1.63 (s, 3H), 1.60 (s, 3H), 1.40 (m, 1 H).

by breaking the acid described above,

Example B43

0.20 g of the isocyanate intermediate prepared in Step A of Example B42 was refluxed in 5 mL of 6 M aqueous HCl overnight. The reaction mixture was washed with ethyl ether and the ether layer was discarded. The aqueous layer was basified to pH 10 by addition of aqueous potassium carbonate solution and then extracted with methylene chloride. The organic extracts were combined, washed with saturated sodium chloride solution, dried over potassium carbonate and evaporated. The crude amine thus obtained is converted to methanesulfonamide by treatment with methanesulfonyl chloride and triethylamine in dichloromethane. After conventional work-up of the mixture, the CBZ group is removed by hydrogenation and work-up of the mixture as above to give the title product.

199 1H-NMR (400 MHz, CD-iodo, mixture of rotamers): 7.30-7.00 (m, 9H), 4.85 (m, 1H), 4.55 (d, 1H), 4.00 and: 3.90 (2 doublets, 1H), 3.30-3.10 (m, 4H); 2.80-2.83 (m, 2H); 2.80 (2 s, 3H); 2.80-2.60 (m. 3H); 1.90-1.65 (m. 9H); 1.60 (s. 3H) 1.56 (s, 3H); 1.55 (m, 1 H).

Example B44

Stage A:

HHCI

To a solution of 5.0 g of the pyridine aldehyde intermediate prepared in Step A of Example BI in 100 ml of methanol was added 4.0 g of sodium cyanide, 5 ml of glacial acetic acid and 20 g of manganese dioxide, and the mixture was stirred for 2 hours. The solid was then filtered through a pad of celite and the filtrate was evaporated. The residue is dissolved in 100 ml of saturated sodium bicarbonate solution and extracted with 3 x 100 ml of ethyl acetate. The organic extracts were combined, washed with saturated brine, dried over sodium sulfate and evaporated to give pyridine methyl ester. This material was dissolved in methanol and 5 ml of saturated hydrogen chloride in ethyl acetate was added, then the mixture was evaporated to give the title hydrochloride.

200

To 2 g of the pyridine hydrochloride thus obtained in 15 ml of methanol was added 0.225 g of platinum oxide and the mixture was hydrogenated at 50 psi on a Parr apparatus for a total of 2 hours. The catalyst was then filtered through a pad of celite and washed with methanol. The filtrate was evaporated to give the piperidine hydrochloride as a foam (2.17 g).

Stage B:

The resulting product is obtained from the intermediate prepared in step A and from intermediate 3 as described above. 1 H-NMR (400 MHz, CD 3 OD, mixture of rotamers): 8.10 (t, 1H), 7.78 (dd, 1H), 7.50-7.00 (m, 8H), 4.90 (m, 1H), 4.55 ( d, 1H), 3.94 and. 3.90 (2 doublets, 1 H), 3.85 (s, 3 H), 3.80-3.60 (m, 1 H), 3.05 (dt, 1 H), 2.70-2.50 (m, 4 H), 1.90-1.50 (m, 6 H), 1.55 (s, 3H), 1.50 (s, 3H), 1.40 (m, 1H).

Example B45

201

The resulting product was prepared from the ester intermediate prepared in Step A of Example B44 in an analogous manner to the tetrazole compound prepared according to Example B38.

1 H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 7.60-7.45 (m, 2H),

7.45-7.38 (m, 2H); 7.30-7.10 (m, 5H); 4.90 (m, 1H); 3.95 and 3.90 (2 dubiets, 1H); 3.30-3.00 (m, 2H); 2.80-2.55 (m, 4H), 1.90-1.63 (m, 7H), 1.65-1.50 (4singlets, 6H), 1.40 (m, 1H).

Example B46

Stage A:

The title compound was prepared in a similar manner to the protected piperidine acid prepared according to Example B37, Step A.

Stage B:

HHCI

N.

N-N

202

This intermediate was prepared from the intermediate prepared in Step A using the carbonyldiimidazole procedure described in Example B35 except that aminotetrazole was used instead of aminopyrazole.

Stage C:

The resulting product was synthesized from the pyridine intermediate prepared in step B and from intermediate 3 as described above.

FAB-MS calc. For C ₂ gHggNgO ₃ m / e calculated 532 found 533.1 (m + 1)

Example B47

Stage A:

OH

203

To a solution of 0.30 g of imino ether intermediate of step B of Example B40 in 10 mL ethanol was added 0.124 g of dihydroxyacetone and heated at 60 ^e C with ammonia in a pressure vessel for 16 h. The mixture was cooled to room temperature and the solvent was evaporated. The residue is purified by flash chromatography to give 0.129 g of the desired product which still contains impurities.

Stage B:

The intermediate prepared in Step A is worked up to the title compound after deprotection of CBZ, coupling to intermediate 3, after purification and final deprotection by treatment with ethyl acetate / hydrochloric acid as described above.

@ 1 H-NMR (400 MHz, CDCl3 OD, mixture of rotamers): 8.18 (2 triplet, 1H), 7.30 (s, 1H), 7.30-7.00 (m, 9H), 4.90 (m, 1H), 4.56-4.55 (singlet, overlapping doublet, 3H), 4.05-3.95 (2-doublets, 1H), 3.30-2.95 (m,

4H), 2.95-2.60 (m, 5H), 1.90-1.65 (m, 7H), 1.63 (s, 3H), 1.60 (s, 3H),

1.45 (m, IH).

Example B48

204

Stage A:

To a solution of 1.0 g of the ester prepared in Step B of Example BI in 50 mL of anhydrous THF at 0 ° C was added 0.20 g of lithium aluminum hydride and the mixture was stirred overnight at room temperature. The reaction is stopped by adding 10 ml of water and 10 ml of 30% aqueous sodium hydroxide solution at 0 ° C. The precipitate was filtered off and washed with ethyl acetate. The ethyl acetate extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude alcohol was dissolved in 30 mL of methylene chloride and 1.3 mL of triethylamine, and 1.4 g of di-tert-butyl carbonate was added at 0 ° C and the mixture was then stirred at room temperature for 2 hours. The mixture was poured into saturated sodium bicarbonate solution and the resulting mixture was extracted with methylene chloride. The organic solutions were combined, washed with 0.5 M HCl solution, saturated sodium chloride solution, dried over sodium sulfate and evaporated. The material was purified by flash chromatography (5: 1 hexane / acetone).

The alcohol obtained is dissolved in 10 ml of methylene chloride at 0 ° C, 0.45 ml of triethylamine and 0.14 ml of methanesulfonyl chloride are added and the mixture is stirred for 1 hour. The reaction mixture was diluted with water and extracted with methylene chloride. The organic extracts were combined, washed with 0.5M HCl solution, saturated sodium chloride solution, dried over sodium sulfate and evaporated. The crude mesylate was heated together with 0.20 g of sodium salt

1,2,4-triazole at 60 ° C for 3 hours in 10 mL of anhydrous DMF. The reaction mixture was cooled to room temperature and aqueous ammonium chloride solution was added. The reaction mixture was then extracted with 3 x 15 mL ethyl ether. The organic extracts were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting triazole derivative was used without further purification.

Stage B:

The BOC protecting group is removed from the piperidine synthesized in Step A by treatment with TFA as described above and the resulting mixture is then worked up by coupling with intermediate 3, purifying and finally deprotecting with ethyl acetate / HCl.

FAB-MS calcd for m / e 530 found 531.4 (m + 1)

Example B50

The resulting product was prepared by the procedure of Example B40, Step B, except that Intermediate 1 was used instead of Intermediate 3.

@ 1 H-NMR (400 MHz, CD3OD, mixture of rotamers): 8.32 and 8.20 (2 doublets, 1H), 7.65 and 7.58 (2 doublets, 1H), 7.40 and 7.35 (2 doublets, 1H);

1H), 7.25-7.00 (m, 6H), 6.50 (d, 1 H), 5.30-5.20 (m, 1 H), 4.58 a. 4.55 (2

206 doublets, 1H), 4.10 and 3.95 (doublets, 1 / 2H), 3.90 (d, 1 / 2H), 3.40-3.00 (m, 7H), 2.70-2.45 (m, 3H), 2.80-2.50 (m) 2 H, 1.60 (s, 6H), 1.34 (d, 1 H), 0.95 (d, 1 / 2H), 0.70 (dt, 1 / 2H).

Example B50A

To a solution of 0.330 g of the acid intermediate prepared in Step A of Example B15 in 3.3 ml of anhydrous THF was added 0.196 g of carbonyldiimidazole and the mixture was heated at 60 ° C for 2 hours. A small portion of the reaction mixture was then removed, 4-aminobutanol (0.10 ml) was added to the remaining solution, and the mixture was heated for 2 hours. The reaction mixture was evaporated, the residue was dissolved in chloroform, washed twice with water and once with 1M potassium hydrogen phosphate solution and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to a residue which was subjected to preparative chromatography on thin layer on a 1 mm plate using a 90: 10: 1 mixture of chloroform, methanol and ammonia as eluent to give the desired intermediate.

To a solution of 0.20 g of this material in 2 ml of anisole was added 3-4 ml of TFA and the mixture was allowed to stand at room temperature for 30 minutes. The volatiles were then removed under reduced pressure and the residue was partitioned between chloroform and 1M potassium hydrogen phosphate solution, then the solution was basified by adding sodium hydroxide to a pH greater than 9. The organic phase was separated, the aqueous phase was extracted with chloroform. organic

The 207 aliquots were combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to a gummy material which was subjected to preparative thin layer chromatography on a 1 mm plate using a 90:10 mixture of chloroform, methanol and ammonia. 1: 1 to give the desired product.

1 H-NMR (200 MHz, CDCl 3, mixture of rotamers): 8.24 (d, J = 8) δ, 7.427.07 (m); 6.16 (dd, J = 12.4); 4.97-4.8 (m); 4.69 (bd, J = 13); 3.93 (bt, J-10); 3.75-3.64 (m); 3.54-3.4 (m); 3.35-3.16 (m); 3.07 (quartet, J = 13); 2.77-2.5 (m); 1.97-1.42 (m); 1.34 (s).

FAB-MS for C ₃₁ H ₄₄ N ₄ O ₄ m / e found 537.1 (m + 1). Molecular Weight 536,34.

A solution of 0.150 g of the above free base was lyophilized from 0.50 mL of acetic acid and 0.030 mL of concentrated hydrochloric acid to give the title product.

Example B50B

The product was prepared in an analogous manner to that of Example B50A, but ethanolamine was used instead of 4-aminobutanol.

1 H-NMR (200 MHz, CDCl 3, mixture of rotamers): 8.22 (d, J = 8) δ, 7.457.05 (m); 6.58 (dt, J = 16, 5); 4.88 (bs); 4.64 (bd, J = 12); 3.90 (t, J = 11);

3.79 (bs); 3.65-3.50 (m); 3.25-3.15 (m); 3.05 (quartet, J = 12); 2.8-2.5 (m); 2.32 (vbs); 2.0-1.77 (m); 1.77-1.45 (m); 1.35 (s).

208

FAB-MS for C 29 H 40 N 4 O 4 m / e found 509.2 (m + 1). Molecular Weight 508,30.

A solution of 0.029 g of the above base was lyophilized from a mixture of 0.50 ml of acetic acid and 0.010 ml of concentrated hydrochloric acid to give the title product.

Example B50C

Stage A:

OH

To a solution of 0.379 g of the free base, prepared by alkalization by adding NaOH up to a pH greater than 9 and extracting with chloroform from the intermediate prepared in Step A of Example B44, 5.5 ml of a 1 M solution of lithium aluminum hydride in THF are added. is stirred overnight. The reaction mixture is treated with 10 ml of 30% aqueous NaOH, the organic phase is decanted and the resulting pasty material is extracted with ethyl acetate. The organic extracts were combined, dried (MgSO 4) and evaporated. The residue is purified by preparative chromatography

209 on a thin layer on a 1 mm thick plate to give the desired amino alcohol.

^X H-NMR (200 MHz, CDC1 _3, mixture of rotamers): 738-7 J3 _(m); 4.75 (s); 3.22 (bd, J = 12Hz); 3.1-2.92 (m); 2.81 (td, J = 10.4 Hz); 2.13 (bs); 1.85-1.6 (m).

Stage B:

The intermediate prepared in Step A is bound to (2R) -N-tert-BOC-5-phenylpentanoic acid and treated under standard conditions using EDC / HOBT as described above and then purified by preparative thin layer chromatography on a plate of thickness. 1 mm.

To a solution of 0.145 g of the thus obtained bound product in 2 ml of CDCl3 is added 0.50 ml of 2-chloroethyl isocyanate and the mixture is heated at 60 for 6 hours and then left to stand at room temperature overnight. The mixture was then subjected to preparative thin layer chromatography using 1: 1 hexane: ethyl acetate as the eluent to give 0.11 g of the title carbamate.

^X H-NMR (200 MHz, CDC1 _3, mixture of rotamers): 7:45 to 7:05 (m); 5.50 (bd, J = 6); 5.19 (s); 5.14 (bs); 4.86-4.45 (bdd?); 4.11 (bd, J = 7); 3.93 (bt, J = 12); 3.72-3.42 (bm); 3.2-2.88 (m); 2.8-2.5 (bm); 1.95-1.55 (m); 1.44 (s).

210

Stage C:

The intermediate prepared in Step B was deprotected with ethyl acetate / HCl and the hydrochloride thus obtained was coupled to N-t-BOC-α-methylalanine under standard conditions using EDC / HOBT. The material was then purified by preparative thin layer chromatography using a 1 mm plate and 1: 1 hexane / ethyl acetate as eluent.

1 H-NMR (200 MHz, CDCl 3, mixture of rotamers): 7.407.04 (m); 5.19 (s); 5.17 (bs); 4.98 (s); 4.92 (bs); 4.72 (bd, J = 13); 4.54 (bd, J = 13); 4.18-4.04 (m); 3.95 (bt, J = 13); 3.68-3.45 (m); 3.2-2.85 (m); 2,782.47 (m); 2.0-1.6 (m); 1.6-1.4 (m); 1.44 (s).

About 85 mg (0.13 mmol) of the product obtained above is dissolved in 1.0 mL of DMSO-dg containing 38 mg, 0.37 mmol of LiOAC.2H2O and 30 mg, 0.2 mol of Mal. The solution was heated overnight in an oil bath at 80. The reaction mixture was dried under a stream of nitrogen to give a gum which was then partitioned between chloroform and water, the organic phase was separated, dried over anhydrous magnesium sulfate, filtered and evaporated. to the gummy product under reduced pressure was purified by preparative thin layer chromatography using a 20 cm x 20 cm x 1 mm plate using ethyl acetate and hexane 1: 1 to give 85 mg of the product.

¹ H-NMR (200 MHz, CDCl 3, mixture of rotamers): 7.40-7.04 (m), 5.19 (s); 5.17 (bs); 4.98 (s); 4.92 (bs); 4.72 (bd, J = 13); 4.54 (bd, J = 13); 4.184.04 (m); 3.95 (bt, J = 13); 3.68-3.45 (m); 3.2-2.85 (m); 2.78 - 2.47 (m); 2.0-1.6 (m); 1.6-1.4 (m); 1.44 (s): 7.4 - 7.0 (m); 7.88-7.69 (bm); 5.4 (s);

211

5.14 (s); 4.95-4.74 (m); 4.67 (bd, J = 12); 4.38 (bd, J = 13); 4.15-4.02 (m); 3.93 (bt, J = 14); 3.50-3.30 (m); 3.18-2.8 (m); 2.75-2. 35 (bm); 2.01 (s); 1.9-1.7 (bm); 1.5-1.3 (m); 1.40 (s).

Stage D:

To 49 mg of the intermediate of step C in 0.5 ml of methanol was added 1-2 ml of concentrated sulfuric acid. The mixture is allowed to stand overnight, then 1 M potassium hydrogen phosphate solution is added, the reaction mixture is evaporated to dryness under a stream of nitrogen and the residue is partitioned between chloroform and 1 M potassium hydrogen phosphate, pH is adjusted to greater than 9 by addition of NaOH. The aqueous phase is extracted several more times with chloroform. The organic phases were combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting gum was subjected to preparative thin layer chromatography on a 20 cm.times.20 cm.times.1 mm GF silica gel plate using 1:10:90 concentrated ammonia, methanol and chloroform. Two main belts are formed. The faster strip is isolated to give the final product.

1 H-NMR (200 MHz, CDCl 3, mixture of rotamers): 7.407.05 (m); 5.44-5.12 (m); 5.18 (s); 5.12-4.8 (m); 5.05 (s); 4.69 (bd, J = 12); 4.52 (bd, J = 12); 4.12 (bs); 3.93 (bt, J = 12); 3.78-3.63 (m); 3.44-3.24 (bm); 3.24-2.83 (m); 2.83-2.5 (m); 2.01-1.6 (m); 1.6-1.35 (m); 1.45 (s).

FAB-MS for C 13 H 14 N 2 O 2 O 2 m / e found 639.3 (m + 1). Molecular Weight 638.37.

212

A solution of 23 mg, 0.042 mmol of the free base obtained above in 0.5 mL of concentrated acetic acid in a vial of 0.005 mL, 0.06 mmol of concentrated HCl was frozen and lyophilized overnight to give the title product.

Stage A:

Example B51

To a solution of 4.1 g of the intermediate prepared in Step A1 of Example B12 in 25 ml of ethanol was added 25 ml of 6M NaOH solution and the mixture was stirred for 12 hours. The mixture was diluted with water and extracted with ether. Discard the organic layer. The mixture was diluted with water and extracted with ethyl ether. The organic layer was discarded again. The aqueous layer was cooled to 0 ° C, acidified with concentrated HCl and then extracted with ethyl ether. The organic layer was dried over sodium sulfate, filtered and evaporated to give 2.57 g of crude acid. 438 mg of this acid was dissolved in methanol and hydrogenated using palladium hydroxide at 100 psi for 16 hours. The mixture was then filtered through Celite and the filtrate evaporated in vacuo to give 370 mg of the desired product.

213

Stage B:

BOC

I

N

To 100 mg of the intermediate from Step A in chloroform was added 0.35 ml of morpholine, 95 mg of EDC and 49 mg of HOBT. The reaction mixture was stirred at room temperature for 12 hours, then diluted with methylene chloride and washed with water and saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative thin layer chromatography using hexanes / ethyl acetate 1: 1 to give 71 mg of product.

Stage C:

NH-BOC

CO O I

M

To 71 mg of the intermediate from Step B in ethyl acetate was added hydrogen chloride gas at 0 ° C by bubbling. Bubbling takes 15 seconds. The mixture was allowed to stand at room temperature for 30 minutes and then evaporated to 64 mg of solid. 32 mg of this crude product were mixed with 43 mg of intermediate 1, 29 mg of EDC, 15 mg of HOBT and 21 ml of triethylamine in 2 ml of chloroform. The reaction mixture was stirred at room temperature for 3 hours, then poured into water and extracted with methylene chloride, dried over sodium sulfate and evaporated. Purification by preparative thin layer chromatography using 20: 1 methylene chloride: methanol afforded two diastereomers, 14 mg of the less polar diastereomer d 2 and 16 mg of the more polar diastereomer d ₂ .

Stage D:

mg of the less polar diastereomer of Step C was dissolved in ethyl acetate and hydrogen chloride gas was bubbled through the solution at 0 ° C for 15 seconds. After standing at room temperature for 30 minutes, the mixture was evaporated to give 10 mg of the title compound.

FAB-MS found 546.3 (M + 1).

Example B52 (cis, d ₂ )

215 mg of the title compound were prepared from 16 mg of the more polar diastereomer d ₂ obtained in Step C, Example B51, following step D of Example B51.

FAB-MS found 546.3 (M + 1).

Compounds 1 to 7 of Table B3 below were prepared as described above using various amines in the coupling step. Details are given in steps B, C and D of Example B51.

Table B3

MS FAB-MS (M + 1)

1 di + d2 thiomorpholine 562.2 2 d i + d2 pyrrolidine 530.2 3 di + d2 N-methylpiperazine 559.3 4 di + d2 piperidine 544.3 5 d i + d2 ethanolamine 520.2 6 dj + d2 dimethylamine 504.3 7 dj + d2 glycine ethyl ester 562.3

216

Example B53 (cis, d ^)

Stage A:

Hydrogen chloride gas was bubbled in ethyl acetate in ethyl acetate for 15 seconds at 0 ° C, and the solution was allowed to stand for 30 minutes at room temperature. The mixture was then evaporated to dryness to give the crude product. 99 mg of this crude product is dissolved in 3 ml of chloroform, and 107 mg of Nt-BOC-O-benzyl-D-serine, 92 mg of EDC, 47 mg of HOBT and 67 ml of triethylamine are added, the solution is stirred at room temperature for 3 hours. then pour into water. The resulting mixture was extracted with methylene chloride, the extract was dried over sodium sulfate and evaporated. The residue was purified using RPLC (chromatatron, methylene chloride / methanol 20: 1) to give 97 mg of the title product.

217

Stage B:

NH-BOC

C-N O o

cis, d1 and d2

A solution of 97 mg of the intermediate from Step B in ethyl acetate was bubbled through gaseous hydrogen chloride 15 at 0 ° C and then allowed to stand at room temperature for 30 minutes. Then the reaction mixture was evaporated and the residue was dissolved in 2 ml of chloroform, 52 mg of Nt-BOC-α-methylalanine, 62 mg of EDC, 36 mg of HOBT and 40 ml of triethylamine were added to the solution. After standing at room temperature for 64 hours, the reaction mixture was poured into water and extracted with methylene chloride. The extracts were combined, dried over sodium sulfate, filtered and evaporated to give a solid residue as a mixture which was purified by RPLC (chromatatron, methylene chloride and methanol 20: 1) to yield 65 mg of the less polar diastereomer d 23 and 23. mg of the more polar diastereomer d ₂ .

Stage C:

218 mg of the less polar diastereomer (d) of Step B was treated with hydrogen chloride gas in ethyl acetate by bubbling through the bubble for 15 seconds at 0 ° C. The mixture was allowed to stand at room temperature for 30 minutes, then evaporated to give the title compound (58 mg).

FAB-MS found 537.4 (M + 1).

Example B54

mg of the product was prepared from 23 mg of the more polar diastereomer d ₂ obtained in step C, example B53, following step B of example B51.

FAB-MS found 537.3 (M + 1).

Compounds 1 to 6 of Table B4 were prepared as described above using various amines. Preparation details are given in Example B51, Step B, and Examples B53, A, B and C, respectively.

C — R O ds

219

R FAB-MS (M + 1). 1 di + d2 thiomorpholine 553.3 2 di + d2 pyrrolidine 521.3 3 di N-methylpiperazine 550.4 4 d ₂ N-methylpiperazine 550.4 5 dj + d2 piperidine 535.4 6 di + d2 dimethylamine 495.2

Example B55 (cis, d-£ + d2)

Hydrogen chloride gas was bubbled through a solution of the intermediate from Example B51 Step B in ethyl acetate for 15 seconds at 0 ° C, the reaction mixture was allowed to stand at room temperature for 30 minutes and then evaporated to the crude product. To 209 mg of this material in 10 ml of chloroform was added 295 mg of intermediate 3, 202 mg of EDC, 105 mg of HOBT and 147 ml of triethylamine, and the mixture was stirred at room temperature for 16 hours, then poured into water. The mixture was then extracted with methylene chloride, dried over sodium sulfate, evaporated and the residue purified by RPLC (chromatatron, methylene chloride / methanol 20: 1) to give 387 mg of the title product. The mixture of diastereomers in ethyl acetate thus obtained was treated by bubbling hydrogen chloride gas at 0 ° C for 15 seconds and then allowed to stand at room temperature for 30 minutes. The mixture was evaporated to give 330 mg of product.

FAB-MS found 535.3.

220

The compounds of Table B5 were prepared by known procedures using ethanolamine instead of morpholine as described above in Example B51, Step B, and in Example B53, Steps A, B, and C, using intermediate 3.

Table B5

di d2

R ethanolamine ethanolamine

FAB-MS (M + 1).

509.1

509.2

Stage A:

Example B56

NCO

221

To 1.15 g of the intermediate from Step A of Example B51 in 80 ml of benzene was added 365 ml of oxalyl chloride and two drops of DMF at 0 ° C and the mixture was then stirred at the same temperature for 10 minutes and then at room temperature for 2 hours. to give the acyl chloride. To a solution of this acyl chloride in 10 mL of acetone at 0 ° C was added 741 mg of sodium azide in 3 mL of water, and the mixture was stirred at room temperature for 45 minutes. The mixture was then extracted with ether, washed with water and saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to the acylazide which was dissolved in 35 ml of toluene and refluxed for 12 hours to give 1.02. g of isocyanate.

Stage B:

H HCl I

A solution of 55 mg of the intermediate from Step A and 1247 mg of 2- (methylthio) ethylamine in 5 ml of toluene was refluxed for 1 hour. The reaction was quenched by the addition of 1 M HCl solution, extracted with ether, and dried over sodium sulfate. The mixture was evaporated and the residue was purified (chromatatron, 20: 1 methylene chloride: methanol) to give the desired urea derivative. Removal of the BOC protecting group under the above conditions affords 40 mg of the desired product.

222

Stage C:

To 20 mg of the intermediate of step B in 2 ml of chloroform was added 28 mg of intermediate 1, 19 mg of EDC, 10 mg of HOBT and 14 ml of triethylamine. the reaction mixture was stirred at room temperature for 16 hours and then poured into water. The resulting mixture was extracted with methylene chloride, and the extract was dried over sodium sulfate. The mixture was evaporated and the residue was purified (chromatatron, methylene chloride / methanol 20: 1) to give the desired product. The mixture was treated with hydrochloric acid in ethyl acetate to give 6 mg of product.

FAB-MS found 565.3 (M + 1).

The compounds of Table 6 were prepared in a known manner using various amines and alcohols.

C sharp

223

R FAB-MS 1 dl + d2 ethanol 520.3 2 dl + d2 morpholino 561.4 3 dl + d2 ethanolamine 535.3 4 dl + d2 ethylamine 519.2

Example B57 (cis, d · ^ + d2)

To a solution of 20 mg of the intermediate of Step B of Example B56 in 1 ml of chloroform was added 28 mg of intermediate 3, 19 mg of EDC, 10 mg of HOBT and 14 ml of triethylamine. The reaction mixture was stirred at room temperature for 16 hours and then poured into water. The resulting mixture was extracted with methylene chloride and dried over sodium sulfate. Evaporation and purification of the residue (chromatatron, methylene chloride / methanol 20: 1) gave the desired product, which is a mixture of diastereomers. Removal of the protecting groups by treatment with hydrochloric acid in ethyl acetate gave 8 mg of the final product.

FAB-MS found 554.4 (M + 1).

The compounds listed in Table B7 were prepared by the above procedures using ethanol and various amines.

224

Table B7

MS FAB-MS (M + 1)

1 dl + d2 ethanol 509.3 2 dl + d2 morpholino 550.4 3 dl + d2 ethanolamine 524.3 4 dl + d2 thiomorpholine 566.2

Example B58 (trans, d 1 + d ₂ )

Stage A:

225

To 2.52 g of the intermediate prepared according to Step A of Example B14 in ethanol was added 6 M NaOH solution. The mixture was refluxed for 3 hours and then evaporated. The residue was diluted with water and acidified with 0.5 M hydrochloric acid solution and then extracted with ether. The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (2.12 g).

Stage B:

BOC

I

To a solution of 15 mg of the intermediate from Step A in 1 ml of chloroform was added 9 ml of 4-amino-1-butanol, 19 mg of EDC and 77.5 mg of HOBT. The reaction mixture was then stirred at room temperature for 2 hours and then poured into water. The resulting mixture was extracted with methylene chloride, the extract was dried over sodium sulfate and evaporated, and the residue was purified (chromatatron, methylene chloride / methanol 20: 1) to give the title product.

Stage C:

trans

226

The intermediate prepared in Step B is deprotected by treatment with hydrochloric acid in ethyl acetate. The crude material was mixed with 18 mg of intermediate 1, 19 mg of EDC, 7.5 mg of HOBT in 1 ml of chloroform and 20 ml of triethylamine was added. The reaction mixture was stirred at room temperature for 4 hours, after which time it was poured into water. The resulting mixture was extracted with methylene chloride and the extract was dried over sodium sulfate. Evaporation and purification of the residue (PLC, methylene chloride / methanol 10: 1) gave 20 mg of the product as a mixture of diastereomers, treated with hydrogen chloride gas in ethyl acetate to give 18 mg of the desired product. 1 H-NMR (400 MHz, CD 3 OD, mixture of diastereomers and rotamers):

7.73 (d, 8 Hz, 1/2 H), 7.65 (d, 8 Hz, 1/2 H), 7.54-6.98 (m, 7 1/2 H), 6.87 (t, 7 Hz, 1 1/2 Hz), 5.25 (m, 1H), 4.53 (m, 1H), 3.89 (m, 1H), 3.39-2.47 (m, 10H), 1.71-0.93 (m, 5H), 1.61 (s) 3 / 2H), 1.60 (s, 3H), 1.58 (s, 3/2H), 0.41 (m, 1/2 H), 0.11 (m, 1/2 H).

FAB-MS: 548.2 (M + 1);

The compounds of the following Table B8 were prepared as described above using various amines.

Table B8

trans

227

R FAB-MS (M + 1). 1 dl + d2 ethylamine 504.3 2 dl + d2 morpholino 546.3 3 dl + d2 ethanolamine 520.2 4 dl H 556.1 5 d2 H 556.1 Example l B59 (trans, d ₂ )

Stage A:

To a solution of 915 mg of the intermediate from Step A of Example B58 in chloroform was added 590 mL of (1R, 2R) -N-methyl-pseudoephedrine, 1.14 g of EDC, and a catalytic amount of DMAP. The reaction mixture was stirred at room temperature for 12 hours and then poured into water. The mixture was extracted with methylene chloride, the extract was dried over sodium sulfate, evaporated and purified (MPLC, hexanes: ethyl acetate 3: 1) to give the diastereomers, 316 mg me228 there polar diastereomer D · N, 138 mg of the polar diastereomer d _second

Stage B:

A solution of 138 mg of the more polar intermediate from Step A in methanol was hydrogenated using palladium hydroxide on charcoal and a hydrogen pressure of 1 bar for a total of 2 hours. The mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was redissolved in ether and washed with 1M hydrochloric acid solution. Discard the aqueous layer. The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (84 mg).

Stage C:

To a solution of the intermediate of step B (16 mg) in chloroform was added glycine ethyl ester hydrochloride (21 mg), EDC (19 mg), HOBT (13 mg) and triethylamine (35 ml). After standing at room temperature for 3 hours, the mixture was diluted with methylene chloride and washed with water and saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (hexanes: ethyl acetate 1: 1) to give the title compound (16 mg).

229

Stage D:

8 mg of the intermediate from Step C was treated with hydrogen chloride gas in ethyl acetate to give the crude hydrochloride. To this material was added 8 mg of intermediate 1, 8 mg of EDC, 5 mg of HOBT and 8 ml of triethylamine in 1 ml of chloroform.

The reaction mixture was stirred at room temperature for 12 hours and then poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Evaporation and purification (PLC, 1: 2 hexanes / ethyl acetate) gave the desired product which was deprotected with hydrogen chloride in ethyl acetate to give 11 mg of the title product.

1 H-NMR (400 MHz, CD 3 OD, rotamers mixture): 7.73 (d, 8 Hz, 1/2

H), 7.54 (d, 8Hz, 1/2 H), 7.38-6.99 (m, 8H), 6.84 (d, 7Hz, 1H), 5.285.05 (m, 2H), 4.80-4.52 (m, 1H), 4.09 (m, 1H), 3.59 (m, 1H), 3.34 (m, 1H), 3.24 (m, 1H), 2.98 (m, 1H) H), 2.70-2.48 (m, 2 1/2 H), 1.701.55 (m, 1 1/2 H), 1.61 (s, 3 H), 1.60 (s, 3 H), 1.22 (t, 7 H) Hz, 3 H), 1.00 (m, 1 H), 0.57 (m, 1 H).

FAB-MS: 562.3 (M + 1).

The compounds of Table B9 were also prepared according to the procedure of Example B59

230

Table B9

d2 d2

R β-alanine methyl ester

L-alanine methyl ester

FAB-MS (M + 1).

576.3

562.3

Example B60 (trans, d ₂ )

Hydrogen chloride gas was bubbled through a solution of the intermediate from step C of Example B59 (8 mg) in ethyl acetate for 15 seconds at 0 ° C and hydrogen chloride gas was bubbled through for 15 seconds, then the mixture was allowed to stand at room temperature for 30 min. To this material was added 8 mg of intermediate 3, 8 mg of EDC, 5 mg of HOBT and 8 ml of triethylamine in 1 ml of chloroform. the reaction mixture was stirred for 12 hours at room temperature and then poured into water. The mixture was then extracted with methylene chloride and dried over sodium sulfate. Evaporation and purification (PLC, 1: 2 hexanes / ethyl acetate) gave

231 of the title compound, which was treated with hydrogen chloride gas in ethyl acetate to give 11 mg of the title hydrochloride.

FAB-MS: found 551.4 (M + 1).

The compounds listed in the following Table B10 were also prepared using various amino acids as described above.

Table B10

d2 d2

R β-alanine methyl ester L-alanine methyl ester

FAB-MS (M + 1).

565.4

551.4

Example 61 (trans, d 1 + d ₂ )

NH ₂ HCl trans

CO ₂ Et

232

Stage A:

BOC

I

The

CO ₂ Me trans

To a solution of 200 mg of the intermediate from Step A of Example B12 in methanol was added a catalytic amount of sodium methoxide in methanol, and the mixture was heated under reflux for 2 hours. The mixture was poured into 0.1 M hydrochloric acid solution and extracted with ethyl ether. The organic layer was dried over sodium sulfate, filtered and evaporated to give the title compound (190 mg).

Stage B:

BOC

I

N

CHO trans

To a solution of 120 mg of the intermediate from Step A in 2 ml of toluene was added 0.49 ml of a 1 M solution of diisobutylaluminum hydride in hexanes at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, then methanol was added and the mixture was poured into a 0.5 M hydrochloric acid solution. The resulting mixture was extracted with ethyl ether. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue is purified by PLC (hexanes / ethyl acetate 3: 1) to give 60 mg of the desired product.

233

Stage C:

BOC

To a solution of triethylphosphonacetate in 5 mL of THF was added a total of 1.45 mL of a 0.5 N solution of potassium bis (trimethylsilyl) amide in toluene at 0 ° C. The mixture was allowed to stand at room temperature for 1 hour, then 42 mg of the intermediate from step B in 1 ml of THF was added to the solution and the mixture was refluxed for 1 hour. The mixture was evaporated and the residue was purified by PLC using 4: 1 hexanes / ethyl acetate to give the title compound (50 mg).

Stage D:

mg of the intermediate from Step C was treated with 0.5 ml of TFA at room temperature. After 10 minutes, the mixture was evaporated and subjected to azeotropic distillation three times with toluene. To a solution of the residue in 1 ml of chloroform was added 62 mg of intermediate 1, 53 mg of EDC, 23 mg of HOBT and 58 ml of triethylamine. The mixture was stirred at room temperature for 3 hours and then poured into water. The resulting mixture was extracted with methylene chloride and the extract was dried over sodium sulfate and evaporated, and the residue was purified (PLC, hexanes / ethyl acetate 1: 1) to give 65 mg of the desired product.

234

Stage E:

A solution of 50 mg of the intermediate from Step D in methanol was hydrogenated in the presence of palladium hydroxide on charcoal and a hydrogen pressure of 1 bar for a total of 2 hours. The mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue is treated with hydrogen chloride gas in ethyl acetate to give 36 mg of the desired product.

FAB-MS: found 533.3 (M + 1).

Example B62

Stage A:

EtO ₂ C

235

12.9 ml of ethyl chloroformate are added to the stirred suspension

1.35 g of cuprous chloride in 200 ml of THF. Ethyl nicotinate solution is then slowly added at 0 ° C followed by 25 g of Grignard reagent (prepared from 25 g of 2-bromobenzaldehyde, 20 ml of 1,3-propanediol and 4.9 g of magnesium according to J. Org. Chem. 3490 (1986). The reaction mixture was stirred slowly for 1 hour, then poured into a mixture of saturated ammonium chloride solution and ammonia and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid solution and saturated sodium chloride solution and then dried over sodium sulfate. The solvent was evaporated to give the title product. This material was crystallized from ethyl acetate to give 25 g of pure product.

g of intermediate from step A was dissolved in 500 ml of hot ethyl acetate and the solution was cooled to room temperature. The solution is then hydrogenated in the presence of platinum oxide for 2 hours at a hydrogen pressure of 1 bar, the progress of the hydrogenation is monitored by TLC. The mixture was then filtered through a pad of celite and the filtrate evaporated in vacuo. The residue is dissolved in 150 ml of hot ethanol and then concentrated

M NaOH solution and the mixture was boiled for 10 min. The mixture was evaporated in vacuo, water was added to the residue, and the mixture was stirred at room temperature for 10 minutes, then the off-white solid was filtered off. The filtrate was extracted with methylene chloride, the extract was washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was evaporated and the residue was combined with the above filtered off-white solid to give a total of 13.6 g of product.

add an additional 75 mL of 6 to reflux236

Stage C:

CBZ

EtO ₂ C

To a solution of 10.1 g of the intermediate from Step B in 300 mL of THF at 0 ° C was added a catalytic amount of bromocresol green as an indicator and 64 mmol of NaCl 3. A 1 M hydrochloric acid solution was then added to the reaction mixture until a yellow color persisted (pH = 4.0). After 1 hour, pour the mixture into 1 M NaOH and extract with chloroform. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified on silica gel using a 10: 1 mixture of methylene chloride and methanol to remove the very polar material. The material obtained after evaporation of the filtrate was dissolved in chloroform and 6 ml of triethylamine and 4.6 ml of CBZ-C1 were added to the solution at 0 ° C. The mixture was stirred for 15 minutes, then poured into water and extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution and dried over sodium sulfate. Evaporation and purification (MPLC, 5: 1 hexanes / ethyl acetate) afforded 6.4 g of the title product.

Stage D:

CBZ

EtO ₂ C

CHO

237

To a solution of the intermediate of step C (2.17 g) in methanol (30 ml) was added 1M hydrochloric acid (5 ml) and the mixture was stirred for 1 hour. The mixture was poured into 1M NaOH solution and extracted with ether. The organic layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. The residue was purified (chromatatron, 5: 1 hexanes / ethyl acetate) to give 1.56 g of product.

Stage E:

CBZ

To a solution of 25 ml of triethylphosphonoacetate in THF was added 4.56 ml of a 0.5 N solution of potassium bis (trimethylsilyl) amide in toluene at 0 ° C. The mixture was stirred at room temperature for 1 hour, and then a solution of 860 mg of the intermediate from Step D in 10 mL of THF was added to the solution at room temperature. The mixture was stirred for an additional hour at room temperature and then quenched with 1M hydrochloric acid. The mixture was extracted with ethyl ether, the extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was purified (chromatatron, 5: 1 hexanes / ethyl acetate) to give 837 mg of the title product.

Grade F:

238

870 mg of the intermediate of step E were dissolved in methanol and the solution was hydrogenated for 1.5 hours in the presence of palladium hydroxide on charcoal under a hydrogen pressure of 1 bar. The mixture was then filtered through a pad of celite and the filtrate evaporated in vacuo. The residue was dissolved in chloroform, 749 mg of intermediate 3, 714 mg of EDC and 276 mg of HOBT were added and the mixture was stirred for 2 hours. The mixture was then evaporated and purified (chromatatron, hexanes / ethyl acetate 2: 1) to give two diastereomers, 545 mg of the less polar diastereomer d1 and 500 mg of the more polar diastereomer d2.

G grade:

Hydrogen chloride gas was added to a solution of 200 mg of the less polar diastereomer of Step F in ethyl acetate by bubbling for 15 seconds at 0 ° C. The mixture was allowed to stand at room temperature for 30 minutes and then evaporated and purified (LH-20, 100% methanol) to give 100 mg of the cis, d-product as a white solid.

¹ H-NMR (400 MHz, CDCl 3 OD, rotamer mixture): 7.28-7.06 (m, 9H), 5.09 (m, 1 H), 4.85-4.55 (m, 1 1/2 H) ), 4.17 (m, 1H), 4.10 (q, 7Hz, 2H), 3.77 (m, 2H), 3.46 (m, 1H), 3.25 (m, 1H), 3.15-2.39 (m, 9H), 1.89-1.60 (m, 5H), 1.65 (s, 2H), 1.62 (s, 2H), 1.57 (s, 2H), 1.21 (t, 7Hz, 3 H), 0.91 (t, 7 Hz, 3/2 H), 0.85 (t, 7 Hz, 3/2 H).

FAB-MS: 594.3 (M + 1);

239

3.3 mg of the desired cis, d2 - product is obtained from the polar diastereomer of Step F of Example B62 by the procedure of Step G of Example B62.

³ H-NMR (400 MHz, CD 3 OD, mixture of rotamers): 7.90-7.03 (m, 9H), 4.92-4.61 (m, 2H), 4.10 (q, 7 Hz, 2H), 4.07 ( m, 1H), 3.79 (m, 2H),

3.45 (m, 1H), 3.25 (m, 1H), 3.07-2.38 (m, 9H), 1.94-1.69 (m, 4H), 1.63 (s, 3/2H), 1.61 (s, 3 / 2H), 1.60 (s, 3 / 2H), 1.59 (s, 3 / 2H), 1.20 (t, 7 / 3H), 0.91 (t, 7 / 3H, 3H) ). FAB-MS: 594.3 (M + 1);

Example B64 (cis, d - ^)

Stage A:

240

To 30 mg of the less polar diastereomer from Step F of Example B62 in 1 mL of ethanol was added 30 mL of a 6 M NaOH solution at room temperature. The mixture was stirred for 1 hour and then evaporated. A 1 M hydrochloric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to give 20 mg of the title product.

Stage B:

To a solution of 6 mg of the intermediate from Step A in 0.5 ml of chloroform was added 0.8 ml of ethanolamine, 3.5 mg of EDC and 1.8 mg of HOBT. The reaction mixture was stirred at room temperature for 2 hours and then poured into water. The mixture was extracted with methylene chloride and dried over sodium sulfate. Evaporation and purification (PLC, methylene chloride and methanol 20: 1) gave the product which was deprotected with hydrochloric acid in ethyl acetate to give the title cis, d-product (1.6 mg).

1 H-NMR (400 MHz, CD 3 OD, rotamers mixture): 7.28-7.07 (m, 9H), 5.09 (m, 1 H), 4.85-4.62 (m, 1 1/2) H), 4.19 (m, 1H), 3.75 (m, 2H),

3.55 (t, 6 Hz, 2H), 3.45 (m, 1H), 3.34-2.84 (m, 6 1/2 H), 2.73-2.45 (m, 5 1/2 H), 1.85-1.57 (m) 1.5 H (s), 1.65 (s, 3/2 H), 1.62 (s, 3/2 H), 1.57 (s, 3/2 H), 1.56 (s, 3/2 H), 0.92 (t, 7 Hz, 3/2 H), 0.85 (t, 7 Hz, 3/2 H).

FAB-MS: 609.2 (M + 1).

241

Example B65

To a solution of 6 mg of the intermediate from Step A of Example B64 in 0.5 ml of chloroform was added 1 mg of ethylamine hydrochloride,

3.5 mg EDC, 4 ml triethylamine and 1.8 mg HOBT. The reaction mixture was stirred at room temperature for 2 hours, then poured into water and extracted with methylene chloride and dried over sodium sulfate. The mixture was evaporated and the residue was purified (PLC, methylene chloride and methanol 20: 1) to give the product which was treated with HCl in ethyl acetate to give 1.5 mg of the desired cis, d-product.

¹ H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 7.28-7.07 (m, 9H), 5.09 (m, 1 H), 4.83-4.62 (m, 1 1/2 H) ), 4.17 (m, 1H), 3.75 (m, 2H),

3.50 (m, 1H), 3.25-2.84 (m, 6H), 2.72-2.39 (m, 5H), 1.89-1.58 (m, 5H), 1.65 (s, 3 / 2 H), 1.61 (s, 3/2 H), 1.57 (s, 3/2 H), 1.56 (s, 3/2 H), 1.06 (t, 7 Hz, 3 H), 0.91 (t, 7 H) Hz, 3/2 H), 0.85 (t, 7 Hz, 3/2 H).

FAB-MS: 593.3 (M + 1).

Example B66 (cis, d ^)

242

To a solution of 8 mg of the intermediate from Step A of Example B64 in 1 mL of methylene chloride was added 2.3 mL of ethyl chloroformate and 5 mL of triethylamine at 0 ° C. The reaction mixture was then stirred at 0 ° C for 10 minutes and then at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with methylene chloride. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 2.3 mg of sodium azide in 0.2 ml of water are added to the residue in 0.5 ml of acetone at 0 ° C. The mixture was stirred for one hour at room temperature and then extracted with ethyl ether, the extract was washed with water and saturated sodium chloride solution and then dried over magnesium sulfate. Filtration and evaporation gave the acylazide, which was dissolved in 1 mL of toluene and boiled for 3 hours to give the isocyanate. The solution was then cooled to room temperature and 9 mL of 40% methylamine in water was added. After stirring for 12 hours at room temperature, 1 M HCl solution was added and the mixture was extracted with methylene chloride, dried over sodium sulfate and evaporated. The residue was purified (PLC, methylene chloride and methanol 20: 1) to give the desired urea derivative which was deprotected with HCl in ethyl acetate to give 3.5 mg of the title product.

FAB-MS: found 594.3 (M + 1).

Example B67 (cis, d ^ + d ₂ )

243 mg of the intermediate from Step E of Example B62 was dissolved in methanol and hydrogenated for 1.5 hours in the presence of palladium hydroxide on charcoal under a hydrogen pressure of 1 bar. The mixture was filtered through a pad of celite, the filtrate was evaporated in vacuo to 11 mg of free amine, and to 5.5 mg of this amine in chloroform were added 7 mg of intermediate 1, 6 mg of EDC and 4 mg of HOBT. After 12 hours the mixture was evaporated and the residue was purified (chromatatron, 2: 1 hexanes / ethyl acetate) to give an indivisible mixture of diastereomers. This mixture is treated in ethyl acetate at 0 ° C by bubbling hydrogen chloride gas for 15 seconds. The mixture was allowed to stand at room temperature for 3 minutes, then evaporated to give 8 mg of the product as a white solid.

FAB-MS: found 605.3 (M + 1).

Example B68 (cis, d-^)

H H

Stage A:

CBZ

I

N

EtO ₂ C

244

To a solution of diethyl cyanomethylphosphonate in 25 mL of THF was added 3.44 mL of a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene at 0 ° C. The mixture was stirred at room temperature for 1 hour and then a solution of 650 mg of the intermediate from Example D62 Step D in 10 mL of THF was added at room temperature. The mixture was stirred at room temperature for 1 hour and then quenched with 1M hydrochloric acid. The resulting mixture was extracted with ethyl ether and washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. Purification of the residue (chromatatron, 5: 1 hexanes / ethyl acetate) afforded α, β-unsaturated nitrile (466 mg of the trans form, 124 mg of the cis form).

Stage B:

NH-BOC

WHAT

I

N

, C N

590 mg of the intermediate from Step A was dissolved in methanol and hydrogenated in the presence of palladium hydroxide on charcoal for 1.5 hours under a hydrogen pressure of 1 bar. The mixture was then filtered through a pad of celite and the filtrate evaporated in vacuo. 560 mg of intermediate 3, 560 mg of EDC and 208 mg of HOBT were added to the residue in chloroform. After 2 hours the mixture was evaporated and the residue was purified (chromatatron, hexanes / ethyl acetate 1: 1) to give two diastereomers, 220mg less polar diastereomer d | and 260 mg of the more polar diastereomer

245

Stage C:

To 220 mg of the less polar diastereomer of Step B in 5 mL of toluene was added 206 mg of trimethyltin azide and the mixture was refluxed for 6.5 hours. Then the solvent was evaporated in vacuo. The residue was redissolved in 20: 1: 0.1 methylene chloride: methanol: acetic acid, 20 ml of the mixture was used, then the solution was allowed to stand at room temperature for 12 hours, then the solvent was evaporated in vacuo. The residue is purified by PLC (methylene chloride, methanol and acetic acid 20: 1: 0.1) to give 120 mg of the desired product.

Stage D:

120 mg of the intermediate from Step C was treated with HCl in ethyl acetate to give 98 mg of the desired cis, d-product as a white solid.

246 H-NMR (400 MHz, CDCl3 OD, mixture of rotamers): 7.28-7.08 (m, 9H), 5.08 (m, 1/2 H), 4.84-4.53 (m, 11/2) H), 4.18 (m, 1H), 3.78 (m, 3H), 3.27-3.03 (m, 6H), 2.85-2.30 (m, 4H), 1.90-1.38 (m, 5H), 1.65 (s, 3 / 2H), 1.61 (s, 3 / 2H), 1.57 (s, 3 / 2H), 1.56 (s, 3 / 2H), 0.90 (t, 7 Hz, 3 / 2H) 0.85 (t, 7 Hz, 3/2 H).

FAB-MS: 590.2 (M + 1).

Example B69 (cis, d ₂ )

Using 6.8 mg of the more polar diastereomer from step B of Example B68, 2 mg of the title product was obtained as described in steps C and D of Example B68.

FAB-MS: found 590.4 (M + 1).

Example B70 (cis, d ^)

247

Stage A:

782 mg of the intermediate from Example B68, Step A, was dissolved in methanol and hydrogenated with palladium hydroxide on charcoal at 50 psi for 1.5 hours. The mixture was filtered through celite and the filtrate evaporated in vacuo. To the residue in chloroform was added 468 mg of Boc-D-tryptophan, 534 mg of EDC and 207 mg of HOBT. After 2 hours, the mixture was evaporated and purified (MPLC, 1: 1 hexanes / ethyl acetate) to give 2 diastereomers, 316 mg of the less polar diastereomer d 2 and 300 mg of the more polar diastereomer d ₂ .

Stage B:

To a solution of the less polar diastereomer (316 mg) from Step A in ethyl acetate was bubbled hydrogen chloride gas by bubbling for 15 seconds at 0 ° C. Leave the mixture 30

The mixture was allowed to stand at room temperature for 248 minutes and then evaporated to give the crude product. To a solution of this product in 5 mL of chloroform was added 158 mg of N-BOC-α-methylalanine, 149 mg of EDC, 217 mL of triethylamine and 77 mg of HOBT, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into water and extracted with methylene chloride, the organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was purified (chromatatron, hexanes / ethyl acetate 1: 2) to give 287 mg of the title product.

Stage C:

From 287 mg of the intermediate obtained from step B of Example B70 above, 135 mg of the desired cis, d-product was obtained according to the steps of Example C68 and Step C.

1 H-NMR (400 MHz, CDCl 3 OD, mixture of rotamers): 8.08 (d, 8H, 1 / 2H), 7.80 (d, 8 Hz, 1/2 H), 7.64 (d, 8 Hz, 1 H) / 2 H), 7.57 (d, 8Hz, 1/2 H), 7.35 (d,

Hz, 1 H), 7.22-7.00 (m, 7 H), 5.31-5.20 (m, 1H), 4.71 (d, 12 Hz, 1/2 H), 4.41 (d, 12 Hz, 1/2 H), 4.15 (m, 1 H), 3.92-3.67 (m, 2 1/2 H), 3.433.03 (m, 8 1/2 H), 2.80 (m, 1 H), 2.52-2.25 (m, 1/2 H), 1.59 (s, 3/2 H),

1.54 (s, 3/2H), 1.50 (s, 3/2H), 1.35 (3/2H), 1.43 (m, 1H), 0.93 (t, 7Hz,

3/2 H), 0.84 (t, 7 Hz, 3/2 H).

FAB-MS: 601.1 (M + 1);

249

Example B71 (cis, d ₂ )

From 300 mg of the more polar diastereomer prepared in Example B70, Step A, Example B68, Step B, and Example B68, Step C and D, yielded 125 mg.

1 H-NMR (400 MHz, CD 3 OD, rotamers): 8.24 (d, 8H, 1 / 2H), 8.09 (d, 8 Hz, 1/2 H), 7.59 (d, 8 Hz, 1 H) 7.54 (d, 8 Hz, 1/2 H), 7.346.92 (m, 8 H), 5.40 (m, 1/2 H), 5.15 (m, 1/2 H), 4.64 ( d, 13 Hz, 1/2 H),

4.55 (d, 13 Hz, 1 H), 4.22 (m, 1 H). 4.09 (m, 1/2 H), 3.81-3.58 (m, 2 1/2 H), 3.40-2.84 (m, 9 1/2 H), 2.71-2., 2 (m, 1 1/2 H) ), 1.63 (s, 3 / 2H),

1.52 (3/2 H), 1.48 (3/2 H), 1.29 (3/2 H), 1.53 (m, 1/2 H), 1.32 (m, 1/2 H), 0.90 ( t, 7 Hz, 3/2 H), 0.79 (t, 7 Hz, 3/2 H).

FAB-MS: 601.2 (M + 1);

Example B72 (cis, d ^ + d ₂ )

CO ₂ Et

250

Stage A:

CBZ

I

N.

EtO ₂ C

OH

To a solution of 235 mg of the intermediate from Step C of Example B62 in 3 ml of methanol was added 0.5 ml of a 1 M hydrochloric acid solution and the mixture was stirred for 1 hour. Then, 0.7 ml of a 10 N solution of NaCNBH4 in THF is added to the mixture and after 5 minutes the reaction mixture is poured into 1 M hydrochloric acid and extracted with ethyl ether. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified (chromatatron, hexanes / ethyl acetate 1: 1) to give 142 mg of product.

Stage B:

H HCl I

N

EtO ₂ C

Me

To a solution of 142 mg of the intermediate from Step A in methanol was added a solution of hydrochloric acid in ether and palladium hydroxide, and the mixture was stirred under a hydrogen atmosphere for 12 hours. The mixture was filtered through Celite and the filtrate was evaporated to give 105 mg of product.

251

Stage C:

To 105 mg of the intermediate from step D in 2 ml of chloroform was added 81 mg of intermediate 1, 54 mg of EDC, 28 mg of HOBT and 53 ml of triethylamine, and the reaction mixture was stirred at room temperature for 12 hours and then poured into water. The resulting mixture was extracted with methylene chloride, the extract was dried over sodium sulfate and evaporated. The residue was purified (chromatatron, hexanes / ethyl acetate 1: 1) to give a product treated with hydrogen chloride in ethyl acetate to give 56 mg of the title product.

FAB-MS: found 519.2 (M + 1).

Example B73 (cis, d1 + d2)

252

Stage A:

CBZ

I

EtO ₂ C

, CO ₂ H

To 100 mg of the intermediate from Step A of Example B72 in acetone was added 0.2 ml of a 4 N solution of Jones reagent at 0 ° C. The mixture was stirred at room temperature for 16 hours, then isopropanol was added and the mixture was filtered through a pad of celite. The filtrate was extracted with ethyl acetate. The organic solution was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to give 100 mg of the title product.

Stage B:

CBZ

I

N

EtO ₂ C

, CO ₂ Me

Diazomethane (Blatt, Org. Syn. Collective, Vol. 4, p. 225) was added to 50 mg of the intermediate from Step A in ether at 0 ° C. The mixture was slowly warmed to room temperature and stirred for 12 hours. Evaporation and purification of the residue (PLC, 3: 1 hexanes / ethyl acetate) gave 50 mg of product.

253

Stage C:

mg of the intermediate of Step B was dissolved in methanol and hydrogenated in the presence of palladium hydroxide on charcoal for 1.5 hours at 0.1 MPa. The mixture was then filtered through celite and the filtrate evaporated in vacuo. To the chloroform residue was added 48 mg of intermediate 1, 45 mg of EDC and 24 mg of HOBT. After 2 hours the mixture was evaporated and purified (chromatatron, hexanes / ethyl acetate 1: 1) to give the product deprotected with hydrogen chloride in ethyl acetate to give 47 mg of the title product.

FAB-MS: found 563.1 (M + 1).

254

Stage A:

To 50 mg of the intermediate from Step A of Example B73 in chloroform was added 51 mg of glycine ethyl ester hydrochloride, 46 mg of EDC, 84 ml of triethylamine and 32 mg of HOBT. The reaction mixture was stirred at room temperature for 12 hours and then poured into water. The mixture was then extracted with methylene chloride and dried over sodium sulfate, evaporated and the residue purified (PLC, hexanes / ethyl acetate 1: 1) to give 45 mg of product.

Stage B:

From 45 mg of the intermediate from Step A, 43 mg of the product was obtained according to the procedure for Step C in Example B73.

FAB-MS: found 634.2 (M + 1).

255

Example B75 (cis, d-£ + d2)

To 53 mg of the intermediate from Step A of Example B73 in chloroform was added 12 mL of ethanolamine, 37 mg of EDC and 19 mg of HOBT, stirred for 12 hours at room temperature, then poured into water and extracted with methylene chloride. The extract was dried over sodium sulfate and evaporated. The residue was purified (chromatatron, methylene chloride and methanol 20: 1) to give 29 mg of the title product.

Stage B:

· OH

256

16.8 mg of the desired product was prepared from 29 mg of the intermediate of the preceding step as in steps F and G of Example B62.

FAB-MS: found 581.2 (M + 1).

Example B76

Platinum (IV) oxide was added to a solution of 100 mg of the intermediate from Step A1 of Example B12 in acetic acid, and the mixture was hydrogenated for 24 hours under 50 psi of hydrogen, monitored by TLC. The mixture was filtered through a pad of celite, the filtrate was evaporated and the residue azeotroped with toluene. The distillation residue was dissolved in TFA and the solution was stirred at room temperature for 20 minutes. Then the reaction mixture was evaporated, the residue was dissolved in 0.5 ml of methylene chloride and 15 mg of intermediate 1, 15 mg of EDC, 6 mg of HOBT and 11 ml of triethylamine were added. The mixture was stirred at room temperature for 3 hours and then poured into water. The resulting mixture was extracted with methylene chloride, the extract was dried over sodium sulfate and evaporated. The residue was purified (PLC, hexanes / ethyl acetate 1: 1) to give the product which was treated with hydrogen chloride in ethyl acetate to give 8 mg of the title product.

FAB-MS: found 511.1 (M + 1).

257

Example B77 (cis, d _x + d ₂ )

N

H

CO O I

N

CO ₂ Et

The intermediate prepared in Step B of Example B12 was dissolved in methanol and hydrogenated in the presence of palladium hydroxide at 50 psi hydrogen for 2 hours. The mixture was filtered through celite and the filtrate evaporated in vacuo. 88 mg of the residue are dissolved in 1 ml of chloroform and 48 mg of N-Boc-β, p-dimethyl-β-alanine (VR Schoen et al., J. Med. Chem., 37, 897, 1994), 48 mg EDC are added. and 30 mg of HOBT, the mixture is stirred for 12 hours and then poured into water. The resulting mixture was extracted with methylene chloride, the extract was dried over sodium sulfate and evaporated. The residue was purified (chromatatron, hexanes / ethyl acetate 1: 1) to give the product deprotected with hydrogen chloride in ethyl acetate to give 58 mg of the title product.

FAB-MS: found 519.2 (M + 1).

Example B78 (cis, d ^ + d ₂ )

HCl

N

CO ₂ Et

258

Stage A:

O-THP

To a solution of 1 ml of methyl (R) -lactate in 5 ml of dihydropyran was added one drop of concentrated hydrochloric acid at room temperature. The reaction mixture was stirred for one hour, then evaporated and the residue was purified (chromatatron, 3: 1 hexanes / ethyl acetate) to give 1.49 g of the desired product. To 500 mg of THP-protected lactate in 10 ml of toluene was added 3.45 ml of a 1 N solution of diisobutylaluminum hydride in cyclohexane at -78 ° C and after 1.5 hours the reaction was stopped by adding methanol at low temperature. The mixture was poured into 5% aqueous citric acid solution and extracted with ethyl ether. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to give the protected aldehyde.

Stage B:

To a solution of 25 mg of the product of Example B77 in 0.5 mL of methanol was added 36 mg of the intermediate of Step A and 18 mg of sodium acetate, and the mixture was stirred at room temperature for 1 hour. 90 ml of a 1 N solution of NaCNBH4 in THF are then slowly added to the mixture, stirred for 16 hours and then evaporated. The residue is purified (chromatatron, methylene chloride / methanol / hydroxide mixture)

259 ammonium (10: 1: 0.1) to give the product which was dissolved in 0.5 mL of methanol and then treated with 0.2 mL of 9 M hydrochloric acid. The mixture was stirred for 2 hours then evaporated and dried to give 10.5 mg of the title compound.

FAB-MS: found 577.4 (M + 1).

Example C1

Stage A:

Boe

The

OEt

To a stirred solution of ethyl nipecotate (15 g, 95.4 mmol) and DMAP (0.5 equivalents) in dichloromethane was added dropwise via addition funnel at 0 ° C, di-tert-butyl dicarbonate (21.8 g, 100 mmol) in dichloromethane (200 mL). The mixture was stirred for 2-3 hours, then the resulting solution was washed with 3M HCl solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to give 18.7 g (88%) of the title product.

260

Stage B:

To a stirred solution of ethyl N-t-Boc-nipecotate (7 g, 26.90 mmol) in THF (100 mL) at -78 ° C under argon was added LHMDS (28 mL, 28 mmol) over 10 min. The solution was then stirred at -78 ° C for 30 minutes, then benzyl bromide (4.8 g, 28 mmol) was added slowly. The reaction mixture was stirred overnight, then allowed to warm to room temperature. The mixture was concentrated, diluted with water and extracted with 2 x 200 mL ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with 20% ethyl acetate in hexane to give the title compound (8.32 g, 88%).

FAB-MS calc ^{. For} C20H22N2O4 ^: calc'd 347, found 348 (M + H).

Stage C:

OEt

A solution of the intermediate of Step B (23.02 mmol) (8 g) in 80 mL of ethyl acetate was cooled to 0 ° C. While stirring, hydrogen chloride gas was bubbled through the solution until saturated. The reaction mixture was then stirred for 40 minutes, after which time TLC showed that the reaction was complete. The solution was evaporated to remove ethyl acetate to give 6.53 g (99%) of the product.

261 1H NMR (CDCl3, 400MHz) δ 7.25-7.19 (m, 3H), 7.04-7.01 (m, 2H),

5.35 (broad s, 2H), 4.22-4.10 (m, 2H), 3.44 (d, J = 13 Hz, 1H), 3.21 (br. D, J = 12.7 Hz, 1H), 2.95 (d, J = 13.5Hz, 1H), 2.76-2.68 (m, 3H), 2.22 (br. D, J = 13Hz, 1H), 1.73-1.71 (m, 1H), 1.61- 1.48 (m, 2H), 1.18 (t, J = 7Hz, 3H).

FAB-MS for CigH ₂ iNO _2: calcd 247, found 248 (M + H).

Stage D:

To a solution of 1.2 g, glowing and one

4.23 mmol of the intermediate from previous equivalent of intermediate 1, one equivalent of HOBT and one equivalent of N-methylmorpholine in dichloromethane cooled to 0 ° C were added 1.5 equivalents of EDC. The mixture was stirred overnight at 0 ° C. The mixture was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Purification by MPLC eluting with 40% ethyl acetate in hexane gave two enantiomerically pure compounds. The compound starting from the column was obtained in an amount of 1.14 g and denoted d ^, which has an absolute R configuration at the 3-position of the nipecotate. The compound leaving the column later was obtained in an amount of 1.08 g, denoted d ₂ and has an absolute S configuration at the 3-position of nipecotate, as also evident from Example C2.

d ^ FAB-MS for C _{3 4} gH, gN ₄ Og: calcd 618, found 619 (M + H) _d2: FAB-MS for C ₃₃ H ₄ g of N ₄ · 0 g. calculated 618, found 619 (M + H)

262

Stage E:

The compound was prepared according to the step C from 1 g of intermediate d1 from the previous step in 20 ml of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 1.5 hours. Yield: 860 mg (91%).

FAB-MS calc. For C18H18N3O2: 518, found 519 (M + H).

Example CIA

The compound can be prepared as in Step C of Example C of 1 g of intermediate _d2 from Step D in Example C in 20 ml of ethyl acetate bubbled hydrogen chloride at 0 ° C until saturated, followed by evaporation of the mixture after 30 minutes of standing, in 93% yield, the following the way it gets

878 mg of final product.

FAB-MS calcd for C 18 H 18 N 2 O 4: 518, found 519 (M + H). 1 H-NMR (CD 3 OD, 400 MHz), the compound exists in two rotamers with a ratio of approximately 5/3, slowly mutual

263 relative to the NMR time scale:

δ 7.60 (d, J = 7.9Hz, 5 / 8H), 7.55 (d, J = 7.9Hz, 3 / 8H), 7.346.93 (m, 9H), 5.36 (dd, J = 5.2Hz, 9.7) Hz, 3/8 H), 5.31 (dd, J = 6.7 Hz)

8.8 Hz, 5 / 8H), 4.23 (br. D, J = 13.7Hz, 3 / 8H), 4.10-4.00 (m, 6 / 8H), 4.04-3.98 (m, 3 / 8H), 3.96-3.82 (m, 10/8 H), 3.80 (br. D, J = 13.5Hz, 5/8H), 3.36 (br. D, J = 13.3Hz, 5/8H), 3.29-3.22, 3.17-3.10, (2m, 2H), 3.20 (br. D, J = 14.5Hz, 3 / 8H), 3.10-2.96 (m, 5 / 8H), 2.90 (s, 6 / 8H), 2.60 (d,

J = 13.4 Hz, 5/8), 2.41 (d, J = 13.4 Hz, 5 / 8H), 2.19-2.12, 1.82-1.70, 1.681.60, 1.50-1.40, 1.34-1.25, 1.05-0.95 (6m) , 4 H), 1.55 (s, 9 / 8H), 1.50 (s,

15.8H, 1.09 (t, J = 7.1Hz, 3H).

Other intermediates listed in Table C1 were prepared using the procedures outlined in steps A to C of Example C1. The resulting compounds, which are also listed in the table, were prepared as described in steps D and E of Example C1 and Example CIA using Intermediate 1.

Table C1

^B;

intermediate product

Intermediate Product Y MF MF FAB-MS (M + 2) FAB-MS (M + 2) isomer ^a 1 Me C 9 H 17 NO 2 C 24 H 34 N 4 O 4 171 (M +, EI-MS) ^W dl d2 2 et C10H19NO2 C25H36N4O4 457 dl 185 (M &lt; + &gt;, EI-MS) d2 3 n-Pr C11H21NO2 C26H38N4O4 . 471 dl 199 (M &lt; + &gt;, EI-MS) d2

264

4 allyl C11H19NO2 198 C26H36N4O4 469 dl d2 5 n-Bu C12H23NO2 C27H40N4O4 485 dl 213 (M + EI) d2 6 -CH2OEt C11H21NO3 216 C26H38N4O5 487 RS 7 cyclohexane C15H27NO2 C30H44N4O4 525 dl methyl 254 d2 8 Ph _(CH2) 2 C16H23NO2 C31H40N4O4 533 dl 261 (M &lt; + &gt;, EI-MS) d2 9 Ph (CH2) 3 C17H25NO2 C32H49N4O4 547 dl 275 (M &lt; + &gt;, EI-MS) d2 10 o-MeOBn- CI6H23NO3 C31H40N4O5 549 dl 278 d2 11 m-MeOBn- C16H23NO3 C31H40N4O5 549 dl 278 d2 12 p-MeOBn- C16H23NO3 C31H40N4O5 549 dl 278 d2 13 O-Me-BN C16H23NO2 C31H40N4O4 533 dl 262 d2 14 m-Me-BN C16H23NO2 C31H40N4O4 533 dl 262 d2 15 p-Me-BN CI6H23NO2 C31H40N4O4 533 dl 262 d2 16 o-Cl-BN C15H20NO2CI C30H37N4O4CI dl 282.284 (3: 1) 554,556 3: 1 d2 17 m-Cl-BN C15H20NO2CI C30H37N4O4CI dl 282.284 (3: 1) 554,556 3: 1 d2 15 p-Cl-BN C15H20NO2CI C30H37N4O4CI dl 282.284 (3: 1) 554,556 3: 1 d2 16 2,6-di-Cl-BN C15H19NO2CI2 C30H36N4O4CI2 316,318,320 587,589,591 17 p-Br-BN Cl5H20NO2Br C30H37N4O4Br dl 326.328 (1: 1) 597.599 (1: 1) d2

265

18 m-Br-BN Cl5H20NO2Br 326.328 (1: 1) C30H37N4O4Br 597.599 (1: 1) dl d2 19 o-nitro-BN C15H20N2O4 C30H37N5O6 dl 293 564 d2 20 m-nitro-BN C15H20N2O4 C30H37N5O6 dl 293 564 d2 21 p-nitro-BN C15H20N2O4 C30H37N5O6 dl 293 564 d2 22 l-naphthylmethyl C19H23NO2 C34H40N4O4 dl 298 569 d2 23 /ABOUT C13H18NO2SCI C28H35N4O4SCI dl 288,290 3: 1 559.561 (3: 1) d2 24 BnO2C- C16H21NO4 C31H38N4O6 RS 292 563 25 EtO2C- C11H19NO4 C26H36N4O6 RS 230 501 26 p-Ph-BN C21H25NO4 C36H42N4O4 dl 324 595 d2 27 X y ^ O, CH ₂ - CI6H20NO4CI C31H37N4O6CI dl X ^ O-Cl 326,328 (3: 1) 597.599 (3: 1) d2 28 C17H20N2O4 C32H37N5O6 dl U ΙΛ ° ^Η 2- 317 588 d2

Ο

In these and the following tables, the isomers will be indicated as follows: R and S are stereochemistry at the carbon atom to which X and Y are bonded, R 5 is a mixture of these isomers, d 1 or d ₂ are separate diastereomers as defined in step D of Example C1.

266

The other examples shown in Table D1 were carried out according to the method given in steps D and E of Example C1 using intermediate 1 and commercially available intermediates.

Table Cla

intermediate product

Product X MF FAB-MS (M + 1). isomer 1 OH C20H28N4O3 373 RS 2 -CH20H C21H30N4O3 387 RS 3 -CO2Et C23H32N4O4 429 RS 4 C02Bn C28H34N4O4 491 RS 5 C0NMe2 C23H33N5O3 428 RS

Other intermediates listed in the following Table CIb were prepared as described in steps D and E of Example C1 using Intermediate 3 and some of the intermediates listed in Table C1.

267

Table CIb

ph

nh ₂ hci

Product entry Y MF FAB-MS (M + 1). isomer 1 Bn C30H41N3O4 508 R Bn C30H41N3O4 WITH FROM 508 3 Ph (CH2) 2 C31H43N3O4 522 dl d2 4 Ph (CH2) 3 C32H45N3O4 536 dl d2 5 1-naphthylmethyl. C34H43N3O4 558 RS 6 C28H38N3O4SC1 548.550 (3: 1) RS 7 p-Ph-BN C36H45N3O4 584 RS 8 BnO2C- C31H41N3O6 552 RS 9 / ° uA ^CH! ' C31H40N3O6CI dl ο -'- Ογ. 586.588 (3: 1) d2

The products listed in Table C18 were prepared by the methods outlined in steps D and E of Example C1 using Intermediate 2 and some of the intermediates in Table C1.

268

Table Cic

Y MF FAB-MS isomer 1 Bn C29H39N3O5 510 R 2 Bn C29H39N3O5 510 WITH 3 et C24H37N3O5 448 RS 4 Ph (CH ₂ ) 2 C30H41N3O5 524 dl d2 5 Ph (CH ₂ ) 3 C31H43N3O5 538 dl d2 6 H C22H33N3O5 420 RS

Example C2

269

Stage A:

H L-tartaric acid

50.8 g of the intermediate of Example C1 was dissolved in dichloromethane and the solution was washed with 3M NaOH solution. The aqueous layer was extracted with dichloromethane, the organic solutions were combined, dried over magnesium sulfate and evaporated to give the free amine as an oil. Ethyl 3-benzyl nipecotate and 31 g of D-tartaric acid are dissolved in 880 ml of a 1: 4 mixture of water and acetone with heating. The solution was allowed to stand overnight in the refrigerator and the formed crystals were filtered off. Recrystallization from 470 ml of 1: 4 water / acetone at room temperature gave 21 g of ethyl (R) -benzyl nipecotate D-tartaric acid salt.

The structure of this material was confirmed by X-ray crystallography. Since D-tartaric acid is known to have an S, S configuration, the configuration of the chiral moiety in this salt has been determined by R.

The mother liquors were combined and evaporated and a 3M solution of NaOH in dichloromethane was added, the mixture was stirred for a further 30 minutes and then the organic layer was separated. The aqueous layer was extracted twice with dichloromethane, the organic extracts were combined, dried over magnesium sulfate and evaporated to give 24.4 g of the product enriched in the S-isomer. This product is crystallized with

14.8 g of L-tartaric acid in 400 ml of water / acetone 1: 4 at room temperature to give 27.3 g of ethyl 3- (S) -benzyl nipecotate with L-tartaric acid.

1 H NMR (CD 3 OD, 400MHz) δ 7.31-7.22 (m, 3H), 7.12-7.09 (m, 2H),

4.40 (s, 2H, tartaric acid) 4.30-4.10 (m, 2H), 3.49 (br. D, J = 13)

Hz, 1 H), 3.06 (d, J = 13.6 Hz, 1 H), 2.98 (d, J = 13 Hz, 1 H), 2.92 (dt, J =

3.3 Hz, 13 Hz, 1 H), 2.82 (d, J = 13.6 Hz, 1 H), 2.30 (d, J = 12.4 Hz, 1 H), 1.88 (td, J = 3 Hz, 14.5 Hz, 1 H) ), 1.69 (dt, J = 3Hz, 13Hz, 1H),

1.63-1.51 (m, 1H), 1.25b (q, J = 7.1Hz, 3H).

270

Stage B:

39.74 g of L-tartaric acid ethyl 3- (S) -benzyl nipecotate salt are suspended in a mixture of 70 ml of 3M NaOH solution and 70 ml of water and the mixture is extracted with dichloromethane. The extracts were combined, dried and evaporated to a thick oil. To a stirred suspension of this oil, 30.43 g of N-t-Boc-D-TrpOH,

13.5 g of HOBT and 200 ml of dichloromethane were added in several portions at 0 ° C in 23 portions of EDC. The mixture was stirred overnight, then poured into a mixture of water and 3M HCl solution and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to 67.7 g of crude product, which was used without further purification.

FAB-MS calc. For C ^ ^H ^N ^O O: 533, found 534 (M + H).

271

To a solution of 67.7 g of the crude intermediate from the preceding step in 100 mL of ethyl acetate at 0 ° C was added hydrogen chloride gas by bubbling until saturation. The reaction mixture was stirred at 0 ° C for 30 minutes and then evaporated to remove excess HCl and ethyl acetate. The residue is suspended in dichloromethane and the suspension is washed with a mixture of 70 ml of 3M NaOH solution and 100 ml of water. The organic layer was dried over magnesium sulfate, evaporated to a small volume and used in the next step without further purification. FAB-MS calc. For C18H21N2O4: 433, found 434 (M + H).

Stage D:

A solution of the intermediate from the previous step, 20.3 g of N-Boc-α-Me-AlaOH and 200 mg of DMAP in 100 ml of dichloromethane was stirred at room temperature and 24 g of EDC were added in several portions. The reaction mixture was stirred for 3 hours and then worked up by diluting with dichloromethane and washing with 3M HCl solution, saturated sodium chloride solution and saturated sodium bicarbonate solution. The organic layer was dried (MgSO 4) and evaporated to a thick oil. The oil was passed through a pad of silica gel, eluting with 60% ethyl acetate in hexane to remove some very polar impurities to give 54.2 g of the title product.

FAB-MS calcd for C18H18N3O4: 618, found 619 (M + H).

272

Grade F:

Hydrogen chloride gas was bubbled into the solution of 54.2 g of the intermediate from the previous step in 100 ml of ethyl acetate at 0 ° C until saturation. The reaction mixture was stirred at 0 ° C for 15 minutes, then excess HCl and ethyl acetate were evaporated. The residue is dissolved in 100 ml of dichloromethane and then 300 ml of ethyl acetate are added. The mixture was stirred overnight, and the solid was filtered to give 34 g of product. further evaporation of the mother liquor to a small volume yielded 10.1 g of product. MS and NMR were identical to analysis of the product of Example CIA.

The products listed in Table CII were prepared as described in steps B to F of Example C2 using readily available Boe-protected amino acids instead of N-t-BocD-TrpOH.

Product

273

R MF FAB-MS 1 4-F C30H37N4O4F 537 2 5-F C30H37N4O4F 537 3 6-F C30H37N4O4F 537 4 1-Me C31H40N4O4 533 5 5-MeO C31H40N4O5 549 6 5-HO C30H38N4O5 535 7 6-MeO C31H40N4O5 549

Example C3

Stage A:

Boe

ABOUT.

CO ₂ Et

To a stirred solution of 10 g (69.8 mmol) of ethyl 3-pyrrolidinecarboxylate hydrochloride (J. Chem. Soc., 24, 1618-1616), 7.75 ml of triethylamine and 857 mg of DMAP in 40 ml of dichloromethane was slowly added 18.3 g, 83.7 mmol of di-tert-butyl dicarboxylate and the resulting mixture was stirred at room temperature for 3 days. The mixture was then evaporated, washed with 3M HCl solution, dried and evaporated to give the desired intermediate.

274

Stage B:

CO ₂ Et

The product can be prepared according to the procedure of Example B, Part B, from 500 mg, 2.05 mmol of the intermediate from the previous step, 512 mg, 2.57 mmol of KHMDS and 371 mg, 2.16 mmol of benzyl bromide. The product was purified by flash chromatography on silica gel eluting with 5 to 20% ethyl acetate in hexane to give 385 mg of the product in 56% yield.

Stage C:

The product can be prepared according to the procedure of Example C, Step C, from 385 mg, 1.16 mmol, of the intermediate from the preceding step in 5 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 15 minutes. Yield: 306 mg (98%).

Stage D:

CO ₂ Et

275

The product can be prepared according to the Step D of Example Cl from 138 mg, 0.514 mmol of intermediate from the previous step, 200 mg, 0.514 mmol of intermediate 1, one equivalent of HOBT, one equivalent of N-methylmorpholine and two equivalents of EDC. The product was purified by MPLC eluting with 60% ethyl acetate in hexane to give 250 mg of the product in 80% yield.

FAB-MS calcd for 0β ₄ Η ₄₄ Ν ₄₀ ^ 604, found 605 (M + H).

The product can be prepared according to the procedure of Example C, Step C, from 250 mg, 0.036 mmol of the intermediate of the preceding step in 3 mL of ethyl acetate by bubbling the mixture with hydrogen chloride gas for 10 minutes at 0 ° C.

FAB-MS calculated for C C gH ^ gí ^O O 504, found 505 (M + H).

Example C4

Stage A:

Boe

N.

OEt

276

To a stirred solution of 4 g, 15.7 mmol of ethyl N-t-Boc-nipecotate in 100 mL of THF at -78 ° C under argon was added 32 mL of 1 M LHMDS solution (32 mmol) over 10 min. The solution was stirred at -78 ° C for 30 minutes, then methyl disulfide (1.92 g, 20.37 mmol) was added. The reaction mixture was stirred overnight and then allowed to warm to room temperature. The solution was concentrated, then diluted with water and extracted with 2 x 200 mL ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to give the product.

FAB-MS calcd for C 14 H 25 NO 4 S 271, found 272 (M + H).

Stage B:

The product was prepared according to the procedure of Example C, Step C, from 1 g, 3.3 mmol of the intermediate from the previous step in 25 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 35 min, yielding 993 mg.

FAB-MS calcd for C19H18N3O2S: 271, found 225 (M + H).

Stage C:

277

The product was prepared according to the procedure of Example D, Step D, from 123 mg, 0.514 mmol of intermediate from the previous step, one equivalent of intermediate 1, one equivalent of HOBT, one equivalent of NMM and 197 mg, 1.028 mmol of EDC. The product is purified by MPLC to give diastereomers. A compound which is based on the first column, was obtained in a yield of 37% and an amount of 109 mg, and ^ is D, a compound which is based on the column later, is obtained in a yield of 30% and an amount of 88 mg is D and _{the second}

d _{and FAB-MS} for C ₂₉ H ₄₂ N ₄ O ₆ S: Calc'd 574, found 575 (M + H) _d2: FAB-MS for C ₂₉ H ₄₂ N ₄ OGS: calcd 574, found 575 (M + H)

Stage D:

OEt

The compound was prepared according to Example Cl, Step C, using 80 mg of the intermediate di and 80 mg of Intermediate d ₂ of stage separately, in 5 ml of ethyl acetate, the solution was purged for 20 minutes at 0 "C. HCl.

d _{1 =} 71 mg, 99% H _2: 70 mg, 98%.

d-E: ³ H-NMR (CD 3 OD, 400 MHz): the compound exists as 2 rotamers in a 1: 1: 5 ratio 7.71 (d, J = 7.2 Hz, 1/2 H), 7.56 (d, J =

7.2 Hz, 1 H, 7.38 (d, J = 8.0 Hz, 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.14-7.01 (m, 3 H), 5.44 (dd, J = 6Hz, 8Hz, 1/2H), 4.30-4.10 (m, 5/2H), 3.92 (d, J = 13.3Hz, 1/2H), 3.81 (d, J = 13.3 Hz, 1 H, 3.67 (d, J =

13.3 Hz, 1/2 H), 3.48-3.40 (m, 1/2 H), 3.28-3.09 (m, 7/2 H), 2.55 (dt, 1/2 H), 2.26-2.20 (br. D) 1.05 (s, 3 H), 1.80-1.70 (m, 1 H), 1.67, 1.59, 1.55, 1.43 (4s, 6 H), 1.27 (t, J = 7.0 Hz, 3/2 H), 1.19 (t, J = 7.0 Hz, 3/2 H), 0.90-0.85 (m, 1/2 H).

278 d ₂ : 1 H-NMR (CD 3 OD, 400 MHz): the compound exists as 2 rotamers in a 1: 1: δ ratio 7.77 (d, J = 7.5 Hz, 1/2 H), 7.56 (d, J =

7.9 Hz, 1 H, 7.35-7.30 (m, 1 H), 7.13-6.98 (m, 3 H), 5.53 (dd, J = 5.5 Hz, 8 Hz, 1/2 H), 5.24 (app) t, J = 7 Hz, 1/2 H), 4.30 (br. d, J = 14 Hz, 1/2 H), 4.20-4.10 (m, 2H), 3.90-3.85 (m, 1/2 H), 3.86 (d, J = 13.2 Hz, 1/2 H), 3.70 (d, J = 13.7 Hz, 1/2 H), 3.35-3.10 (m, 4 H), 2.30-2.20 (m, 1 H) / 2 H), 2.12, 2.04 (2s, 3Hs), 2.04-2.00 (m, 1/2sH), 1.80-1.70 (m, 3/2sHs), 1.54, 1.50, 1.43,1.26 (4s, 6s) H), 1.23 (t, J = 6.7 Hz, 3H), 0.90-0.84 (m, 1/2 H).

Ί ^: * 1 ^:

FAB-MS for C ₂₄ H ₃₄ N ₄ O ₄ S: FAB-MS for C ₂₄ H ₃₄ N ₄ O ₄ S:

calculated 474, found 475 (M + H) calculated 474, found 475 (M + H)

Other intermediates of Table CIII were prepared by the above procedures in steps A and B of Example C4. The resulting products were prepared according to Example C, Steps C and D, using intermediate 1.

, CO ₂ Et

intermediate product

Intermediate Product

MF MF

FAB-MS (M + 1) FAB-MS (M + 1) isomer

PhSBnS2-pyridylthioC14H19NO2S

266

C15H21NO2S

280

C13HI8N2O2S

267 · ³ λΤ

CH <

C29H36N4O4S dl

537 d2

C30H38N4O4S dl

551 d2

C28H35N5O4S RS

538

C27H35N5O4S2 RS

558

279 Example C5

Stage A:

Boe

OEt

To a stirred solution of NaIO ₄ (316.5 mg, 1.48 mmol ₎ in water (5 mL) and ethanol (5 mL) was added the intermediate of Example C4 Step A (300 mg, 0.99 mmol). The mixture was stirred at room temperature for 5 hours and then the ethanol was evaporated. The material was extracted with 2 x 10 mL ethyl acetate. The organic layer was dried (MgSO 4) and evaporated to give the title compound (286 mg, 90.5%).

FAB-MS calcd for C 14 H 25 NO 5 S 319, found 320 (M + H).

Stage B:

H HCl N.

The product was prepared according to the step C of Example Cl from 230 g, 0.72 mmol of the intermediate from the previous step in 10 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 25 min. Yield 197 mg (100%). FAB-MS calc. For C8H14N3O3S: 219, found 220 (M + H).

280

Stage C:

The product was prepared according to the procedure of Example D, Step D, from 140 mg, 0.547 mmol of the intermediate from the previous step, one equivalent of intermediate 1, one equivalent of HOBT, one equivalent of N-methylmorpholine and 210 mg, 1.094 mmol of EDC. After purification by MPLC, 177 mg of a mixture of diastereomers is obtained in a yield of 55%.

FAB-MS calcd for C 29 H 42 N 4 O 7 S 590, found 591 (M + H).

Stage D:

The product was obtained according to Step C of Intermediate C1 using 150 mg, 0.254 mmol of the intermediate from the previous step in 10 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 20 min. Yield: 118 mg (90%).

FAB-MS calcd for C 24 H 34 N 4 O 5 S 490, found 491 (M + H).

Example C6

281

Stage A:

To a stirred solution of Oxone (910 mg, 1.48 mmol) in water (5 mL) and methanol (5 mL) was added the intermediate from Example A, Step A, 300 mg, 0.99 mmol. The mixture was stirred at room temperature for 4 hours and then evaporated to remove methanol. The residue was extracted with 2 x 10 mL ethyl acetate. The organic layer was dried (MgSO 4) and evaporated to give 321 mg (97%) of the title compound.

FAB-MS calcd for C ^ HH ^NOgS: 335, found 336 (M + H), (found 336 (M-t-Boc)).

Stage B:

Prepared by the procedure of Example Cl, Step C from 221 mg, 0.66 mmol of the intermediate in 10 ml of ethyl acetate and HCI gas for 25 min at 0 ^{& C.} in a yield of 99% was obtained 192 mg. FAB-MS for the CGH ₁₇ NO ₄ S: calcd 235, found 236 (M + H).

282

Stage C:

The product was prepared according to the procedure for Step D of Example Cl using 140 mg, 0.515 mmol of the intermediate from previous step, one equivalent of intermediate 1, one equivalent of HOBT, one equivalent of N-methylmorpholine and 197 mg, 1.03 mmol of EDC. After purification by MPLC, 251 mg of the diastereomeric mixture was obtained in 80% yield.

FAB-MS calcd for C 29 H 42 N ₄ O ₈ S: 606, found 607 (M + H).

Stage D:

The product was prepared according to the procedure of Example C, Step C, from 210 mg, 0.317 mmol, of the intermediate from the previous step in 10 mL of ethyl acetate by bubbling hydrogen chloride gas for 30 min at 0 ° C. Yield: 98.5%.

FAB-MS calcd.

283

Example C7

To a stirred solution of ethyl N-t-Boc-nipecotate (50 g, 0.196 mol) in THF (600 mL) at -78 ° C under argon was added 298 mL of a 0.5 M KHMDS solution (0.298 mol) over 30 minutes. Meanwhile, a suspension of 25 mg of 2-picolyl chloride hydrochloride in dimethylmethane was washed with a mixture of 3M NaOH solution and saturated sodium chloride solution to remove the hydrochloride. Dry the organic layer over magnesium sulfate and evaporate to a brown oil, which is slowly added to the previous solution at -78 ° C. The reaction mixture was stirred overnight and allowed to warm to room temperature. The mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The product was purified by flash chromatography on silica gel, eluting with a gradient of 20 to 80% ethyl acetate in hexane to give 54.8 g of the product in 80% yield.

1 H NMR (CD 3 OD, 400MHz) δ 8.45 (dd, J = 1.5Hz, 5Hz, 1H), 7.52 (app dt, J = 2Hz, 8Hz, 1H), 7.07 (dd, J = 5Hz, 6.6 Hz, 1H, 7.05 (d, J = 8 Hz, 1H), 4.09-4.04 (br. M, 2H), 3.92 (br. D, 1H), 3.46 (br. M, 1H) ), 3.30-3.10 (br. M, 1H), 3.06 (d, J = 13.7 Hz, 1H), 2.95 (d, J = 13.7 Hz, 1H), 2.01-1.91 (br. M, 1 H), 1.63-1.50 (br. M, 3H), 1.36 (v. Br. S, 9H), 1.13 (t, 7.1 Hz, 3H).

FAB-MS calc. For C18H284.24 ^: 348, found 349 (M + H).

284

Stage B:

The product was prepared according to the procedure of Example C, Step C, from 6.36 g, 18.2 moles of the intermediate from the previous step in 100 ml of ethyl acetate by bubbling hydrogen chloride at 0 ° C for 45 minutes. 6.10 g of product are obtained in a yield of 100%.

FAB-MS calc. 248, found 249 (M + H).

Stage C:

The product was prepared according to the procedure of Example D, Step D, from 500 mg, 1.566 mmol of the compound from the preceding step, one equivalent of intermediate 1, one equivalent of HOBT, two equivalents of N-methylmorpholine and 597 mg, 3.11 mmol of EDC. After purification by MPLC eluting with ethyl acetate in yield

91.5% yielded 883 mg of product.

FAB-MS calc. For &lt; 34 &gt;

285

Stage D:

The product was prepared according to the procedure for Example C, Step C, using 250 mg, 0.404 mmol of the intermediate from the preceding step in 25 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 25 min. Yield: 204 mg (85%).

FAB-MS calc. 519, found 520 (M + H).

Other intermediates listed in the following Table CIV were prepared according to the procedure of Example C7, Steps A and B. The resulting products were prepared according to the steps C and D of Example C7 using intermediate 1.

Table CIV

Product

intermediate product

286

intermediate product

MF

FAB-MS (M + 1).

Product

MF

FAB-MS (M + 1) isomer

3-picolyl

4-picolyl

2-chinolinometyl

OG ™ ··

A '

Bn ^gh 2 ch ₃

C14H20N2O2

249

C14H20N2O2

249

C18H22N2O2

298

C16H21N3O2

288

C19H25N3O2

328

C15H22N2O2

263

C29H37N5O4

520

C29H37N5O4

520

C33H39N5O4

569

C31H38N6O4

559

C34H42N6O4

599

C30H39N5O4

534

RS

RS

RS d1 d2

RS

RS

N CH;

Other compounds listed in the following Table CIVa were prepared according to the steps C and D of Example C7 using some of the intermediates in Table CIV and intermediate 3 instead of intermediate 1.

Table CIVa

YcO ₂ Et

- 287 1

2- picolyl

3-picolyl

4-picolyl

C31H41N5O4

548

C30H42N4O4

523.545 (M + Na)

MF

FAB-MS (M + 1).

C29H40N4O4

509

C29H40N4O4

509

C29H40N4O4

509

C33H42N4O4

559 isomer d1 d2 d1 d2 d1 d2

RS d1 d2 d1 d2

Example C8

Stage A:

OAc OAc

288

The product was prepared according to Part D, Example D, from 6 g, 18.67 mmol of the intermediate from Example C7, using one equivalent of (R) - (-) - (O) -acetylmandelic acid, one equivalent of HOBT, two equivalents of N-methylmorpholine and 7.16 g, 37.34 mmol of EDC. Purification by MPLC eluting with 80% ethyl acetate in hexane gave two enantiomerically pure compounds. In a yield of 99%, 3.92 g of the isomer that emerged from the column above was obtained, which isomer was designated d1. Further, 3.69 g of the isomer that emerged from the column later was obtained in 93% yield. This isomer was designated d2. The structure of the intermediate d1 was determined by X-ray crystallography. Assuming that the absolute stereochemical configuration of acetyl-butyric acid is (R) -, the stereochemistry of the piperidine residue at the 3-position is determined as (S) - in the isomer d 1.

FAB-MS for C 24 H 28 N 2 O 8 found 425.

Stage B:

A solution of intermediate (d1) (2.91 g, 6.86 mmol) in a mixture of ethanol (30 ml) and concentrated HCl (25 ml) was refluxed for 5 hours. The reaction mixture was then evaporated in vacuo and the residue purified by flash column chromatography on silica gel, eluting with a gradient of 1:10:90 to 2:20:80 ammonium hydroxide, methanol and chloroform to give a 70% yield. yielding 1.52 g of the product d ₁ .

1 H NMR (CD 3 OD, 400MHz) δ 8.84 (app. d, J = 6Hz, 1H), 8.60 (app. dt, J = 1.5Hz, 8Hz, 1H), 8.04 (t, J = 6Hz, 1 H), 7.94 (d, J = 8Hz,

H), 4.34-4.27 (m, 1H), 4.23-4.17 (m, 1H), 3.75 (d, J = 13 Hz, 1H),

3.46 (d, J = 13.3Hz, 1H), 3.40 (d, J = 13.3Hz, 1H), 3.31-3.29 (m, 2H),

289

3.20 (d, J = 13Hz, 1H), 3.03 (app dt, J = 3.1Hz, 12.8Hz, 1H), 2.24 (br. D, 1H), 2.00-1.93 (m, 1H), 1.88 (dd, J = 3.7Hz, 13.5Hz, 1H), 1.63-1.60 (m, 1H), 1.23 (t, 7.1Hz, 3H).

FAB-MS calc. 248, found 249 (M + H).

Stage A:

Prepared according to Step D of Example Cl from 1.50 g, 4.67 mmol of intermediate dj from Step B, one equivalent of N-t-Boc-D-Trp, one equivalent of HOBT, and 1.53 g, 8.00 mmol of EDC. After purification by MPLC, 1.646 g of product was obtained with 71% yield of ethyl acetate.

FAB-MS calc. For C18H18N3O4: 534, found 535 (M + H).

Stage D:

The product was prepared according to the procedure of Example C, Step C, from 1.658 g, 3.11 mmol of the intermediate from the previous step in 50 mL of ethyl acetate by bubbling hydrogen chloride at 0 ° C for 35 minutes to give 1.56 g of product.

FAB-MS calcd for C 25 H 30 N 4 O 3 434, found 435 (M + H).

290

Stage E:

The product was prepared according to the procedure of Example D, Step D, from the intermediate prepared in Step D of this Example. 1.5 g (2.96 mmol) of the intermediate, 1.1 equivalents of N-t-Boc-α-methylalanine, 0.15 equivalents of DMAP, 1 equivalent of N-methylmorpholine and 1.135 g, 5.92 mmol of EDC were used. After purification by MPLC, 1.488 g of product are obtained in a yield of 81%.

FAB-MS calcd for C- ^H ^ NN ^Og: 619, found 620 (M + H).

Grade F:

Prepared according to Step C of Example C1 from 1.40 g, 2.26 mmol of the intermediate from Step E in 100 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 1 hour. 1.888 g of the title compound are obtained in a yield of 100%.

1 H NMR (CD 3 OD, 400 MHz): 8.79-8.78 (M, 1H), 8.56-8.48 (M, 24), 8.0-7.96 (M, 1H), 7.72 (d, J = 8.21Hz, 1H) 7.53 (d) J = 7.98 (Hz, 1H) 7.257.22 (M, 2H) 6.89-6.86 (M, 1H) 5.48-5.43 (M, 1H) 3.89 (1, J = 7.1Hz,

2H) 2.30 (d, J = 14.3Hz, 1H) 1.85 (d, J = 14.4Hz, 1H) 1.01 (t, J = 7.1Hz,

3H)

291

FAB-MS calcd for C29H37N5O4 519, found 520 (M + H).

Example C9

The resulting compound can be prepared from the intermediate d2 of Step A of Example C8 as described above.

FAB-MS calcd for C29H37N5O4 519, found 520 (M + H).

Example CIO

Stage A:

Boe

OH

292

To a stirred solution of nipecotic acid (5 g, 38.7 mmol) in water (2 equivalents) was added di-tert-butyl dicarbonate (10 g, 46.44 mmol). The mixture was stirred at room temperature for two days. The mixture was then slowly acidified to pH 3 and stirred for a further 2 hours. The solution was extracted with ethyl acetate, dried and evaporated to give 6.25 g of a white solid in 70% yield.

Grade B

To a solution of 6.25 g, 27.3 mmol of the intermediate from the previous step, 3.4 mL, 32.7 mmol of benzyl alcohol and 33 mg, 0.273 mmol of DMAP in dichloromethane was added at 0 ° C.

6.9 g of EDC 35.4 mmol. The reaction mixture was stirred at room temperature for 7 hours and then washed with a mixture of saturated sodium chloride solution and 3M HCl solution, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10 to 30% ethyl acetate in hexane to give 7.41 g of the benzyl ester in 85% yield.

The product was prepared according to the procedure of Example B, Step B, from 7.12 g (22.2 mmol) of benzyl N-t-Boc-nipecotate, 33.3 mL,

33.3 mmol of LHMDS in THF and 4.0 g, 33.3 mmol of benzyl bromide. Purification by flash chromatography on silica gel, eluting with 5-20% ethyl acetate in hexane, afforded 9.10 g (100%) of the title compound.

293 1 H NMR (CDCl 3, 400 MHz) δ 7.33-7.28 (m, 3H), 7.23-7.17 (m, 5H), 7.01-6.98 (m, 2H), 5.00 (br. ABq, JAB = 12 Hz, 2 H), 4.00 (br. S, 1H), 3.55-3.50 (m, 1H), 3.18 (d, J = 13 Hz), 3.14 (v. Br. S, 1H), 2.92 (d, J) =

13.5 Hz), 2.74 (d, J = 13.4 Hz), 2.03-1.99 (m, 1H), 1.63-1.50 (m, 3H), 1.39 (s, 9H).

Stage D:

OBn

The product was prepared according to the procedure of Example C, Step C, from 3.08 g, 7.52 mmol of the intermediate from the previous step in 40 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 15 minutes. 2.65 g of the title compound are obtained in a yield of 100%.

FAB-MS calc. For C20 H23 NO2: calc. 309, found 310 (M + H).

Stage E:

The product was prepared according to the procedure of Example D, Step D, from 768 mg, 2.22 mmol of intermediate from the previous step, 720 mg, 1.85 mmol of intermediate 1, 1 equivalent of HOBT, 1 equivalent of N-methylmorpholine and 2 equivalents of EDC. The mixture was purified by MPLC eluting with 50% ethyl acetate in hexane to give a mixture of two diastereomers. Yield: 40%

294

504 mg of the first isomer leaving the column in a yield of 38% yielded 474 mg of the isomer d2 > leaving the column later.

FAB-MS calc. For C18H18N3O3: calcd 680, found 681 (M + H) FAB-MS calc.

Grade F:

The product was prepared according to the procedure of Example C, Step C, from 25 mg, 0.036 mmol of intermediate d) from Step E in 3 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 10 min. Yield: 20.2 mg (91%). FAB-MS calcd for C 58 H 49 N ₄ O ₄ 580, found 581 (M + H).

Example C1

The product was prepared according to the procedure of Example C, Step C, from 20.1 mg, 0.03 mmol of intermediate d2 from Example C10, Step E in 3 mL of ethyl acetate by bubbling hydrogen chloride gas over 10 minutes at 0 ° C. Yield: 12.8 mg (70%).

FAB-MS for C GH _{3 4 4} 0 ₄ QN: calc'd 580, found 581 (M + H).

Example C12

Stage A:

A suspension of 60 mg of 10% palladium on charcoal and 442.6 mg, 0.65 mmol of intermediate d | from Step C of Example C10 in 20 ml of ethanol was vigorously stirred for 30 minutes under an atmosphere of hydrogen. The reaction mixture was filtered through celite and evaporated to give 376.0 mg (98%) of the product.

FAB-MS calcd for C ₃₃ H ₄₂ N ₄ O ₆ 590, found 591 (M + H).

296

Stage B:

The product was prepared according to the procedure of Example C, Step C, from 211 mg, 0.357 mmol of intermediate mL of ethyl acetate by bubbling at 0 ° C. In the yield of product.

from the previous step in 15% hydrogen chloride gas for 10 minutes 93% gave 175.6 mg of the result. 1 H-NMR (CD 3 OD, 400 MHz), the compound exists in two rotamers in a 1: 1 ratio. δ 7.57-7.54 (m, 1H), 7.38 (d, J = 8.2Hz, 1/2 H), 7.33 (d, J = 8.2Hz, 1/2 H), 7.25-7.00 (m, 8H) 6.81-6.79 (m, 1H),

5.36 (dd, J = 6Hz, 8.5Hz, 1/2 H), 5.18 (app t, J = 7.5Hz, 1/2H), 4.32 (br. D, J = 13Hz, 1/2H) 4.00 (br. D, J = 13Hz, 1/2 H), 3.78 (br. D, J = 13Hz, 1/2 H), 3.26-3.02 (m, 11/2H), 2.86 (d) J = 13.4 Hz, 1/2 H), 2.46 (d, J = 13.4 Hz, 1/2 H), 2.53 (d, J = 13.4 Hz, 1/2 H), 2.46 (d, J = 13.4 Hz) (1/2 H), 2.29 (dt, 1/2 H), 2.09 (d, J = 12.7 Hz, 1/2 H), 1.92-1.88 (m, 1/2 H),

1.55.1.50.1.44 (3s, 6H), 1.40-1.25 (m, 1H), 1.20-1.12 (m, 1/2 H). calcd 490, found 491 (M + H).

Example C13

297

Stage A:

The product was prepared in a manner analogous to the previous example using 224.2 mg, 0.33 mmol of intermediate d ₂ from step E of Example C10. 169.3 mg of product are obtained in a yield of 87%.

FAB-MS calc. 590, found 591 (M + H).

Stage B:

The product was prepared according to the procedure of Example C, Step C, from 139 mg, 0.235 mmol of the intermediate from the previous step in 15 mL of ethyl acetate by bubbling hydrogen chloride gas for 10 minutes at 0 ° C. Yield: 122.7 mg (99%).

1 H-NMR (CD 3 OD, 400 MHz), the compound exists in two rotamers in a 1: 1 ratio. δ 8.21 (d, J = 7.4Hz, 1/2 H), 7.91 (d, J = 7.4Hz, 1/2 H), 7.62 (d, J = 7.9Hz, 1/2 H), 7.50 (d, J = 7.9 Hz, 1/2 H), 7.34.90 (m, 9 H), 5.40-5.34 (m, 1H), 4.40 (d, J = 13.7 Hz, 1/2 H), 4.13 (d, J

298 = 12.6 Hz, 1/2 H), 3.30 (d, J = 13.3 Hz, 1/2 H), 3.50 (d, J = 13.3 Hz, 1/2 H), 3.30-3.10 (m, 7/2 H), 2.93 (ABq, 1 H), 2.88 (v. Br. D, 1 H), 2.60 (d, J = 13 Hz, 1 H), 2.40 (d, J = 13 Hz, 1/2) 2 H), 2.19-2.16 (m, 1/2 H), 1,781.75 (m, 1 H), 1.60-1.40 (m, 3/2 H), 1.20-1.10 (m, 1 H), 1.58,1.50,

1.47.1.15 (4s, 6H), 1.00-0.90 (m, 1/2 H).

_d2 FAB-MS for C ₂ GHG ₄ N ₄ O _4: calcd 490, found 491 (M + H).

Further examples are given in Table C5 below. Compounds were prepared according to Examples C10 to C12 using intermediate 3 and the intermediate from step D of example C10.

Table CV

ph ^ h ΑχΑ hci c = o 0 A X MF isomer FAB-MS 1 CO2Bn C35H43N3O4 RS 570 2 CO 2 H C28H37N3O4 RS 480

Example C14

ABOUT

OEt

299

Stage A:

A solution of 4.9 mL, 12.36 mmol of n-BuLi in hexane was added to a stirred solution of 2.3 mL, 1.92 g, 13.5 mmol of 2,2,6,6-tetramethylpiperidine, TMP, in 25 mL of THF while cooling with an ice bath. In a separate vessel, a mixture of 1.73 g (5 mmol) of ethyl Nt-Boc-3-benzyl nipecotate from Step B of Example Cl and 0.78 mL, 2.15 g, 12.4 mmol of CH ₂ Br ₂ in 20 ml THF to -78 ° C, then add the above prepared solution of lithium salt in TMP over 15 minutes at a temperature below -65 ° C. The mixture is allowed to stand for 10 minutes, then 11.2 ml is added over 10 minutes at -78 ° C.

11.2 mmol of LHMDS solution. After the addition was complete, the cooling bath was removed and the resulting mixture was allowed to warm slowly to 0 ° C. The mixture is then cooled in an ice bath and a solution is added over 15 minutes at a temperature of less than 5 ° C

13.5 mL, 33.7 mmol of n-BuLi in hexane. The resulting mixture was allowed to warm to room temperature and was stirred at room temperature for 45 minutes. The mixture is then recooled to -78 ° C and 30 ml of acidified ethanol are added to the mixture at 0 ° C with stirring over 50 minutes. The resulting mixture is evaporated to dryness and the residue is suspended in 100 ml of dichloromethane. 0.7 ml (5.0 mmol) of triethylamine and 1.09 g (5.0 mmol) of di-tert-butyl dicarbonate are added successively with stirring. After stirring at room temperature for 1 hour, the mixture was washed with saturated aqueous sodium chloride solution, dried and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with a gradient of 10 to 30% ethyl acetate in hexane. 1.44 g of the title compound are obtained in a yield of 80%.

300

Stage B:

OEt

The product was prepared according to the procedure of Example C, Step C, from 1.30 g, 3.56 mmol of the intermediate from the previous step in 50 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 45 min. 975 mg of the title compound are obtained in a yield of 91%.

FAB-MS calc. 261, found 262 (M + H).

Stage C:

The product was prepared according to the procedure of Example D, Step D, from 55 mg, 0.21 mmol of the intermediate from the preceding step, one equivalent of intermediate 1, one equivalent of HOBT, one equivalent of N-methylmorpholine and 80 mg, 0.42 mmol of EDC. Purification by MPLC, eluting with 60% ethyl acetate in hexane, afforded 77 mg of the product in 61.5% yield.

301

Stage E:

The product was prepared according to the procedure of Example C, Step C, from 77 mg, 0.13 mmol of the intermediate from the previous step in 8 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 15 minutes. Yield: 59 mg (85%).

FAB-MS calc. 532, found 533 (M + H).

Example C15

Stage A:

The intermediate of Example C10 (1.85 g, 4.52 mmol) was hydrogenated under a hydrogen pressure of 1 bar in the presence of 150 mg of 10% palladium on charcoal in 20 ml of ethanol. Filtration through a pad of Celite and evaporation gave 1.36 g of the product in 94% yield.

302 1H NMR (CDCl3, 400 MHz) δ 7.27-7.19 (m, 3H), 7.14-7.10 (m, 2H), 4.08-3.59 (br. M, 1H), 3.63-3.59 (m, 1H) ), 3.15-3.05 (br. M, 2H), 2.9. (d, J = 13.5Hz, 1H), 2.79 (d, J = 13.5Hz, 1H), 2.05-1.95 (br. m, 1H), 1.70-1.45 (m, 3H), 1.42 (s) 9H). EI-MS calc.

EI-MS calculated for C C- ^ ^ sNCO ^: 319, found 319 (M +).

Stage B:

To a solution of 320 mg, 1.0 mmol of the intermediate from the previous step in dichloromethane containing 163 mg, 2.0 mmol of ethylamine hydrochloride, 1.0 equivalents of DMAP and 2 equivalents of N-methylmorpholine was added 2 equivalents of EDC. The reaction mixture was stirred overnight at room temperature. The solution was washed with 3M HCl and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. yield 76%, 262 mg.

1 H NMR (CDCl 3, 400 MHz) δ 7.21-7.13 (m, 3H), 7.03 (d, 2H). 6.68 (br. S, 1H), 4.18 (br. D, 1H), 3.96 (br. D, 1H), 3.12-3.00 (m, 4H), 2.70-2.40 (br. M, 5H) 1.60-1.50 (m, 1H), 1.37 (s, 9H), 1.201.30 (m, 1H), 0.90 (q, J = 7.3 Hz, 3H).

EI-MS for C 20 H 30 F 3 O 3 ^: calculated 346, found 346 (M +).

Stage C:

NHeT

303

The product was prepared according to the procedure of Example C, Step C, from 262 mg, 0.76 mmol of the intermediate of the preceding step in 5 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 1 hour to give 194 mg of the product.

1 H NMR (CD 3 OD, 400MHz) δ 8.28 (br. S, 1H), 7.30-7.24 (m, 3H), 7.14-7.12 (m, 2H), 3.43 (d, J = 12 Hz, 1H) 3.34-3.28 (m, 2H), 3.263.20 (br. D, 1H), 3.11 (d, J = 14Hz, 1H), 2.88 (dt, J = 3.2Hz, 13Hz,

1H), 2.81 (d, J = 12.5Hz, 1H), 2.77 (d, J = 14Hz, 1H), 2.24 (d, J = 13Hz, 1H), 1.87 (td, J = 2.8Hz) 14 Hz, 1 H), 1.75 (dt, J = 3.3 Hz, 13.5Hz,

H), 1.64-1.55 (m, 1H), 1.17 (t, J = 7Hz, 3H).

Stage D:

The product was prepared according to the Step D of Example Cl from 62.2 mg, 0.22 mmol of the intermediate from the previous step, 1 equivalent of intermediate 1, 1 equivalent of HOBT, 1 equivalent of N-methylmorpholine and 2 equivalents of EDC. Purification by MPLC eluting with ethyl acetate gave two diastereomers. In a yield of 26%, 35.8 mg of the isomer d 2 which exits the column earlier is obtained, and in a yield of 31%, 43.8 mg of the isomer d ₂ which exits the column later is obtained.

@ 1 H-NMR (CDCl3, 400 MHz); the compound exists in two rotamers in a ratio of 1: 1: .delta.

8.7 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.25-6.96 (m, 8 H), 6.69 (br. S, 1/2 H), 5.28-5.12 (m, 1 / 2 H), 4.94 (v. Br. M, 1/2 H), 4.31 (br. D, J = 14.6 Hz,

1/2 H), 3.49 (v. D, J = 13 Hz, 1/2 H), 3.22 (dd, J = 4.7 Hz, 14.3 Hz, 1/2 H), 3.03-2.97 (m, 2 H), 2.90 (d, J = 13.4 Hz, 1/2 H), 2.40 (br. D, 1/2 H),

2.36 (d, J = 13.3Hz, 1/2 H), 2.10 (d, J = 13.5Hz, 1/2 H), 1.92-1.82 (br. M, 3/2H), 1.47 (s, 3H) ), 1.41 (s, 9H), 1.38 (s, 3H), 1.32-1.20 (m), 1.ΙΟΙ.00 (dt, 1/2H), 0.85 (t, J = 7.2Hz, 3H) ).

304 d ^: FAB-MS for ^C 35 ^H 47 ^N 5 ° 5 ^: calculated 617, found 618 (M + H) d ₂ : FAB-MS for ^C 35 ^H 47 ^N 5 ° 5 ^: calculated 617, found 618 (M + H)

Stage E:

The product was obtained according to the procedure of Example C, Step C, using 35 mg, 0.057 mmol of intermediate d1 from the previous step in 3 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 30 min. Yield: 32.5 mg (100%).

FAB-MS for C ₃ GH ₃ g of N ₃ O _3: Calculated 517 ', found 518 (M + H).

Example C16

Prepared according to Step C of Example C1 from 41 mg, 0.66 mmol of intermediate d ₂ from Step D of Example C15 in 3 mL of ethyl acetate by bubbling hydrogen chloride gas for 30 min at 0 ° C. Yield: 36.5 mg (100%).

H-NMR (CD ₃ OD, 400 MHz) The compound exists in two rotamers in a ratio of 4: 1: δ 8.21 (d, J = 7.4 Hz, 5.4 H), 2.8 (d, J = 7.4 Hz, 1 / 5H), 7.68 (d, J = 7.8Hz, 1/5H), 7.54 (d, J = 7.8Hz, 4/5H), 7.35 (d, J = 7.1Hz, 4/5H), 7.31 (d, J = 7.1Hz, 1/5H), 7.26-6.98 (m,

305

6), 5.46-5.40 (m, 1/5 Η), 5.25-5.20 (m, 4/5 Η), 4.00 (br. D, 4 / 5H), 3.85 (br. D, 1 / 5H) 3.65 (br. D, J = 13.2 Hz, 4 / 5H), 3.60-3.54 (m, 1 / 5H), 3.36 (br. D, 1 / 5H), 3.30-3.03 (m), 2.99 -2.90 (m); 2.82-2.62 (m); 2.46 (d, J =

13.3 Hz, 8 / 5H), 2.08 (br. D, 4 / 5H), 1.90-1.84 (m, 1 / 5H), 1.76-1.65 (m), · 1.51,1.49 (2s, 6H) 1.40-1.20 (m), 1.00 (t, J = 7.2Hz, 3 / 5H), 0.88 (t, J =

7.2 Hz, 12/5 H).

FAB-MS calcd for C17 H18 N6 O5: 517, found 518 (M + H).

Example C17

Stage A:

To a suspension of 2.3 g (68.8 mmol) of the S-isomer of the intermediate from Example C2, Step A in 25 mL of 3M sodium hydroxide solution, 200 mL of dichloromethane and 100 mL of water was slowly added 18 g, 1.2 equivalents of di-tert. . -butyldicarbonate. After the addition was complete, the mixture was stirred for a further 5 hours, then carefully acidified to pH 3 and extracted three times with ethyl acetate. The organic extracts were combined, dried and evaporated to give 23.7 g of a white solid. A solution of this intermediate (11.5 g, 33.1 mmol) and 3M NaOH (30 ml) in a mixture of ethanol (200 ml) and water (10 ml) was refluxed for one day. Ethanol was evaporated from the solution and the residue was acidified to pH 3 with 3M hydrochloric acid solution and then extracted with ethyl acetate. The extract is dried, evaporated and the residue is purified to a residue

A short column of silica gel was used, eluting first with 20% ethyl acetate in hexane and then with pure ethyl acetate, yielding 8.76 g of the product in 83% yield. The NMR and MS spectra were identical to those of the product of Step C of Example C15.

Stage B:

Boe .K

NHeT

To a mixture of 660 mg, 2.07 mmol of intermediate from the previous step, 251 mg, 1.5 equivalents of ethylamine hydrochloride, 0.23 mL, 1 equiv of NMM and 1 equivalent of HOBT in 10 mL of 1: 1 dichloromethane: DMF was added EDC . The mixture was stirred at room temperature for two days, then refluxed for 2 hours and then poured into a mixture of dilute hydrochloric acid and saturated sodium chloride solution. The resulting mixture was extracted with ethyl acetate, the organic layer was washed with dilute sodium hydroxide, dried and evaporated. The residue was purified by flash chromatography eluting with 20 to 80% ethyl acetate in hexane to give 540 mg of the product in 75% yield. The NMR and MS spectra were identical to those of the product of Step C of Example C15.

The product was prepared according to the procedure of Example C, Step C, from 0.33 g, 0.95 mmol of the intermediate from the previous step in 5 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 15 min. Yield 0.279 mg (100%).

307

FAB-MS calcd. 246, found 247 (M + H).

Stage D:

Prepared according to Part D, Step D, from 100 mg, 0.354 mmol of intermediate from the previous step, 134 mg, 0.354 mmol of intermediate 3, 48 mg, 1 equivalent of HOBT, 0.039 mL, 1 equivalent of N-methylmorpholine and 102 mg, 1.5 equivalents EDC. After purification by MPLC eluting with ethyl acetate, 140 mg of the title intermediate was obtained in a yield of 65%. FAB-MS calcd for C 35 H 50 N 4 O 5 606 ', found 607 (M + H).

Stage E:

The product was prepared according to the procedure of Example C, Step C, from 132 mg, 0.217 mmol of the intermediate from the preceding step in 5 mL of ethyl acetate by bubbling hydrogen chloride gas for 10 minutes at 0 ° C.

dj: FAB-MS for C 30 H 42 N 4 O 3: calculated 506, found 507 (M + H)

The further prepared intermediates shown in Table CVIa were as per Examples C15 and Example C17, grades A to C.

308

The resulting products were prepared according to Example C17, steps D and E using intermediate 1.

Table CVIa

intermediate product Product X MF FAB-MS (M + 1). MF FAB-MS (M + 1). isomer 1 -COI ^mor folino) C17H24N2O2 288 (M &lt; + &gt;, EI) C32H41N5O4 560 WITH 2 -CONHCH3 C14H20N2O 233 C29H37N5O3 504 with 3 -CONH- CH2CO2EI C17H24N2O3 304 (M &lt; + &gt;, EI) C32H41N5O5 576 with 4 -CO2CH2CO2Et C17H23NO4 306 C32H40N4O6 577 R WITH 5 -CO2 (CH2) 2SMe C16H23NO2S 294 C31H40N4O4S 565 R WITH 6 CON (CH3) 2 C15H22N2O 247 C30H39N5O3 518 dl d2 7 -CONH- (CH 2) 2 OH C15H22N2O2 263 C30H39N5O4 534 WITH

In the same way, compounds of Table CVIb can be obtained using intermediate 1 and 3-aminopropanol or 2- (ethylthio) ethylamine.

309

Table CVIb

-CONH (CH 2) 3 OH

-CONHCH2CH2SCH3

Other compounds listed in the following Table CVIc were prepared according to the steps of Example C17, Step C and D, using some of the intermediates in Table CVIa and Intermediate 3.

Table CVIc

FAB-MS (M + 1).

1 -CO (morpholino) C 32 H 44 N 4 O 4 549 WITH 2 -CONHCH3 C29H40N4O3 WITH 493 3 -CONH- C32H44N4O5 WITH CH2CO2Et 565 4 -CONH- C30H42N4O4 WITH (CH 2) 2 OH 523

310

The compounds listed in the following Table CVId can be prepared in an analogous manner using 3-aminopropanol and 2- (methylthio) ethylamine.

-CONH (CH 2) 3 OH

-CONHCH2CH2SCH3

Compounds of the following table CVIe were prepared according to steps C and D of Example 17 using intermediate 2 and some of the intermediates in table CVIe.

Table CVIe

H

HCl

ph '

FAB-MS (M + 1).

-CO (morpholino) C 31 H 42 N 4 O 5 551

-CONHCH3

-CONHCH2CO2Et

C28H38N4O4

495

C31H42N4O6

567

WITH

311

Example C18

Stage A:

Boe ^{ν ί} · OH

To a stirred solution of 10.4 g (29.93 mmol) of ethyl N-t-Boc-phenylmethyl nipecotate in 100 mL of dichloromethane at -78 ° C was added 45 mL, 14 hours at the reaction completion temperature.

M of DIBAL solution. The reaction mixture is stirred at -78 ° C and then 5 ml of methanol are added. The reaction mixture is carefully washed with aqueous tartaric acid solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The product was purified by flash chromatography on silica gel using a gradient of 40 to 80% ethyl acetate in hexane to give 6.81 g of the product in 5% yield.

EI-MS for calc. 305, found 305 (M +).

Step B: 3-phenylmethyl-3-piperidine-methanol hydrochloride

OH

312

A solution of the intermediate from the previous step (770 mg, 2.52 mmol) in a mixture of 20 ml of ethanol and 1 ml of concentrated HCl was refluxed for 3 hours. The reaction mixture was cooled to room temperature and evaporated to give 609.0 mg of the product as a white solid in 100% yield.

1 H NMR (CD 3 OD, 400 MHz) δ 7.31-7.19 (m, 5 H). 3.45 (ABq, J = 11Hz, 2H), 3.18 (d, J = 13Hz, 1H), 3.19-3.13 (m, 1H), 3.03-2.99 (m, 1H), 2.96 (d, J = 13 Hz, 1H), 2.72 (s, 1H), 1.92-1.84 (m, 2H), 1.60-1.50 (m, 2H).

EI-MS calc. For C H ^ HH ^ ^NONO: calcd 191, found 191 (M +).

Stage C:

The product was prepared according to the step D of Example Cl from 142 mg, 0.587 mmol of the intermediate from the previous step, 0.8 equivalents of intermediate 1, 1 equivalent of HOBT, 1 equivalent of N-methylmorpholine and 2 equivalents of EDC. The product was purified by MPLC, eluting with ethyl acetate to give two compounds. In a yield of 58% gave 98.5 mg of the isomer d ₁ which projects from the column first, and in a yield of 12% gave 34.5 mg of the isomer d _2, which protrudes from the column later.

d ^ FAB-MS for C ₃₂ H ₄₂ N ₂ Og calcd 562, found 563 (M + H) _d2 FAB-MS for C ₃₂ H ₄₂ N ₂ 0 g calcd 562, found 563 (M + H).

313

The intermediate (d) (60 mg, 0.104 mmol) from the previous step was treated with hydrogen chloride gas in 3 mL of ethyl acetate for 5 min at 0 ° C. Evaporation of the mixture affords the diastereomer d of the title compound.

FAB-MS calcd for 476, 364, 436, found 477 (M + H).

To 20 mg of the intermediate _d2 from Step C was bubbled hydrogen chloride gas for 5 minutes at 0 DEG C. in 3 ml of ethyl acetate. Evaporation of the mixture afforded the diastereomer d _{2 of the} title compound.

_d2 FAB-MS for C 28 ^ 36 ^ 4θ3 ^{in the} read YP 476, found 477 (M + H).

Example C19

Stage A:

314

To a stirred solution of the intermediate of Example C18 (5.12 g, 6.8 mmol) and triethylamine (4.7 mL) in dichloromethane was added mesyl chloride (1.95 mL) at 0 ° C. The reaction mixture was stirred for 2 hours, then poured into a mixture of saturated sodium chloride solution and 3M HCl solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give the mesylate, which was heated together with 2.2 g, 33.6 mmol of sodium azide in 20 mL of DMSO at 80 ° C for two weeks. The mixture was then poured into a mixture of water and ice and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried and evaporated. The residue was purified by silica gel column chromatography to give 4.14 g of the title azide in 75% yield. 1 H NMR (CDCl 3, 200 MHz) 57.29-7.13 (m, 5H), 3.61-3.57 (br. m, 1H), 3.47 (d, J = 12 Hz, 1H), 3.20-3.10 (v. br.) s, 2H, 3.10-2.96 (v. br. d,

H, 2.60-2.45 (br. M, 2H), 1.65-1.48 (m, 4H), 1.44 (s, 9H), 1.41-1.35 (m, 1H).

FAB-MS for C gH2gN ₂ 0 ₄ calculated 330, found 331 (M + H).

Stage C:

The azide (1.60 g, 4.84 mmol) from the previous step was hydrogenated in the presence of 160 mg of 10% palladium on charcoal in 25 ml of ethanol for 2 hours in a flask under a hydrogen pressure of 1 bar. The reaction mixture was filtered through a pad of celite and evaporated to give 1.42 g (96%) of the title amine.

FAB-MS for C _{1 2} 0 ₂ gH2gN calcd 304, found 305 (M + H).

315

Stage D:

To a stirred solution of the preceding step 1.30 g (4.27 mmol) in 20 mL of dichloromethane containing 20 mg of DMAP and 1 mL of triethylamine at 0 ° C was added 0.73 mL, 5.12 mmol of CbzCl. The reaction mixture was stirred for 2 hours, then poured into a mixture of saturated sodium chloride solution and 3M HCl solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated, the residue was purified by flash chromatography, eluting with 20% ethyl acetate to give 1.52 g of product.

FAB-MS calcd for C26H34N2O4 438, found 439 (M + H).

Stage E:

To a stirred solution of the intermediate from 1.50 g (3.42 mmol) in ethyl acetate (50 mL) at 0 ° C was added hydrogen chloride gas by bubbling until saturation. The reaction mixture was stirred for 1 hour, then evaporated to give 1.32 g of the title salt in 100% yield.

1 H NMR (CD 3 OD, 400MHz) δ 7.40-7.18 (m, 10H), 5.14 (s, 2H), 3.43, 3.42 (2 d, J = 14.8 Hz, 1H), 3.23 (td, J = 4 Hz, 12.1 Hz, 1H), 3.00 (d, J = 13 Hz, 1H), 2.94 (d, J = 14.7 Hz, 1H), 2.83 (dt, J = 3.4 Hz, 12 Hz, 1H) 2.74 (d, J = 13.6 Hz, 1 H), 2.68 (d, J = 13.6 Hz, 1 H), 2.00-1.90 (m, 1) H, 1.92-1.88 (m, 1H), 1.59-1.52 (m, 1H), 1.47-1.44 (m, 1H).

316

FAB-MS calcd for C ₂₁ H 22 N ₂ O ₂ 338, found 339 (M + H).

Grade F:

Prepared according to Part D, Example D, from 1.00 g, 2.67 mmol of intermediate from the previous step, 1.04 g, 1 equivalent of intermediate 1, 1 equivalent of HOBT, 2 equivalents of N-methylmorpholine and 820 mg, 4.27 mmol EDC. the product was purified by MPLC eluting with 60% ethyl acetate in hexane to give 1.54 g of product in 81% yield.

G grade:

The intermediate from 1.30 g, 1.83 mmol was hydrogenated in the presence of 100 mg of 10% palladium on charcoal in 15 ml of ethanol under a hydrogen-filled flask. The reaction mixture was then filtered through celite and evaporated to give 1.20 g of the amine in 100% yield.

FAB-MS calc. For C CHH ^^N NO ^ requires 575, found 576 (M + H).

317

Grade H:

To a stirred solution of the intermediate of the previous step (286 mg, 0.497 mmol), DMAP (10 mg) and N-methylmorpholine (0.109 mL) in dichloromethane (0 mL) was added mesyl chloride (0.042 mL) at 0 ° C. The reaction mixture was stirred for 2 hours and then poured into a mixture of saturated sodium chloride solution and 3 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated, and the residue was purified by flash chromatography eluting with 90% ethyl acetate in hexane to give 285.9 mg of the product.

FAB-MS calcd for C C HH ^ yNgOgS 653, found 654 (M + H).

Stage I:

The product was prepared according to the procedure of Example C, Step C, from 265 mg, 0.405 mmol of the intermediate from the previous step in 8 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 30 min. 189 mg (79%) of product are obtained.

FAB-MS calc. For C29H39N5O4S 553; found 554 (M + H).

318

Example C20

The product was prepared according to Step C of Example C1 from 109 mg, 0.154 mmol of the intermediate from Step F of Example C19 in 4 mL of ethyl acetate by bubbling hydrogen chloride gas for 30 minutes at 0 ° C. Yield: 90 mg (90%).

FAB-MS calcd for C36H43N5O4 609, found 610 (M + H).

Example C21

Stage A:

A mixture of 208 mg, 0.362 mmol of the intermediate of Example C19, G, 2 ml of pyridine and 2 ml of acetic anhydride was heated at 60 ° C for 30 minutes. The mixture was evaporated

319 under vacuum. The residue was purified by MPLC eluting with 80% ethyl acetate in hexane to give 202 mg of the title product in 90% yield.

FAB-MS calcd for C35H47N5O5 617, found 618 (M + H).

Stage B:

The product was prepared according to Part C, Example C, from 192 mg, 0.311 mmol of the intermediate from the previous step in 4 mL of ethyl acetate by bubbling hydrogen chloride gas for 30 minutes at 0 ° C. 168.1 mg of the title compound are obtained in a yield of 98.5%.

FAB-MS calculated for C7 ^HHHN ^O ^ 517, found 518 (M + H).

Example C22

Stage A:

OEt

320

A suspension of 200 mg of platinum oxide, 5.0 g, 30.3 mmol of ethyl 3-pyridylacetate and 10 ml of concentrated hydrochloric acid in 50 ml of ethanol is stirred overnight under a flask filled with hydrogen. The mixture was then filtered through a pad of celite and evaporated to dryness, and the residue was boiled for 30 minutes with anhydrous acidified ethanol. After evaporation of the mixture, 6.28 g of product are obtained in a yield of 100%.

1 H NMR (CD 3 OD, 400MHz) δ 4.13 (q, J = 7.2Hz, 2H), 3.40 (dd, J =

3.5 Hz, 12 Hz, 1H), 3.35 (br. D, 1H), 2.90 (br. T, 1H), 2.73 (t, J = 12 Hz,

H), 2.35 (d, J = 7.5 Hz, 2H), 2.26-2.17 (m 1H), 1.96-1.80 (br. M, 2H), 1.80-1.70 (m, 1H), 1.37-1.26 (m, 1H), 1.24 (t, J = 7.1Hz, 3H).

Stage B:

The product was prepared according to the procedure of Example D, Step D, from 128 mg, 0.617 mmol of the intermediate from the previous step, 200 mg, 0.514 mmol of intermediate 1, 1 equivalent of HOBT, 1 equivalent of N-methylmorpholine and 200 mg EDC. Purification by MPLC eluting with 80% ethyl acetate in hexane yielded 247 mg of the product in 89% yield.

Stage C:

ABOUT

OEt

321

The product was prepared according to the procedure of Example C, Step C, from 225 mg, 0.415 mmol of the intermediate from the previous step in 5 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 15 minutes. Yield 100%

184 mg of the title compound.

FAB-MS for C 24 ^ 34 ^ 4 ^ 4 ^{in the} read yP ° 442, found 443 (M + H).

Example C23

7.25 g (7.08 mmol) of the less polar intermediate (d) from Step A of Example C8 were refluxed for 8 hours with a NaOH solution. Thereafter, 3 to the solution was added slowly with stirring in a mixture of 20 ml of ethanol and 8.5 ml of a 10 M mixture, cooled to room temperature with a solution of HCl to pH 11. Di-tert-butyl dicarbonate in 20 ml of dioxane was added. the mixture was stirred for 2 hours. The solution was acidified to pH 4 and then neutralized to pH 7 and extracted three times with ethyl acetate. The organic extracts were combined, dried and evaporated to give 6.80 g of a white solid.

FAB-MS calc. For C17 H14 F3 O4 320, found 321 (M + H).

322

Stage B:

Boe

To a solution of 6.5 g of the intermediate from the previous step, 2 equivalents of benzyl alcohol and 20 mg of DMAP in 100 mL of dichloromethane was added 1.2 equivalents of EDC. The mixture was stirred at room temperature for 3 days and then poured into dilute sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, dried over magnesium sulfate and evaporated. The residue is purified by flash chromatography eluting with 40% ethyl acetate in hexane to give 6.53 g (78%) of the desired product.

FAB-MS for C ₂ 4 H ₃ q N ₂ O4 Calc'd 410, found 411 (M + H).

311 (M ^{@ +} -Boc (100)).

Stage C:

H HCl N

OBn

The product is prepared according to step C of Example C1 from 1.0 g,

2.44 mmol of the intermediate from the previous step in 40 ml of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 15 minutes. 935 mg of product are obtained in a yield of 99%. FAB-MS for C ₁ gH ₂₂ N ₂ O ₂ Calc'd 310, found 311 (M + H).

323

Stage D:

The product was prepared according to the procedure of Example D, Step D, from 800 mg, 2.09 mmol of intermediate from the previous step, 812 mg, 2.09 mmol of intermediate 1, 1 equivalent of HOBT, 1 equivalent of N-methylmorpholine and 2 equivalents of EDC. After purification by MPLC eluting with 80% ethyl acetate in hexane, 1.10 g of intermediate was obtained in 77% yield.

dFAB-MS calcd for C17 H18 N3 O8 681, found 682 (M + H).

Stage E:

A suspension of 150 mg of 10% palladium on charcoal and 1.05 g, 1.54 mmol of the intermediate from the previous step in 20 ml of ethanol was stirred vigorously under a hydrogen atmosphere for 30 minutes. Then the reaction mixture was filtered through celite and evaporated to give 828 mg of the title product in a yield of 91%, dj FAB-MS calc. 591, found 592 (M + H).

324

Grade F:

The product was prepared according to the procedure of Example C, Step C, from 211 mg, 0.35 mmol of the intermediate from the previous step in 15 mL of ethyl acetate by bubbling hydrogen chloride gas for 10 minutes at 0 ° C. Yield: 175.6 mg (93%).

FAB-MS calcd for C27H33N5O4 491, found 492 (M + H).

Example C24

Stage A:

Boe fk

O (CH ₂ ) ₂ SCH ₃

To a stirred solution of the product from Example C, Step A, 5.67 g, 18.1 mmol, 2- (methylthio) ethanol, 2.49 g, 27.1 mmol, DMAP (220 mg) in dichloromethane (100 mL) was added EDC and the mixture was stirred for one day. stirred. The reaction mixture was washed with saturated sodium chloride solution, dried and evaporated and the residue was evaporated

325 was purified on a silica gel column eluting with 60% ethyl acetate in hexane to give the title compound (6.64 g, 94%).

FAB-MS calc. For C20H30QN2O4S 394, found 395 (M + H).

Stage B:

O (CH ₂ ) ₂ SCH ₃

The product was prepared according to the procedure of Example C, Step C, from 6.12 g, 15.5 mmol of the intermediate from the previous step in 30 mL of ethyl acetate by bubbling hydrogen chloride gas for 30 minutes at 0 ° C. 5.38 g of product are obtained in a yield of 95%.

FAB-MS calcd for O2H2O2O2O2: 294, found 295 (M + H).

Stage C:

The product was prepared according to Example D, Step D, from 2.0 g,

5.44 mmol of intermediate from the previous step, 2.12 g,

5.44 mmol of intermediate 1, 1 equivalent of HOBT, 1 equivalent of N-methylmorpholine and 1.5 equivalent of EDC. After purification by MPLC eluting with 80-100% ethyl acetate in hexane, 3.44 g of intermediate was obtained in a yield of 95%.

FAB-MS calcd for C35H47N5O6S 665, found 666 (M + H).

326

Stage D:

^ O (CH ₂ ) ₂ SCH ₃ h

^{Ν γ <ΝΗ} ₂ HCl

The product was prepared according to the procedure of Example C, Step C, from 2.94 g, 4.42 mmol of the intermediate from the previous step in 10 mL of ethyl acetate and hydrogen chloride gas, which was bubbled through the solution for 20 minutes at 0 ° C. 2.80 g of product are obtained in a yield of 99%.

FAB-MS calc. For ¢30? 39? 048 calculated 565, found 566 (M + H).

Other intermediates listed in Table CVII below were prepared according to the steps of Example C24, Steps A and B. The resulting compounds were prepared according to the steps D and E of Example C17 using intermediate 1.

Table CVII

intermediate product

Product

327

X intermediate product MF FAB-MS (M + 1) Product MF FAB-MS (M + 1) 1 CO2 (CH2) 2SMe C15H22N2O2S 295 C30H39N5O4S 566 2 c02Bn C19H22N2O2 311 C34H39N5O4 582 3 c02Bn C19H22N2O2 311 C34H39N5O4 582 4 CO2 (CH2) 3CH3 C16H24N2O2 277 C31H41N5O4 548 5 CO2 (CH2) 2CH3 C15H22N2O2 263 C30H39N5O4 534 6 CO2CH (CH3) 2 C15H22N2O2 263 C30H39N5O4 534 7 CONH (CH2) 3CH3 CI6H25N3O 276 C31H42N6O3 547 8 CONHCH (CH 3) 2 C15H23N3O 262 C30H40N6O3 533 9 CO2CH2CO2EI C16H22N2O4 306 C31H39N5O6 578 10 CONHEt C14H21N3O C29H38N6O3 248 519 11 CONHCH2CO2Et CI6H23N3O3 307 C31H40N6O5 577

isomer

R

R

WITH

RS

RS

RS

RS

RS

RS

RS

RS

Compounds having the RS configuration were prepared using racemic intermediates instead of chiral intermediates.

Example C24A

To a stirred solution of the product of Example C24 (120 mg, 0.188 mmol) in ethanol (3 mL) and water (2 mL) was added sodium periodate (100 mg, 0.46 mmol) and the resulting mixture was stirred at room temperature. The reaction mixture was poured into 10 ml of a saturated aqueous sodium bicarbonate solution (32 ml) and extracted with dichloromethane (3 x 10 ml). The organic extracts were combined and evaporated to give 89 mg (81%) of the desired product.

FAB-MS calcd for C 30 H 39 N 5 O 5 S 581, found 582 (M + H).

Example C25

Stage A:

To a stirred solution of the intermediate of step E, Example E23 (100 mg, 0.17 mmol), 3- (methylthio) -propanol intermediate (18 mg, 0.17 mmol) and DMAP (3 mg) in dichloromethane (15 mL) was added EDC (1.5 equivalents). Stir at room temperature for 1 day. The reaction mixture was washed with water and saturated brine, dried, evaporated and purified by MPLC eluting with 80% ethyl acetate in hexane to give 88 mg of the title product.

FAB-MS calcd. For C gHHH NNgOgS: 679, found 680 (M + H).

329

Stage B:

The product was prepared according to the procedure of Example C, Step C, from 85 mg, 0.125 mmol, of the intermediate from the previous step in 3 mL of ethyl acetate by bubbling hydrogen chloride gas at 0 ° C for 20 minutes, yielding 95 mg.

FAB-MS calc. 579, found 580 (M + H).

The compounds listed in the following Table CVIII were prepared as in Example C25 using the appropriate amines and alcohols.

_FAB-MS (M + 1)

C0 (morpholino) C31H4ON6O4

560 (M &lt; + &gt;, EI MS)

CO2 (CH2) 4SMe C32H43N5O4S

594

CONH (CH 2) 2 SMe C 30 H 40 N 6 O 3 S

565

CONHEt C29H38N6O3

519

CONH (CH 2) 2 OH C 29 H 38 N 6 O 4

535

330

In a similar manner, using the intermediate from Step C of Example C23 following the steps of D and E using Intermediate 3 instead of Intermediate 1, the compounds of Table CVIIIa were obtained.

X MF FAB-MS (M + 1) 1 CONHEt C29H41N5O3 508 2 CONH (CH2) 2 OH C29H41N5O4 524 Similarly is possible using of the intermediate of step

E of Example C23 by the above method or using the intermediate of Step A of Example C23 by the method of Step A to D of Example C24 using Intermediate 1 or Intermediate 3 to prepare the compounds listed in the following Table CVIIIb.

331

-CONH (CH 2) 3 OH

H _{(CH2) 3} 5 ^^ / ^(CH2) 3U

-CONHCH2CH2SCH3

Example C26

Step A: 3-carboxybenzyloxyaminopyridine

To a solution of 3-aminopyridine (10 g, 0.106 mol) and triethylamine (16.3 ml, 0.117 mol) in dichloromethane (100 ml) was added benzyl chloroformate (15.2 ml, 0.106 mol) at 0 ° C. Benzyl chloroformate is added slowly in portions. The reaction mixture was stirred overnight, then washed with water, saturated sodium bicarbonate solution, dried (MgSO 4) and evaporated. The residue was purified by silica gel column chromatography to obtain 9.51 g of product. FAB-MS for ^the yp read ° 228, found 229 (M + H).

332

Step B: 3-carbobenzyloxyaminopiperidine

A solution of 9.51 g (41.7 mmol) of the intermediate from the previous step and 3.5 ml (41.7 mmol) of hydrochloric acid in 300 ml of ethanol was hydrogenated in the presence of 0.9 g of platinum oxide overnight under a hydrogen pressure of 1 bar. Filtration and evaporation of the filtrate gave the product as a brown solid.

FAB-MS calc. 234, found 235 (M + H).

Stage C:

To a solution of the intermediate of 4.65 g, 17.2 mmol, 6.68 g, 1 equivalent of intermediate 1, 2.32 g, 1 equivalent of HOBT and 2.1 mL, 1 equivalent of NMM in 100 mL of dichloromethane was added 3. 94 g, 1.2 equivalents of EDC. The reaction mixture was stirred overnight and then worked up by washing with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated. Purification by silica column chromatography gave 2.5 g of the desired product.

FAB-MS calcd for C- ^H ^ NNgOg 605, found 606 (M + H).

Stage D:

NHBOC

H

333

A suspension of 2.5 g of the intermediate from the preceding step and 250 mg of 10% palladium hydroxide on charcoal in 60 ml of methanol was stirred for 3 days at a hydrogen pressure of 1 bar. The reaction mixture was then filtered through a pad of celite and evaporated to give the title product.

Stage E:

To a solution of 326 mg, 0.5 mmol of the intermediate from the preceding step and 0.11 mL, 0.6 mmol of Ν, di-diisopropylethylamine in 10 mL of dichloromethane was added 0.053 mL, 0.5 mmol of isobutyryl chloride at 0 ° C. The reaction mixture was stirred for 2 hours, then washed with water, saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica eluting with 90-100% ethyl acetate in hexane to give the title product.

FAB-MS calcd. For <RTIgt;% < ^/ RTI> 541, found 541, found 542 (M + H).

Grade F:

334

Hydrogen chloride was added by bubbling at 0 ° C to the intermediate from the previous step in 5 mL of ethyl acetate until saturated. The mixture is stirred for a further 30 minutes, then evaporated to dryness to give the product.

FAB-MS calc. 441, found 442 (M + H).

In a similar manner, the compounds of the following table can be prepared using various acylating reagents.

Table CIX

Acylating agent Y MF FAB-MS (M + 1) 1 Ac 2 O AcNH C22H31N5O3 414 2 ChxCOCl ChxCONH C27H39N5O3 482 3 ChxCH2COCl ChxCH2CONH C28H41N5O3 496 4 BzCl BzNH C27H33N5O3 476 5 PhSO2Cl PhSO2NH C26H33N5O4S 512 6 i-pmC iso-PrNHCONH C24H36N6O3 457

335

Example C27

\ ^ N HCl

NH ₂ HCl

Stage A:

WITH.

\ ^ N

CO ₂ Et

To a stirred solution of KHMDS (27.4 g, 0.138 mol) in THF (500 mL) at -78 ° C under argon was added ethyl N-t-Boc-nipecotate (28.3 g, 0.11 mol) in THF (100 mL) over 20 minutes. The solution was stirred for 30 minutes at -78 ° C and then a solution of 4-bromomethylthiazole or 4-chloromethylthiazole in 100 ml THF was slowly added to the reaction mixture, and 4-bromomethylthiazole was prepared by 10 ml, 0.11 mmol. 4-methylthiazole,

19.6 g, 0.11 mol of N-bromosuccinimide and 0.2 g of AIBN in 300 ml of carbon tetrachloride are refluxed for 2 hours, then the mixture is cooled to room temperature, filtered and evaporated. 4-Chloromethylthiazole can be prepared according to Hsiao, C. H. et al., Synthetic Communications, 20, (22), 3507-3417, 1990 and Caldwell V. and Fox S. M., J. Am. Chem. Soc., 73, 2935, 1955. The resulting black mixture was stirred overnight and then allowed to warm to room temperature. The material was evaporated, diluted with water and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with a gradient of 30 to 65% ethyl acetate in hexane to give 7.58 g of the title product (20%).

FAB-MS calc. 354; found 355 (M + H).

Stage B:

To a solution of the intermediate from 7.0 g (19.9 mmol) in ethyl acetate (100 mL) at 0 ° C was bubbled hydrogen chloride gas until saturation. The reaction mixture was stirred for 30 minutes and then ethyl acetate was evaporated, yielding 5.3 g of the product in 93% yield.

1 H NMR (CDCl 3, 400MHz) δ 9.67 (s, 1H), 7.75 (s, 1H), 4.34-4.15 (2 m, 2H), 3.67 (d, J = 12.8 Hz, 1H), 3.34 ( d, J = 15Hz,

H), 3.28 (d, J = 12.5Hz, 1H), 3.21 (d, J = 15Hz, 1H), 3.01 (dt, J = 3.0,

12.5 Hz, 1H), 2.26 (br. D, J = 13.7 Hz, 1H), 1.97-1.92 (m, 1H), 1.80 (dt, J = 3.5.13 Hz, 1H), 1.78-1.58 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H).

FAB-MS calcd for C ^ HHig ^ ^ íS S 254, found 255 (M + H).

Stage C:

OAc OAc

C'Y'Sh ° Y ^And Ph

To a stirred solution of 6 g, 18.67 mmol of intermediate from step B, 1 equivalent of (R) - (-) - (O) -acetyl-butyric acid, 1 equivalent of HOBT and 2 equivalents of NMM, at 0 ° C was added 7.16 g. , 37.34 mmol of EDC. The reaction mixture was stirred overnight. During this time, it is allowed to warm to room temperature. The resulting solution is poured into a saturated solution

337 of sodium chloride and extracted with methylene chloride. The organic layer was dried over magnesium sulphate, evaporated and purified by flash chromatography on silica eluting with 40-80% ethyl acetate in hexane to give two pure materials. In the enantiomorphs yield 30 g of isomer Tape dimensions d ^, d g of isomer _2, to give 2.17 exiting from the column first, 12%, 0.87 exiting from the column and subsequent addition of 700 mg of mixed fractions. The material was analyzed by comparing the NMR spectrum of these compounds with that of the intermediates of Step C of Example C8. The absolute stereochemical configuration was determined by X-ray analysis. The result was confirmed by X-ray analysis of intermediate 1. FAB-MS for C ₂₂ H ₂ O ₂ g of N ^ S Calc'd 430, found 431 (M + H). @ 1 H-NMR (CDCl3, 400 MHz): the compound exists as a mixture of two conformers: δ 8.77, 8.65 (2H, 1H), 7.46-7.34 (m, 5H), 7.07, 7.02 (2 s, 1H, 6.64, 6.23 (2s, 1H), 4.29 (br. d, J = 13.9Hz, 1/2 H), 4.10-4.02 (m, 3/2 H), 3.92-3.87 (m) 3.40 (d, J = 13.5 Hz, 1/2 H), 3.40 (d, J = 14 Hz, 1/2 H), 3.40-3.32 (m, 1/2 H), 3.25 -3.21 (m, 1/2 H), 3.18 (d, J = 14Hz, 1/2 H), 3.06 (d, J = 14Hz, 1/2 H), 2.96 (d, J = 14Hz, 1 H, 2.84 (d, J = 14 Hz, 1 H), 2.85-2.75 (br. M, 1 H), 2.14,2.11 (2s, 3 H), 1.90-1.82 (m 1/1 H, 1.80-1.75 (m, 1 H), 1.61-1.55 (m, 1 H), 1.50-1.40 (br. M, 1 H), 1.14 (t, J = 7 Hz) 1.03 (t, J = 7Hz, 3 / 2H). d ₂ : 1 H-NMR (CDCl 3, 400 MHz): the compound exists as a mixture of two conformers: δ 8.71, 8.68 (2d, J = 1.8 Hz, 1H), 7.41-7.34 (m, 5H, 7.06, 6.83 ( 2 d, J = 1.8 Hz, 1 H), 6.41 6.20 (2s, 1 H), 4.46 (br. D, J = 13.4 Hz, 1/2 H), 4.24-3.93 (m, 3 H), 3.41 ( d, J = 13.5 Hz, 1/2 H), 3.313.28 m, 1 H), 3.13 (d, J = 14.2 Hz, 1/2 H), 3.04 (d, J = 14.2 Hz, 1/2 H) ), 3.04 (d, J = 14.2Hz, 1/2 H), 2.92 (d, J = 14Hz, 1/2 H), 2.73 (d, J = 14Hz, 1/2 H), 2.54 (d J = 13.8 Hz, 1 H), 2.30 (br. D, J = 13 Hz), 2.15, 2.09 (2 s, 3 H), 2.00-1.95 (m, 1/2 H), 1.65-1.49 (m) H, 1.37 (dt, J = 4.12, 8 Hz, 1/2 H), 1.17-1.10 (m, 3 H).

Stage D:

338

A solution of intermediate (d) (2.0 g, 4.65 mmol), concentrated hydrochloric acid (25 ml) and ethanol (25 ml) was refluxed for 3 hours and then evaporated to dryness. The residue was neutralized with aqueous ammonium hydroxide solution, extracted with dichloromethane and purified by flash chromatography on silica eluting with 1: 10:90 ammonia / methanol / chloroform to give 0.72 g (61%) of the product.

1 H NMR (CD 3 OD, 400MHz) δ 8.88 (d, J = 2 Hz, 1H), 7.21 (d, J = 2 Hz, 1 H)

H), 4.20-4.07 (m, 2H), 3.28 (br. D, 1H), 3.06 (d, JAB = 14Hz, 1H), 2.97 (d, JBA = 14Hz, 1H), 2.92 -2.80 (md, 1H), 2.61-2.57 (m, 2H), 2.21-2.16 (br. D, 1H), 1.66-1.40 (m, 3H), 1.20 (t, J = 7.3 Hz, 3 H).

FAB-MS calcd for C-j ^H g g ^Cl CS S 254, found 255 (M + H).

Stage E:

To a stirred solution of intermediate of the previous step (163 mg, 0.642 mmol), intermediate 1 (250 mg, 0.642 mmol) and HOBT (87 mg, 0.642 mmol) in dichloromethane (20 mL) at 0 ° C was added EDC (247 mg, 1.28 mmol). The reaction mixture was stirred overnight and then allowed to warm to room temperature. The solution was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Purification by MPLC eluting with 60% ethyl acetate in hexane afforded 285 mg of the title product in 71% yield.

FAB-MS calcd for C25 H25 N5 O5 S 625, found 626 (M + H),

526 (M &lt; ^{+ &gt;} -Boc (100)).

339

Grade F:

Hydrogen chloride gas was bubbled through a solution of 270 mg (0.43 mmol) of the intermediate from the previous step in 10 mL of ethyl acetate at 0 ° C until saturation. The reaction mixture was stirred for 30 minutes and then evaporated to remove ethyl acetate, yielding 226 mg of the product in 93% yield. 1 H NMR (CD 3 OD, 400MHz):

9.90 (d, J = 2.2Hz, 4/5H), 9.5 (d, J = 2.2Hz, 1/5H), 8.48 (d, J = 7.15,4 / 5H), 8.15 (d, 7.15,1 / 5H) 7.70 (d, J = 2.2Hz, 4 / 5H), 7.68 (d, J = 2.2, 1 / 5H), 7.55 (d, J = 7.89Hz, 1 H), 7.27 (d, J = 8.0Hz, 1H), 7.06-6.95 (M, 1H), 3.94 (q, J = 7.1Hz, 2H), 3.94 (q, J = 7.1Hz, 2H), 2.37 (d, J = 14.9, 1H), 1.90 (d) J = 14.9 (1H), 1.60 (s, 6H), 1.07 (t, J = 7.1Hz, 3H),

FAB-MS calcd for C27H35N5O4S 525, found 526 (M + H).

Example C27A

^S , NHCl

The procedure of Example C27 was followed using product d2 from Step C to give the title product.

FAB-MS calcd for C27H35N5O4S 525, found 526 (M + H).

340

Additional intermediates from the following Table CX were prepared using the appropriate alkylating agents according to steps A and B of Example C27. The resulting compounds are then prepared according to steps D and E of Example C1 using intermediate 1.

Table CX

Product

intermediate product

Intermediate Product

Y MF MF FAB-MS isomer FAB-MS 1 ^{H 3>} ^ ~ * ^CH2 C14H22N2O3 · N / J 267 ° Λη ₃ C29H39N5O5 538 RS 2 2-thiazolylmethyl Cl 2 H 18 N 2 O 2 S 255 C27H35N5O4S 526 RS 3 4-thiazolylmethyl C12H18N2O2S 255 C27H35N5O4S 526 RS 4 5-thiazolylmethyl C 12 H 18 N 2 O 2 S 255 C27H35N5O4S 526 RS 5 (4-methyl-2-C13H2ON2O2S) thiazolyl) methyl 269 C28H37N5O4S 540 RS 6 (2-methyl-4-C13H2ON2O2S) thiazolyl) methyl 269 C28H37N5O4S 540 RS 7 (4 - methyl 1 - 5 - C13H2ON2O2S thiazolyl) methyl 269 C28H37N5O4S 540 RS 8 (5 - Methyl - 4 - _{C 3} H 2 ON 2 O 2 thiazolyl) methyl 269 C28H37N5O4S 540 RS

341

Example C28

A solution of 50 mg of the product of Example C27, 5 equivalents of a 3 M NaOH solution in 5 mL of ethanol: water (3: 1) was stirred at 60 ° C for two days. The reaction mixture was then evaporated in vacuo to remove ethanol. The residue was acidified with hydrochloric acid to pH 1 and then evaporated to dryness. The white residue was purified by silica gel column chromatography using a 3:30:70 mixture of ammonia, methanol and chloroform to give 25 mg of the title product. FAB-MS calcd for C 25 H 33 N 5 O 4 S 497, found 498 (M + H).

Example C29

Stage A:

BOC

342

1.5 g, 3.48 mmol of the less polar intermediate d - from step C of Example C27 was boiled for 2 hours in 10 ml of ethanol and 3.5 ml of a 5 M NaOH solution. The mixture was then cooled to room temperature and 3M HCl solution was slowly added until pH 11. Di-tert-butyl dicarbonate (1.52 g, 7 mmol) was added to the stirred solution, stirred for 2 hours, then acidified. to pH 4 and finally neutralized to pH 7 and extracted 3 times with ethyl acetate. The organic extracts were combined, dried and evaporated to give 810 mg of a white solid.

Stage B:

Boe .K

OBn \ ííN

To a solution of 800 mg of the intermediate from the previous step, 1.27 ml of benzyl alcohol and 30 mg of DMAP in 40 ml of dichloromethane was added 935 mg, 4.9 mmol of EDC. The mixture was stirred at room temperature for 3 days and then poured into dilute sodium bicarbonate solution. The resulting mixture was extracted three times with ethyl acetate, and the extract was dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography eluting with 20-40% ethyl acetate in hexane to afford 145 mg of the title product.

Stage C:

The product was prepared according to the procedure of Example C, Step C, from 140 mg of the intermediate of the preceding step in 20 ml of ethyl acetate by bubbling hydrogen chloride gas for 15 minutes at a temperature of 343 ° C. After evaporation, the residue was dissolved in dichloromethane and the solution was washed with aqueous ammonia. The organic layer was dried and evaporated to give the title product.

Stage D:

\ ^ N

The product was obtained according to Example D, Step D, from 140 mg, 0.443 mmol of intermediate from the previous step, 172 mg, 0.443 mmol of intermediate 1, 60 mg HOBT and 170 mg EDC. Purification by MPLC and eluting with 80% ethyl acetate in hexane gave 210 mg of the intermediate.

Stage E:

The product was prepared according to the step C of Example Cl from 12 mg, 0.018 mmol of the intermediate from the previous step and hydrogen chloride gas in 3 ml of ethyl acetate by bubbling for 10 minutes at 0 ° C.

The compounds listed in the following Table CXa can also be obtained by the method of this Example by reacting

The 344 intermediate of Example C29, Step A, is reacted with methylamine, ethylamine, ethanolamine, 3-aminopropanol, or

2- (methylthio) ethylamine instead of benzyl alcohol in step B and at the same time intermediate step 1 or intermediate 3 is used in step D.

Table CXa

H (CH ₂ ) ₃ -CONHCH ₂ CH ₃

Cho-CONHCH2CH2OH

345

-CONHCH2CH2OH

-CONH (CH 2) 3 OH

-CONH (CH 2) 3 OH

-CONH (CH2) 2SCH3

-CONH (CH2) 2SCH3

Example C30

Stage A:

Prepared according to Part D, Example D, from 134 mg, 0.528 mmol of the intermediate from Example C27, 200

346 mg, 0.528 mmol of intermediate 3, 71 mg, 1 equivalent of HOBT and 200 mg, 2 equivalents of EDC. Purification by MPLC eluting with 60% ethyl acetate in hexane gave an intermediate (160 mg, 49%).

FAB-MS calcd for C ^^ g gN ^OgS 606, found 607 (M + H).

The product was prepared according to the procedure of Example C, Step C, from 155 mg, 0.252 mmol of the intermediate from the previous step in 5 mL of ethyl acetate by bubbling hydrogen chloride at 0 ° C for 10 min. Yield: 142 mg (96%).

FAB-MS calcd for C27H38N4O4S 506, found 507 (M + H).

Example C31

Stage A:

NCO

347

Oxalyl chloride (0.89 g, 6.89 mmol) was added slowly at 0 ° C to a stirred solution of the product of Example 15 Step A (2.00 g, 6.26 mmol) and three drops of DMF in 20 mL of benzene. The reaction mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 20 minutes. The mixture was then evaporated in vacuo to give the acyl chloride, which was used for the next reaction without further purification. To a stirred solution of the residue in 20 mL of acetone at 5 ° C was added a solution of 1.22 g, 18.8 mmol of sodium azide in 3 mL of water, and the resulting mixture was stirred at room temperature for 30 minutes. Acetone was evaporated from the reaction mixture, diluted with water and extracted with ethyl ether. The ether extracts were combined and dried over magnesium sulfate. Filtration and evaporation gave the crude azide which was dissolved in 70 mL toluene without further purification and the solution was refluxed overnight to give a toluene isocyanate solution.

FAB-MS calc. 316, found 317 (M + H-Boc (100)).

Boe

Stage B:

NHCOOMe

A solution of 5 mL of methanol and 15 mL of 70 mL of the above solution (1.3 mmol) was refluxed overnight. Then, the reaction mixture was evaporated to give 331 mg of the product as a white solid.

FAB-MS calc. 348, found 349 (M + H).

Stage C:

HHCI N.

NHCO ₂ Me

348

To a solution of 21 mg of the intermediate from the preceding step in 15 ml of ethyl acetate at 0 ° C was bubbled hydrogen chloride gas until saturation. The mixture was stirred for 30 minutes or until TLC analysis was complete. The solution was then evaporated to remove ethyl acetate to give 284 mg of product.

FAB-MS calcd for C 14 H 20 N 2 O 2 248, found 249 (M + H).

Stage D:

The product was prepared according to the procedure of Example D, Step D, from 0.284 g, 1 mmol of intermediate from the previous step, 0.388 g, 1 mmol of intermediate 1, 1 equivalent of HOBT, 1 equivalent of N-methylmorpholine and 1.5 equivalents of EDC. Purification by MPLC eluting with 60% ethyl acetate in hexane gave 0.35 g of the desired intermediate.

FAB-MS calcd for C19H18N6O6 619, found 620 (M + H).

Stage E:

Hydrogen chloride gas was bubbled into the solution of 200 mg of the intermediate from the preceding step in 10 mL of ethyl acetate at 0 ° C until saturation. The reaction mixture was stirred

349 was stirred for 30 minutes and then the ethyl acetate was evaporated to give 158 mg of product.

FAB-MS calc. For ¢29.337.35-4.45 519, found 520 (M + H).

Example C32

To a stirred solution of the intermediate hydrochloride of Step C of Example C2 (2.51 g, 5.34 mmol), 1.16 g, 1 equivalent of N-Boc-p-amino-p-Me-butyric acid, 0.6 mL, 1 equivalent of NMM and 33 mg, 0.05 equivalents of DMAP in 30 mL of dichloromethane are added 1.55 g, 1.5 equivalents of EDC in several portions. The reaction mixture clarified rapidly, stirred for 3 hours, then diluted with dichloromethane and washed successively with 3M HCl solution, saturated sodium chloride solution and saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), evaporated and purified by silica gel column chromatography using 60% ethyl acetate in hexane to give 3.40 g (100%) of product.

FAB-MS calcd for C18 H18 N3 O6 632, found 633 (M + H).

350

Stage B:

To a stirred solution of the intermediate from 3.28 g, 5.18 mmol in 30 mL of ethyl acetate at 0 ° C was bubbled hydrogen chloride gas until saturation. The reaction mixture was stirred for 10 minutes and then evaporated to dryness. The residue was dissolved in dichloromethane and ethyl ether was added. The solid formed is filtered off and dried, first in air and then under high vacuum overnight, to give 2.44 g of the product in 83% yield.

FAB-MS calc. For C31H4QN4O4 532, found 533 (M + H).

The compounds listed in the following table were prepared in the same manner as above, but using different Boe-protected amino acids which were deprotected as described above.

351

rn

D-Alal-Alaβ AlaDL-a-Me-Ser ^JI Y'nh ₂

MF

FAB-MS (M + 1).

C29H36N4O4

505

C29H36N4O4

505

C29H36N4O4

505

C30H38N4O5

535

C30H36N4O4

517

C33H42N4O4

559

D-prone-Me-Aib-

C31H38N4O4

531

C31H40N4O4

To a stirred solution of the product of Example C32 (808 mg, 1.42 mmol), 923 mg, 5 equivalents of (R) -glycerylacetonide and 582 mg, 5 equivalents of sodium acetate in 15 mL of methanol at 0 ° C was slowly added 134 mg. 5 equivalents of sodium cyanoborohydride and the resulting mixture was stirred at room temperature overnight. The mixture was then evaporated to remove methanol and partitioned between sodium bicarbonate solution

352 and dichloromethane. The organic layer was separated and the aqueous layer was extracted twice more with dichloromethane. The organic extracts were combined, dried over magnesium sulfate and purified on a silica gel column, eluting with 5-10% methanol in dichloromethane to give 835 mg of the product in 91% yield.

FAB-MS calcd for C 24 H 18 N 4 O 6 646, found 647 (M + H).

To a solution of the product of Example C33 (367 mg, 0.566 mmol) in methanol (10 mL) was added 3M hydrochloric acid (1 mL) and the resulting mixture was stirred at room temperature for one day. Thereafter, the reaction mixture was evaporated in vacuo, toluene was added and the mixture was again evaporated in vacuo to remove residual water to give 350 mg of the product in 99% yield.

FAB-MS calcd for C 6 H 16 N 2 O 6 606, found 607 (M + H).

Example C35

Other benzyl-substituted intermediates and products listed in Table CXII below were prepared as described in steps A and B of Example Cl using appropriately substituted benzyl halides during the alkylation step. If desired, the functional groups have been altered in step B to transform the cyano groups to carboxamides, esters and tetrazoles, nitro groups to amines and acetylamines and to convert esters to acids (step D) under conventional conditions.

Table CXII

intermediate product Product RL2 MF FAB-MS (M + 1). MF FAB-MS (M + 1). isomer 1 o-cyano C16H20N2O2 C31H37N5O4 dl 273 544 d2 2 m-cyano- C16H20N2O2 C31H37N5O4 dl 273 544 d2 3 p-cyano- C16H20N2O2 C31H37N5O4 dl 273 544 d2 4 P-NH2OC- C16H22N2O3 C31H37N5O4 RS 291 562 5 p-EtO2C- C18H25NO4 C33H42N4O6 dl 320 591 d2 6 P-H02C- C31H38N4O6 dl 563 d2 7 p- (lH-tetrazol 5- C 16 H 21 N 5 O 2 C31H38N8O4 RS yl) 316 587

354

8 m-NH20C- CI6H22N2O3 291 C31H37N5O4 562 RS 9 m-EtO2C- CI8H25NO4 320 C33H42N4O6 591 dl d2 10 Z71-HO2C- C31H38N4O6 563 dl d2 11 m- (1H-tetrazole-5- yl) C16H21N5O2 316 C31H38N8O4 587 RS 12 O-NH2OC- C16H22N2O3 291 C31H37N5O4 562 RS 13 o-EtO2C- CI8H25NO4 320 C33H42N4O6 591 dl d2 14 o-HO2C- C31H38N4O6 563 dl d2 15 o- (1H-tetrazole-5- yl) CI6H21N5O2 316 C31H38N8O4 587 RS 16 p-AcNH- C17H24N2O3 305 C32H41N5O5 576 RS 17 marks-AcNH- C17H24N2O3 305 C32H41N5O5 576 RS

The invention has been described in connection with a number of certain preferred embodiments, but it will be understood that a number of modifications, changes, modifications, substitutions, or substitutions could be made in the processes or compounds without departing from the spirit and scope thereof. invention.

For example, it would be possible to use different doses of the active substances than those indicated during the application due to different mammalian responses treated for any possible indication of the compounds of the invention. It will be appreciated that specific responses in pharmacological testing may also vary depending upon the particular use of the active ingredient or the particular carrier or even the type of pharmaceutical composition and the mode of administration. All of these expected changes or differences in results are within the scope of the invention and are within the scope of the invention.

Claims (33)

PATENT CLAIMS CLAIMS 1. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of the general formula I HH 0 R ⁴ iin _R 1-y-NCAN C = O R ⁵ (CH ₂ ^ y ^w M-x R ³ Y (I) wherein R ¹ is selected from alkyl of 1 to 10 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety, alkyl-K- alkyl of 1 to 5 carbon atoms in each alkyl moiety, aryl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) and (cycloalkyl of 3 to 7 carbon atoms) (alkyl of 0 to 5 carbon atoms) carbon atoms) -K- (C 1 -C 5 alkyl) wherein K is O, S (O) _m , N (R ² ) C (O), C (O) N (R ² ), OC (O) ), C (0) 0, -CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, O benzofuranyl, thiazolyl and benzimidazolyl, wherein R and alkyl radicals are optionally substituted with 1 to 9 halogen atoms, S (O) _m R ^2a , 1 to 3 OR ^2a or C (O) OR ^2a and the aryl is optionally substituted 1 to 3 alkyl radicals having 1 to 6 carbon atoms, 1 to 3 carbon atoms; O halogen atoms, 1 to 2 OR groups, methylenedioxy groups, -S (O) _m R, 1 to 2 -CF 6 groups, -OCF ₃ , nitro, -N (R ² ) C (O) (R ² ), -C (O) OR ² , -C (O) N (R ² ) (R ² ), -1H-tetrazol-5-yl, -SO ² N (R ² ) (R ² ), -N (R ² ) SO ² phenyl or -N (R ² ) S0 ₂ R ² 356 R ² is H, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, wherein in case of one atom are attached two alkyl groups having 1 to 6 carbon atoms, may together form a ring of 3 to 8 members, optionally containing O, S or NR ^a, R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group, Rf is hydrogen, - _{(CH2) r-phenyl,} - _{(CH2) r-naphthyl,} alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, where phenyl, naphthyl and the cycloalkyl ring of 3 to 7 carbon atoms may be substituted by 1 to 3 substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen or one of the following groups -OR, -NHSO ₂ CF ₃ , - (CH ₂ ) _r OR ⁶ , - (CH ² ) r N (R ² ) (R ⁶ ), - (CH 2) _r (R ⁶ ), - (CH ₂ ) _r C (O) OR ² , - (CH 2) r C (O) OR ⁶ , - (CH 2) _r OC (O) OR ² , - (CH ₂ ) _r OC (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) R ⁶ , - (CH ₂ ) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ , - (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² , - (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² , - (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (O) R ² , - (CH ₂ ) _r C0NHC (O) R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ⁶ , - (CH _{2) r} C0NHS0 ₂ R ^2, - (CH 2) rCONHSO2N (R ²⁾ (R ^2), - _(CH2) C0NHS0 ₂ N (R ²⁾ (R ^6), - (CH 2) r -N (R ² ) SO 2 N (R ²⁾ (R ^6), - (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ⁶ and - (CH ₂ ) _r S (O) _m R ² , 357 R ^3a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group, V is hydrogen, cyano or one of -C (O) OR ⁸ , -C (O) OR ² , -C (O) O (CH ₂ ) ₁ -aryl, -C (0) N (R ²⁾ (R ^2); -C (O) N (R ² ) (R ⁸ ), -C (O) N (R ² ) (CH 2) 1 -aryl, -CH 2 N (R ² ) C (O) R ⁸ , -CH 2 N (R ²⁾ C (O) (CH 2) 1 -aryl, - (CH ² ) r OR ² , -CH (OH) R ² , -CH (OH) (CH 2) ₁ -aryl, -C (O) R ² , -O ( O) (O) - aryl, 1H-tetrazol-5-yl, 5-amino-1,2,4-oxadiazol-3-yl and 5-methyl-1,2,4-oxadiazol-3-yl, wherein R ⁸ represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or an alkyl of 1 to 6 carbon atoms, substituted with one of OR ² , C (O) OR ² , CON (R ² ) (R ² ), N (R ²⁾ ) C (0) ^R2, N (R ² ) C (O) N (R ² ) (R ² ) and aryl means phenyl, pyridyl or 1H-tetrazol-5-yl, X is selected from hydrogen, -C = N, - _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl, - (CH ₂ ) _q N (R ² ) SO ₂ (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH 2) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - _{(CH2) q} N ^(R2) C (0) N (R ²⁾ (R ²⁾ (CH _{2) q} C (O) N (R ²⁾ (R ²⁾ (CH _{2) q} C (0) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) C (O) OR ² , - (CH ₂ ) _q C (O) 0 (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q 0 C (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) N ( R ²⁾ (R ^2), - (CH 2) _q C (O) R ^2, - (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH ₂ ) _q N (R ² ) SO ² N (R ² ) (R ² ), - (CH 2) _q S (O) _m R ² and - (CH ₂ ) S (O) _m (CH ₂ ) _t - aryl, wherein the group R, _{(CH2) q} and _{(CH2) t} optionally substituted by 1 to 2 alkyl groups of 1 to 4 carbon atoms, hydroxy groups, lower alkoxy groups having 1 to 4 carbon atoms, carboxyl, _CONH2, With (O) _m CH 3, carboxylate alkyl esters of 1 to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl, optionally substituted with 1 to 3 atoms halogen, 1 to 3 -OR ² , -CON (R ² ) (R ² ), -C (O) OR ² , 1 to 3 alkyl groups of 1 to 4 carbon atoms, -S (O) _m R ² or 1H tetrazol-5-yl, 358 Y represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, - (CH ₂ ) _q -aryl, - (CH ₂ ) _q -cycloalkyl of 3 to 7 carbon atoms, - (CH ₂ ) _q -K-alkyl of 1 to 6 carbon atoms in the alkyl moiety, - (CH ₂ ) _q -K- (CH ₂ ) _t aryl, - (CH ₂ ) _q -K- (CH ₂ ) _t (cycloalkyl of 3 to 7 carbon atoms containing 0, NR ² or S) and - (CH ₂ ) _q -K - (CH ₂ ) _t - (C 3 -C 7 cycloalkyl) wherein K is O, S (O) _m , C (O) NR ² , CH = CH, OC, N (R ² ) C (O) , C (O) NR ² , C (O) 0 or OC (O), wherein the alkyl, R, (CH ₂ ) _q and (CH ₂ ) _t are optionally substituted with C 1 -C 4 alkyl, hydroxyl , C 1 -C 4 lower alkoxy, carboxyl, -CONH ₂ or C 1 -C 4 carboxylate alkyl and aryl means phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -C ( O) OR ² , -C (O) N (R ² ) (R ² ), nitro, cyano, benzyl, 1 to 3 alkyl of 1 to 4 carbon atoms, -S (O) _m R ² or 1 H- tetrazol-5-yl provided that at least one of a, R, V, X and Y have a meaning other than hydrogen, R ⁴ and R ⁵ independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, 1 to 3 alkanoyloxy groups of 1 to 10 carbon atoms, 1 to 3 alkoxy groups of 1 to 6 atoms carbon, phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety or S (O) m-alkyl of 1 to 6 carbon atoms in the alkyl moiety, or R ⁴ and R 6 together may form - (CH 2) j L ^and (CH 2) e -, wherein L ^a is C (R ² ) 2, O, S (O) _m or N (R ⁶ ), d and e independently represent an integer of 1 to 3 and R is as defined above, 359 A represents a group R ⁷ R ⁷ - (CH _{2) x} O - _(CH2) - or _- - _{(CH2) x} -Č - _(CH2) - R ^7a R ^7a wherein x and y independently represent an integer of 0, 1, 2 or 3, Z is NR or 0 ^and wherein R ⁸ is H or alkyl of 1 to 6 carbon atoms, R 6 is H, C 1 -C 6 alkyl or (CH ₂₎ -aryl, wherein the alkyl, and (CH ₂ ) _V is optionally substituted with 1 to 2 O (R ² ), S (O) m R ² , 1H-tetrazol-5-yl, C (O) OR ² , C (O) N (R ² ) ( R ^2), or SO 2 N (R ²⁾ (R ²⁾ or N ^(R2) C (0) N ^{(R2) (R2),} and aryl is phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl , thiazolyl, pyrazolyl, thiadiazolyl, imidazolan-1-yl, benzimidazol-2-yl, triazolinonyl, optionally substituted with C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino or hydroxyl, * 7 * 7 R and ^{R independently} are H, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl, where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) O-alkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or R ⁷ and R ^{7a may} be joined to one or both of R ⁴ and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R 7 or R 7 wherein the bridges contain 1 to 5 carbon atoms or R ⁷ and R ^7a together may form a cycloalkyl ring of 3 to 7 carbon atoms, 360 1 means 0, 1 or 2, m means 0, 1 or 2, n means 1, 2 or 3, q means 0, 1 , 2,3 or r means 0, 1 , 2 or 3 T means 0, 1 , 2 or 3 in means 0, 1 or 2, as well as pharmaceutically acceptable salts thereof and their individual diastereomers. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 1 of the general formula Al R ^J HHOR ^z I II. N-C-A-N C = O R '(Al) where R ¹ is selected from alkyl of 1 to 10 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl and 1 to 6 carbon atoms in the alkyl moiety, alkyl-K- alkyl of 1 to 5 carbon atoms in each alkyl moiety, aryl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) or (cycloalkyl of 3 to 7 carbon atoms) (alkyl of 0 to 5 carbon atoms) carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) wherein K is O, S (O) _m , N (R ² ) C (O), C (O) N (R ² ), OC (O) ) C (O) O, -CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl and benzimidazolyl, wherein R and alkyl radicals are optionally substituted with 1 to 9 halogen atoms, S (O) _m R ^2a , 1 to 3 groups 361 OR ^2a or C (O) OR ^2a and the aryl is optionally substituted 1 to 3 alkyl radicals having 1 to 6 carbon atoms; 1 to 3 halogen atoms, 1 to 2 OR groups, methylenedioxy, -S (O) _m R, 1 to 2 -CF 3 groups, -OCF 3, nitro, -N (R ² ) C (O) (R ² ), -C (O) OR ² , -C (O) N (R ² ) (R ² ), -1 H -tetrazol-5-yl, -SO ₂ N (R ² ) (R ² ), -N (R ² ) SO 2 -phenyl or -N (R ² ) SO ² R ² , R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 3 to 8 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing an oxygen, sulfur or NR ^3a group, R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group, Q R ^J represents a hydrogen atom, - (CH 2) r -phenyl, - (CH 2) r -naphthyl, alkyl of 1 to 10 carbon atoms or cycloalkyl of 3 to 7 carbon atoms, the phenyl, naphthyl and cycloalkyl ring of 3 to 7 atoms the carbon may be substituted by 1 to 3 substituents selected from the group consisting of alkyl of 1 to 6 carbon atoms, halogen or one of the following groups -OR ² , -NHSO 4 F 6, - (CH 2) _r OR ⁶ , - (CH 2) ) r N (R ² ) (R ⁶ ), - (CH 2) _r (R ⁶ ), - (CH _{2) r} C (O) OR ^2, - (CH 2) r C (O) OR ^6, - _(CH2) 0C (0) 0R ^2, - (CH ₂ ) _r OC (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) R ⁶ , - (CH ₂ ) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ , - (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² , - (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (0) R ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ , 362 - (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² , - (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (0) R ² , - (CH ₂ ) _r CONHC (O) R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ² , - (CH ₂ ) _r CONHSO ₂ N (R ² ) (R ² ), - (CH _{2) r} CONHSO ₂ N (R ²⁾ (R ^6), - (CH 2) r -N (R ²⁾ SO 2 N (R ²⁾ (R ^6), - (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ^6, and - (CH ₂ ) _r S (O) _m R ² , R ^I is H or alkyl of 1 to 6 carbon atoms, optionally substituted with hydroxy, V is selected from -CN, -C (O) OR ⁸ , -C (O) OR ² , -C (O) O (CH ₂ ) ₁ -aryl, -C (O) N (R ² ) (R ² ); -C (O) N (R ² ) (R ⁸ ), -C (O) N (R ² ) (CH ₂ ) ₁ -aryl, -CH ₂ N (R ² ) C (O) R ⁸ , -CH ₂ N (R ² ) C (O) (CH 2) 1 -aryl, - (CH ² ) r OR ² , -CH (OH) R ² , -CH (OH) (CH 2) ₁ -aryl, -C (O R ² , -C (O) (CH ₂ ) -1 H -aryl, 1H-tetrazol-5-yl, 5-amino-1,2,4-oxadiazol-3-yl O and 5-methyl-1,2,4-oxadiazol-3-yl, wherein R ° is hydrogen, alkyl of 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms, substituted with one of OR ² , C ( 0) 0R ² , CO (N ² ) (R ² ), N (R ² ) C (O) R ² , N (R ² ) C (O) N (R ² ) (R ² ) and aryl means phenyl, pyridyl or 1H-tetrazol-5-yl, X is selected from hydrogen, -C = N, - _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl, - (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q OC (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) R ² , - (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH ₂ ) _q N (R ² ) SO ² N (R ² ) (R ² ), - (CH 2) _q S (O) _m R ^2, and - (CH ₂ ) S (O) _m (CH ₂ ) _t -aryl, _w -9 wherein R, (CH ₂ ) _q and (CH ₂ ) _t groups are optionally substituted with 1 to 2 alkyl groups of 1 to 4 atoms carbon, hydroxyl groups, lower alkoxy groups having 1 to 4 carbon atoms, carboxyl groups, 363 CONH 2, S (O) _m CH ₃ , C 1 -C 4 carboxylate alkyl esters or 1 H -tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl, thiazolyl or 1 H -tetrazol-5-yl, optionally substituted with? up to 3 halogen atoms, 1 to 3 -OR ² , -CON (R ² ) (R ² ), -C (O) OR ² , 1 to 3 alkyl groups with 1 to 4 carbon atoms, -S (O) _m R ² or 1H-tetrazol-5-yl, Y represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, - (CH 2) _q -aryl, - (CH 2) q -cycloalkyl of 3 to 7 carbon atoms, - (CH ₂ ) q "K-alkyl of 1 to 6 carbon atoms in the alkyl moiety, - (CH ₂ ) q K- ( CH ₂ ) _t aryl, - (CH ₂ ) _q -K- (CH ₂ ) _t (C 3 -C 7 cycloalkyl containing O, NR ² or S) and - (C 1-6 q-K- (CH 2) _t) - (C 3 -C 7 cycloalkyl) wherein K is O, S (O) _m , C (O) NR ² , CH = CH, OC, N (R ² ) C (O), C (O) NR ² , C (O) O or OC (O), wherein alkyl, R, (CH ₂ ) q and (O ₂ ) - (optionally substituted with C 1 -C 4 alkyl, hydroxyl, lower alkoxy) C 1-4 alkyl, and aryl means phenyl, naphthyl, pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -C (O) OR ² , -C (O) N (R ² ) (R ² ), nitro, cyano, benzyl, 1 to 3 C 1 -C 4 alkyl, -S (O) _m R or 1H-tetrazol-5-yl, R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, 1 to 3 alkanoyloxy groups of 1 to 10 carbon atoms, 1 to 3 alkoxy groups of 1 to 6 carbon atoms , phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety or S (O) _m- alkyl of 1 to 6 carbon atoms in the al364 keel moiety or may and R8 together form group - (CH 2) e - ^and (CH 2) e -. wherein L ^a is C (R ² ) 2, O, S (O) m or N (R), d and e are independently an integer of 1 to 3 and R is as defined above, A represents a group R ⁷ R ⁷ - (CH _{2) x} -O- (CH ₂₎ - or _ _Z - (CH _{2) x} -O- _(CH2) ^ R ^7a _R 7a where x and y are independently an integer of 0, 1, 2 or 3, Z is NR or 0 ^and wherein R ^a is H or alkyl of 1 to 6 carbon atoms, R c is hydrogen, alkyl of 1 to 6 carbon atoms or (CH ₂ ) _v -aryl, the alkyl and (CH ₂ ) _V groups being optionally substituted with 1 to 2 O (R ² ), S (O) m R groups ² , ΙΗ-tetrazol-5-yl, C (O) OR ² , C (O) N (R ² ) (R ² ) or SO ² N (R ² ) (R ² ) or N (R ² ) C (0) N (R ² ) (R ² ) and aryl means phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolan-1-yl, benzimidazol-2-yl, triazolinonyl, optionally substituted with an alkyl residue (C 1 -C 6), (C 3 -C 6) cycloalkyl, amino or hydroxyl group, R 'and R' ^{, and} independently represent hydrogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted alkyl of 1 to 6 carbon atoms, wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) O-alkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkyl of 3 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ), or R ⁷ and R ^{7a may} be linked to one or both of R 6 and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R ² or R ^2a , wherein the bridges contain 1 to 5 carbon atoms or R ² and R ^2a together may form a cycloalkyl ring of 3 to 7 carbon atoms, 1 m n means means means 0 about, First 1 1 2 or 2, or 2, or 3 q means about, 1 , 2, 3 or 4, r means 0 1 , 2 or 3 T means 0 1 , 2 or 3 in means about, 1 or 2 as well as pharmaceutically acceptable salts and individual diastereomers thereof. The piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of claim 2, wherein: R1 is selected from alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 4 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl moiety, (alkyl of 1 to 4 atoms) (C 1 -C 2 alkyl) -, aryl (C 2 -C 2 alkyl) -K- (C 1 -C 2 alkyl) or (C 3 -C 7 cycloalkyl) (alkyl (0 to 2 carbon atoms) -K (1 to 2 carbon atoms) wherein K is O, S (O) _m , OC (O), C (O) O and the alkyl groups are optionally further substituted C 1-7 halogen, S (O) _m R, 1-3 OR ² or C (O) OR ² and aryl means phenyl, naphthyl, indolyl, pyridyl, benzothienyl, benzofuranyl, optionally further substituted with 1 to 2 alkyl groups of 1 up to 4 carbon atoms, 1 to 2 OR ² , S (O) _m R ² or C (O) OR ² , R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 4 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing an oxygen, sulfur or NR ^2a group, R1 represents a hydrogen atom, phenyl optionally substituted in the ortho position with an alkyl group having 1 to 6 carbon atoms, -NHSO2CF3, - (CH2) _r- (1H-tetrazol-5-yl), - (CH ₂ ) _r C (O) OR ² , - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), R ^8a represents a hydrogen atom or an alkyl of 1 to 4 carbon atoms, V is selected from -CN, -C (O) OR ² , -C (O) N (R ² ) (R ² ), -C (O) N (R ² ) (CH 2) 1 -phenyl, 1H-tetrazol-5-yl or - (CH ₂ ) _r OR ² , X is selected from hydrogen, - (C · ^) _q C (O) N (R ²⁾ (R **) or - _{(CH2) q} C (0) 0R ^2, Y is hydrogen, alkyl of 1 to 8 carbon atoms, - (CH2) _t- phenyl, - (CH2) _t- pyridyl or - (CH2) _t -thiazolyl, R ⁴ and r ⁵ independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, S (O) _m- alkyl of 1 to 6 carbon atoms or phenyl, r 6 is hydrogen or alkyl of 1 to 6 carbon atoms, A represents a group R ⁷ (CH ₂ ) _x -OR ^7a wherein x represents 0 or 1, R ⁷ and R ^{7a are} independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , s (O) _m R ^2, C (O) O-C 1 -C 6 alkyl, cycloalkyl of 5-7 carbon atoms, N (R ²⁾ (R ²⁾ or C (O) N ( R ² ) (R ² ) or may R ⁷ M and R ^{/ and} be connected to one or both of the moieties in the definition of ^R4 and R ^ to form alkylene bridges between the terminal nitrogen and the alkyl portion of the group R ⁷ or R ⁷ to form a 5-or 367 A 6-membered ring or R ⁷ and R ^7a together may form a cycloalkyl ring of 3 carbon atoms, 1 means 0 or 1 m means 0 , 1 or 2 n means 2 * q means 0 or 1 r means 0 , 1, 2 or T means 0 or 1 as well as pharmaceutically acceptable salts and individual diastereomers thereof. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 2, of the general formula Alb (Alb) wherein: R ¹ R ² is selected from alkyl of 1 to 10 carbon atoms, arylalkyl of 1 to 3 carbon atoms in the alkyl moiety or aryl (alkyl of 0 to 1 carbon atom) -K- (alkyl of 1 to 2 carbon atoms) wherein K is O or S (O) _m and aryl is phenyl, naphthyl, pyridyl or indolyl, optionally further substituted with 1 to 2 alkyl groups of 1 to 4 carbon atoms, 1 to 2 halogen atoms, 1 to 2 OR ² , S (O) ) _m R ² or C (O) OR ² , represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, provided that two alkyl groups of 1 to 6 atoms are attached to one atom carbon, may together form a ring of 5 to 7 members optionally containing an oxygen, sulfur or NR ^3a group, 368 R ³ represents a hydrogen atom, phenyl, optionally substituted in the ortho position with an alkyl group having 1 to 3 carbon atoms or - (CH ₂ ) _r - (1H-tetrazol-5-yl) or - (CH ₂ ) _r C (O) OR ² , R ^3a represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, V is selected from -CN, -C (O) OR ^2, or -C (O) N (R ² ) (R ² ), X is selected from hydrogen or C (O) O (R ² ), Y is hydrogen, benzyl, picolyl or thiazolylmethyl, R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 3 carbon atoms, optionally substituted with 1 to 2 hydroxy groups, A represents a group R ⁷ (CH ₂ ) x C - Where R is 0 or 1, R ⁷ and R ^{7a are} independently hydrogen, C 1 -C 4 alkyl, m is 0, 1 or 2, r is 0, 1 or 2, as well as pharmaceutically acceptable salts and individual diastereomers thereof. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 2, stereospecifically defined by the general formula yhor ⁴ R ¹ —pN ^_ C “A ^_ N C = 0 ^rS I K w (CH ₂ ) _n y M-χ R ³ Y 369 wherein the individual symbols have the meaning given in claim 2. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 2, selected from the group of: 370 - zl As well as the pharmaceutically acceptable salts and individual diastereomers of these compounds. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 1, of the general formula BI HH 0 _r 4 I II, --NCAN C = O ' _r 5 (BI) wherein t> 1 is selected from alkyl of 1 to 10 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 7 carbon atoms in the cycloalkyl about 6 carbon atoms in the alkyl moiety, alkyl-K-alkyl of 1 to 5 carbon atoms in each alkyl moiety, aryl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms), or (cycloalkyl) (C až-C alkyl) alkyl (C až-C) alkyl) -K- (C až-C alkyl alkyl) wherein K is O, S (O) _m , N (R ² ) C (O), C (O) N (R ² ), OC (O), C (O) O, -CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl, indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl or benzimidazolyl, wherein R and alkyl radicals are optionally substituted by 1 372 to 9 halogen atoms, S (O) _m R ^2a , 1 to 3 OR ^2a or C (O) OR ^2a, and aryl is optionally substituted with 1 to 3 alkyl radicals having 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 to 2 OR, methylenedioxy, -S (O) _m R, 1 to 2 -CF 3, -OCFg, nitro, -N (R ² ) C (O) (R ² ), -C (O) OR ² , -C (O) N (R ² ) (R ² ), 1H-tetrazol-5-yl, -SO ₂ N (R ² ) (R ² ), -N ^(R2) S02 phenyl, or -N (R ²⁾ SO 2 R ^2, R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 3 to 8 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing an oxygen, sulfur or NR ^3a group, wherein R ^3a represents a hydrogen atom or a C 1-6 alkyl group optionally substituted by a hydroxyl group, R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group, R is - _{(CH2) r-phenyl,} - _{(CH2) r-naphthyl,} alkyl of 1 to C 10 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl, the phenyl, naphthyl and C 3 -C 7 cycloalkyl ring may be substituted with 1 to 3 substituents selected from C 1 -C 6 alkyl, halogen or one of the following: from the following groups -OR ² , -NHSO 4 F 6, - (CH ² ) _r OR ⁴ , - (CH ₂ ) _r N (R ² ) (R ⁶ ), - (CH 2) _r (R ⁶ ), - (CH ₂ ) _r C (0) 0R ^2, - (CH ₂ ) _r C (O) OR ⁶ , - (CH ₂ ) _r OC (O) OR ² , - (CH 2) _r O C (O) R ⁶ , - (CH ₂ ) _r C (O) R ² , - (CH 2) r C (O) R ⁶ , - (CH 2) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ , - (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² , - (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ), 373 - (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² , - (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (O) R ² , - (CH ₂ ) _r CONHC (O) R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ² , - (CH ₂ ) _r C ₀ NHSO ₂ N (R ² ) (R ² ), - (CH _{2) r} C0NHS0 ₂ N (R ²⁾ (R ^6), - (CH 2) r -N (R ²⁾ SO 2 N (R ²⁾ (R ^6), - (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ^6, and - (CH ₂ ) _r S (O) _m R ² , R ^I is H or alkyl of 1 to 6 carbon atoms, optionally substituted with hydroxy, X is selected from hydrogen, -C = N, - _{(CH2) q} N (R ²⁾ C (O) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _x -aryl, - (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q OC (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) N (R ² ) (¾) χaryl, - (CH 2) q OC (O) N (R ²⁾ ) (R ² ), - (CH 2) _q C (O) R ² , - (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH ₂ ) _q N (R ² ) SO ² N (R ² ) (R ² ), - (CH 2) _q S (O) _m R ^2, and - (CH ₂ ) S (O) _m (CH ₂ ) _t -aryl, _w * · 9 wherein R, (CH ₂ ) _q and (CH ₂ ) _t groups are optionally substituted with 1 to 2 alkyl groups of 1 to 4 carbon atoms, hydroxyl groups, lower alkoxy groups having 1 to 4 carbon atoms, CO ₂ NH ₂ , S (O) _m CH ₃ , carboxylate alkyl esters having 1 to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl, optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR ² , -CO (R ² ) (R ² ), -C (O) OR ² , 1 to 3 3 alkyl groups having 1 to 4 carbon atoms, ABOUT -S (O) _in R ^x 'or 1H-tetrazol-5-yl, Y represents a hydrogen atom, an alkyl of 1 to 10 carbon atoms, - _{(CH2) χ-aryl,} - _{(CH2) q-cycloalkyl} having 3 to 7 carbon uh- 374 lic of cycloalkyl, - _(CH2) qK- (C 1 -C 6 alkyl), - (CH ₂ ) qK- (CH ₂ ) _t -aryl, - (CH ₂ ) q K (CH ₂ ) _t - (C 3 -C 7 cycloalkyl containing O, NR ² or S) or - (CH ₂ ) q K- ( CH ₂ ) _t - (C 3 -C 7 cycloalkyl) wherein K is O, S (O) _m , C (O) NR ² , CH = CH, OC, N (R ² ) C (O), C (O) NR ² , C (O) 0 or 0C (O), wherein alkyl, R ² , (CH ₂ qa (CH ₂ ) 4 are optionally substituted with C 1 -C 4 alkyl, hydroxyl, C 1 -C 4 alkoxy, -CO NH ₂ or C 1 -C 4 carboxylate alkyl and aryl means phenyl, naphthyl , pyridyl, 1H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with 9 1 to 3 halogen atoms, 1 to 3 -OR 1 to 1 groups; 2 -N (R ² ) (R ² ), -C (O) OR ² , -C (O) N (R ² ) (R ² ), nitro, -NHC (O) R, cyano, benzyl, (1 to 3) alkyl groups having 1 to 4 carbon atoms, -S (O) _m R or 1H-tetrazol-5-yl, R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, 1 to 3 alkanoyloxy groups of 1 to 10 carbon atoms, 1 to 3 alkoxy groups of 1 to 6 carbon atoms , phenyl, phenoxy, 2-furyl, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety or S (O) m-alkyl of 1 to 6 carbon atoms in the alkyl moiety, or R ⁴ and R 6 together may form a group - (CH 2) ^a _£ jL (CH2) e, wherein L ^a is C (R ²⁾ 2, 0, S (0) _m or N (R), d and e independently represent an integer of 1 to 3 and R is as this meaning, A is - (CH ₂ ) _X -C- (CH ₂ ) - R ^7a or -2- (CH ₂ ) _x -O- (CH ₂ ) - _R 7a 375 wherein x and y independently represent an integer of 0, 1, 2 or 3, Z is NR or 0 ^and wherein R ^a is H or alkyl of 1 to 6 carbon atoms, R 6 is H, C 1 -C 6 alkyl or (CH 2) _v -aryl, wherein the alkyl, and are optionally substituted 1 to 2 groups, 0 ^(R2), S (0) m R ^2, H-tetrazol-5-yl, C (O) OR ^2, C (0) N ^{(R2) (R2)} or S02N ^(R2) ( R ^2), or N ^(R2) C (0) N ^{(R2) (R2),} and aryl is phenyl, pyridyl, lH-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, pyrazolyl, thiadiazolyl, imidazolan-l -yl, oxadiazolyl, benzimidazol-2-yl, triazolinon-1-yl, optionally substituted with C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino or hydroxyl; R and ^{R independently} are H, alkyl of 1 to 6 carbon atoms, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl, where the substituents are imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , cycloalkyl of 3 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or may R ⁷ and R ^{7a may} be joined to one or both of R ⁴ and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl part of R ⁷ or R ^7a , wherein the bridges contain 1 to 5 carbon atoms or R ⁷ and R ^{7 7a} together form a cycloalkyl ring of 3 to 7 carbon atoms, provided that it is set forth in claim 1, m means 0 1 or 2 n means 1 2 or 3 q means 0 1 , 2, 3 or r means about, 1 , 2 or 3 T means about, 1 , 2 or 3 in means 0 1 or 2 As well as pharmaceutically acceptable salts and individual diastereomers thereof. The piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of claim 7, wherein: R ¹ is selected from the group consisting of alkyl of 1 to 10 carbon atoms, aryl, arylalkyl of 1 to 4 carbon atoms in the alkyl moiety, cycloalkylalkyl of 3 to 6 carbon atoms in the cycloalkyl and 1 to 4 carbon atoms in the alkyl moiety; (C 1 -C 2 alkyl) -K- (C 1 -C 2 alkyl), aryl (C 2 -C 2 alkyl) -K- (C 1 -C 2 alkyl) or (C 3 -C 7 cycloalkyl) (alkyl of 0 to 2 carbon atoms) -K- (alkyl of 1 to 2 carbon atoms), wherein K is O, S (O) m, OC (O) or C (O) O, and the alkyl groups are optionally substituted with 1 up to 7 halogen atoms, S (O) mR ² , 1 to 3 OR ² or C (O) OR ² and aryl means phenyl, naphthyl, indolyl, pyridyl, benzimidazolyl, azaindolyl, benzothienyl or benzofuranyl, optionally further substituted with 1 up to 2 alkyl groups having 1 to 4 carbon atoms, 1 to 2 halogen atoms, 1 to 2 OR ² groups, -S (O) m R ² or -C (O) OR ² , R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 4 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^3a group, R is phenyl, optionally substituted with 1 to 2 alkyl groups of 1 to 6 carbon atoms, 1 to 2 halogen atoms, or 1 to 2 -OR ² groups, and optionally further substituted in ortho position by one of the -NHSO ₂ CF ₃ groups - (CH ₂ ) _r OR ⁶ , - (CH ₂ ) _r N (R ² ) (R ⁶ ), - (CH 2) _r (R ⁶ ), - (CH _{2) r} C (O) OR ^2, - (CH _{2) r} C (0) 0R ^6, - (CH 2) R0C (0) 0R ^2, - (CH 2) _r OC (O) R ^6, - (CH 2) r C (O) R ² , - (CH 2) _r C (O) R ⁶ , - (CH ₂ ) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ , 377 _R 3a X - (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ , - (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² , - (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (O) R ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r C (O) NHC (O) NR ² , - (CH ₂ ) _r C (O) NHC (O) NR ⁶ , - (CH ₂ ) _r C (O) NHC (O) R ² , - (CH ₂ ) _r CONHC (O) R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ⁶ , - (CH _{2) r} CONHSO ₂ R ^2, - (CH 2) rCONHSO2N (R ²⁾ (R ^2), - _(CH2) C0NHS0 ₂ N (R ²⁾ (R ^6), - (CH 2) r -N (R ² ) S02N ^{(R2) (R6),} - (CH ₂ ) _r N (R ⁶ ) SO ² N (R ² ) (R ⁶ ), - (CH 2) _r S (O) _m R ⁶ and - (CH ₂ ) _r S (O) _m R ² , represents an atom hydrogen or alkyl of 1 to 6 carbon atoms is selected from the group consisting of hydrogen, alkyl, and the like - _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl, - _{(CH2) q} N (R ²⁾ C (O) OR ^2, - (CH 2) q N (R ²⁾ SO 2 (CH _{2) t} -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH 2) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q S (O) _m R ² and - (CH 2) q S (O) m (CH 2) 1 -aryl, wherein R ² groups are optionally substituted by hydroxyl, carboxyl, CONH 2, S (O) _m CH ₃ , carboxylate alkyl esters of 1 to 4 carbon atoms in the alkyl moiety or tetrazolyl and aryl means phenyl, naphthyl, pyridyl or 1H-tetrazolyl, optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR ² , -CONH ₂ , Q -C (O) OR, 1 to 3 alkyl groups of 1 to 4 carbon atoms, -S (O) _m R or 1H-tetrazol-5-yl, represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms, 378 - (CH _{2) t} -aryl, - (CH ₂₎ q (C 5 -C 6 cycloalkyl), - _(CH2) qK- (C 1 -C 6 alkyl), - _(CH2) qK- (CH ₂ ) _t -aryl, - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 3 -C 7 cycloalkyl containing 0, NR ² or S) or - (CH ₂ ) q K- (CH ₂ ) _χ - (C 5 -C 6 cycloalkyl) wherein K is O, S (O) _m , wherein the alkyl groups are optionally substituted with a hydroxyl group, a carboxyl group, -CONH _2, or a C 1 -C 4 carboxylate alkyl ester or 1H-tetrazoly-5-yl, aryl means phenyl, naphthyl, pyridyl, ΙΗ-tetrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl and is optionally substituted with 1 to 3 halogen atoms, 1 to 3 -OR, 1-2 groups -N (R ² ) (R ² ), -C (O) OR ² , -C (O) N (R ² ) (R ² ), cyano, 1 to 2 C 1 -C 4 alkyl, -S (O) _m R or 1H-tetrazol-5-yl groups, R ⁴ and R 4 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted alkyl of 1 to 6 carbon atoms, wherein the substituents are 1 to 5 halogen atoms, 1 to 3 hydroxy groups, S (O) _m -alkyl of 1 or (C ₂ -C 6) -alkyl or (CH ₂ ) _v -aryl, the alkyl and (CH ₂ ) _v groups being optionally substituted with 1 to 2 O (R ² ) groups , S (O) _m R ² , C (O) OR ² , C (O) N (R ² ) (R ² ), or SO ₂ N (R ² ) (R ² ) or N (R ² ) C (O) N (R ² ) (R ² ) and aryl means phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl , oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino or hydroxyl, A represents a group R ⁷ (CH ₂ ) x -CR ^7a 379 wherein x is 0 or 1 R ⁷ and R ^7a independently represent hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (0) _m R ² , C (O) OR ² , cycloalkyl of 5 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or R ⁷ and R ^{7a may} be linked to one or both R ⁴ and R 5 to form alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R ⁷ or R ^7a , wherein the bridges contain 5 to 6 carbon atoms or R ⁷ and R ^7a together may form a cycloalkyl ring of 3 carbon atoms, with the proviso set out in claim 1, n m means means 2 about, 1 or 2, q means 0 1, 2 or 3 r means about, 1, 2 or 3 T means about, 1, 2 or 3 in means 0 1 or 2, as well as pharmaceutically acceptable salts and individual diastereomers thereof. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 7, of the general formula BIb H * H _n4 i ¹¹ from R R ¹ -cnca-nCi ii p5 C = 0 ^R (Bib) where R ¹ is selected from the group consisting of alkyl having 1 to 10 carbon atoms, arylalkyl having 1 to 3 carbon atoms in the alkyl moiety, cycloalkylalkyl having 3 to 7 carbon atoms in the cycloalkyl moiety and 1 to 3 carbon atoms in the alkyl moiety, aryl (alkyl of 0) (C 1 -C 2 alkyl) wherein K is O, S (O) _m and aryl is phenyl, naphthyl, indolyl, pyridyl, azaindolyl, benzimidazolyl, optionally substituted with 1 to 2 alkyl groups C 1 -C 4 alkyl, 1 to 2 halogen, 1 to 2 of oR ^2, s (O) _m R ² or -C (O) oR ^2, the R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 5 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^3a group, Q R is phenyl optionally substituted with 1 to 2 alkyl groups of 1 to 6 carbon atoms, 1 to 2 halogen atoms or 1 to 2 -OR groups and optionally further substituted in ortho position by one of the -NHSO ₂ CF ₃ groups - (CH ₂₎ ) 0R _R ^6, - (CH 2) r -N (R ²⁾ (R ^6), - _(CH2) ^(R6), - (CH ₂ ) _r C (O) OR ⁶ , - (CH ₂ ) _r OC (O) R ² , - (CH 2) _r O C (O) R ⁶ , - (CH ₂ ) _r C (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ , - (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² , - (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (0) R ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) R ² , - (CH ₂ ) _r SO ₂ NHC (O) OR ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r CONHSO ₂ R ⁶ , - (CH ₂ ) _r CONHSO ₂ R ² , - (CH ₂ ) _r S (O) m R ^6, and - (CH 2) _r S (O) _m R ² , R ^3a represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, X is selected from hydrogen, 381 - _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl, - _{(CH2) q} N ^(R2) S02 (CH2) t-ary1, - (CH 2) q N (R ²⁾ SO 2 R ^2, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), - (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH 2) q C (O) N (R ² ) (CH 2) _t -aryl, - (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) t -aryl, - (CH ² ) _q S (O) _m R ² and - (CH 2) _q S (O) _m ( CH ₂ ) _t -aryl, wherein the R ² groups are optionally substituted by hydroxyl, carboxyl, -CONH ₂ , -S (O) _m CH ₃ , in the form of a C 1 -C 4 carboxylate alkyl or tetrazolyl group, and aryl is phenyl, naphthyl or pyridyl, optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR groups, J -C (O) OR, 1 to 3 alkyl groups having 1 to 3 atoms O, -S (O) _m R or 1H-tetrazol-5-yl, Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms, - (CH ₂ ) _t -aryl, - (CH ₂ ) _q - (cycloalkyl of 5 to 7 carbon atoms), - (CH ₂ ) _q -K- (alkyl of 1 to 6 carbon atoms), - (CH ₂ ) _q- K- (CH ₂ ) _t -aryl or - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 5 -C 6 cycloalkyl, wherein K is S (O) _m , wherein the alkyl groups are optionally substituted with hydroxy, carboxyl, -CONH ₂ or karboxylátalkylesterom 1 -C 4 alkyl or lH-tetrazole-5-yl, aryl is phenyl, naphthyl, pyridyl, thiazolyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl and imidazolyl, and is optionally substituted with 1 to 2 halogen, 1 to 2 -OR ^2, 1 to 2 -N (R ²⁾ (R ^2), -C (O) OR 1 to 2 alkyl groups of 1 to 4 atoms O is C, -S (O) _m R, or-1H-tetrazol-5-yl, R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted alkyl of 1 to 3 carbon atoms, wherein the substituents are 1 to 2 hydroxy groups, r 6 is hydrogen, alkyl of 1 to 6 carbon atoms or (CH ₂ ) _v -aryl, the alkyl and (CH ₂ ) _V groups being optionally substituted with 1 to 2 groups 382 0 ^(R2), S (O) m R ^2, C (O) OR ^2, C (O) N ^{(R2) (R2),} S02N ^{(R2) (R2)} or N (R ²⁾ C (0) N (R ² ) (R ² ) and aryl means phenyl, pyridyl, 1H-tetrazol-5-yl, triazolyl, imidazolyl, thiazolyl, oxadiazolyl, pyrazolyl, thiadiazolyl, benzimidazol-2-yl, optionally substituted with an alkyl residue with (C 1 -C 6), (C 3 -C 6) cycloalkyl, amino or hydroxyl group; A represents a group R ⁷ (CH ₂ ) x C _R 7a where x is 0 or 1 R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 2 carbon atoms, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (0) _m R ² , or R ⁷ and R ^{7a may} be linked to each other to form a C 3 cycloalkyl group, provided that it is as claimed in claim 1, m means 0 1 or 2, q means about, 1 , 2 or 3 r means 0 1 , 2 or 3 T means about, 1 , 2 or 3 in means about, 1 or 2, as well as pharmaceutically acceptable salts and individual diastereomers thereof. 10. The piperidine, pyrrolidine and hexahydro-lH-azepine compound according to claim 7, of formula YH BIC _{R 4} R ¹ -E-N-can: _c ^{11 1? 5} C = 0 O ^K (BIc) i 383 where R ¹ is selected from groups and their regioisomers where not specifically mentioned, R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 5 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom , optionally containing an oxygen, sulfur or NR ^3a group, 384 R 13a is phenyl, optionally substituted in the ortho position with a substituent selected from the following groups -NHSO ₂ CF ₃ , - (CH ₂ ) _r OR ⁶ , - (CH 2) r (R ⁶ ), - (CH 2) _r C (O) OR ² - (CH ₂ ) _r C (O) OR ⁶ , - (CH ² ) _r OC (O) R ² , - (CH 2) _r OC (O) R ⁶ , - (CH ₂ ) _r C (O) R ⁶ , - (CH 2) r C (O) R ² , - (CH 2) _r C (O) N (R ² ) (R ² ), - (CH ₂ ) _r C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) R ² , - (CH ₂ ) _r N (R ² ) C (O) R ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) R ² , - (CH ₂ ) _r N (R ⁶ ) C (O) R ⁶ , - (CH ₂ ) _r N (R ² ) C (O) OR ² , - (CH ₂ ) _r N (R ² ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ² , - (CH ₂ ) _r N (R ⁶ ) C (O) OR ⁶ , - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _r N (R ⁶ ) C (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r N (R ² ) SO ² R ⁶ , - (CH ₂ ) _r N (R ² ) SO ² R ² , - (CH 2) _r N (R ⁶ ) SO ₂ R ² , - (CH ₂ ) _r N (R ⁶ ) SO ² R ⁶ , - (CH 2) _r OC (O) N (R ² ) (R ⁶ ), - (CH ₂ ) _r OC (O) N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ⁶ ), - (CH ₂ ) _r SO ₂ N (R ² ) (R ² ), - (CH ₂ ) _r SO ₂ NHC (0) R ⁶ , - (CH ₂ ) _r SO ₂ NHC (0) R ² , - (CH ₂ ) _r SO ₂ NHC (0) OR ⁶ , - (CH ₂ ) _r SO ₂ NHC (O) OR ² , - (CH ₂ ) _r CONHSO ₂ R ⁶ , - (CH ₂ ) _r COnHSO ₂ R ² , - (CH ₂ ) _r S (O) m R ^6, and - (CH 2) _r S (O) _m R ² , represents a hydrogen atom or a C 1 -C 4 alkyl, represents a hydrogen atom or one of the following groups An ' ^CH = U V A ₀ ' ^and A _o o ch ₃ - ^ch 3 AcAch ₃ OH 385 Ο Λ · _{CH3 CH3} ^ is H, alkyl of 1 to 8 carbon atoms, - (CH _{2) t} -aryl, - (CH ₂₎ q (C 5 -C 7 cycloalkyl), - _(CH2) qK- (C 1 -C 6 alkyl), - (CH ₂ ) -K- (CH ₂ ) _t -aryl or - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 5 -C 6 cycloalkyl, wherein K is S (O) _m , wherein the alkyl groups are optionally substituted with a hydroxyl group, a carboxyl group, -CONH _2, or a C 1 -C 4 carboxylate alkyl ester or 1 H -tetrazoly-5-yl, aryl is phenyl, naphthyl, pyridyl, thiazolyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrimidinyl or imidazolyl and is optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR groups, 1 to 2 with -C (O) OR, 1 to 2 (C 1 -C 4) alkyl, -S (O) _m R or 1H-tetrazol-5-yl group, 386 A is selected from and R 5 are independently selected from - H - CH ₃ CH ₂ CH ₃ A \ ^ ^CH3 / ^ / ^CH 2 OH OH ^h ° is H, C 1 -C 6 alkyl or (CH 2 _and -aryl, wherein the alkyl groups and the groups O (CH ₂ ) _V are optionally substituted with halogen, OR, 2 2 -N (R) (R), C 3 -C 6 cycloalkyl, 1H-tetrazol-5-yl, C (O) OR, C (O) N (R ² ) (R ² ), SO ₂ N (R ²⁾ (R ²⁾ or N ^(R2) C (0) N ^{(R2) (R2),} and aryl is selected from the following aromatic groups and their regioisomers 387 wherein the aromatic groups are optionally substituted with C 1 -C 2 alkyl, -N (R ² ) (R ² ) or hydroxy, m is 0, 1 or 2, q is 0 or 1, r is 0, 1, 2 or 3, t is 0 or 1, v is 0 or 1, as well as pharmaceutically acceptable salts and individual diastereomers of these compounds. The piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 7, stereospecifically defined by the general formula yhor ^4. R ¹ —NCAN C = 0 'R ⁵ I n (CH ₂ ) _n \ M-x R ³ Y wherein the symbols are as defined in Claim 7th The piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of claim 7, selected from the group consisting of: 388 d _b cis d ₂ . trans d _b trans d _? cis d _b cis d ₂ , trans d _b trans d ₂ 389 390 F> SO ₂ NHCH ₃ CO O 391 as well as pharmaceutically acceptable rates of these compounds when the salts and individual diastereonies are listed. 13. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 1, of the general formula C1. H H 0 * I II f _r 1_í | _N-CAN C = 0 _r 5 (Cl) I * (CH ₂ ) _n \ Y kde R1 is selected from alkyl of 1 to 10 carbon atoms, aryl, arylalkyl of 1 to 6 carbon atoms in the alkyl moiety, (cycloalkylalkyl of 3 to 7 carbon atoms) (alkyl of 1 to 6 carbon atoms) -, (alkyl of 1 to 6 carbon atoms); up to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) -, aryl (alkyl of 0 to 5 carbon atoms) -K- (alkyl of 1 to 5 carbon atoms) 392 (C 3 -C 7 cycloalkyl) (C 0 -C 5 alkyl) -K- (C 1 -C 5 alkyl) wherein K is O, S (O) _m , N (R) ² ) C (O), C (O) N (R ² ), OC (O), C (O) O, -CR ² = CR ² - or -C = C- and aryl is selected from phenyl, naphthyl , indolyl, azaindole, pyridyl, benzothienyl, benzofuranyl, thiazolyl and benzO imidazolyl, wherein R and alkyl radicals are optionally substituted with 1 to 9 halogen atoms, S (O) _m R ^2a , 1 to 3 OR ^2a or C (O) OR groups ^2a and aryl is optionally substituted with 1 to 3 alkyl radicals of 1 to 6 carbon atoms, 1 to 3 halogen atoms, 1 to 2 groups 9 9 OR, methylenedioxy groups, -S (O) _m R, 1-2 groups -CF ₃ , -OCF 3, nitro, -N (R ² ) C (O) (R ² ), -C (O) OR ² , -C (O) N (R ² ) (R ² ), 1H-tetrazol-5-yl, -SO ₂ N (R ² ) (R ² ), -N (R ² ) SO 2 -phenyl or -N (R ² ) SO ² R ² , o R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 3 to 8 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing O, s or NR ^a, wherein R ^a is hydrogen or alkyl of 1 to 6 carbon atoms, optionally substituted with hydroxy, R ^2a represents a hydrogen atom or an alkyl of 1 to 6 carbon atoms, optionally substituted by a hydroxyl group, X is selected from hydrogen, -C = N, - _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl, - (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OR ² , - (CH ₂ ) _q OC (O) R ² , - (CH 2) _q O C (O) (CH) _{2) t} -aryl, - _{(CH2) q} 0C (0) N ^(R2) (CH2) taryl, - (CH 2) q OC (O) N (R ²⁾ (R ^2), - (CH 2) _q C (0) ^R2, - (CH ₂ ) _q C (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² , "(CH ₂ ) _q N (R ² ) SO ² N (R) ² ) (R ² ), - (CH 2) _q S (O) _m R ² and - (CH ₂ ) _q S (O) _m (CH ₂ ) _t -aryl, 393 wherein the groups R, (CH ₂ ) q and (CH ₂ ) _t are optionally substituted with 1 to 2 alkyl groups of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, carboxyl, CONH ₂ , S (O ) _m CH ₃ , in the form of a carboxylate alkyl ester of 1 to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl and aryl means phenyl, naphthyl, pyridyl, thiazolyl or 1H-tetrazol-5-yl optionally substituted with 1 to 3 halogen atoms , 1 to 3 -OR, -CON (R ² ) (R ² ), -C (O) OR ² , 1 to 3 C 1 -C 4 alkyl, -S (O) _m R ^2, or 1H- tetrazol-5-yl, Y is hydrogen, alkyl of 1 to 10 carbon atoms, - (CH ₂ ) 4 -aryl, - (CH ₂ ) q - (cycloalkyl of 3 to 7 carbon atoms), - (CH ₂ ) q K -alkyl of 1 to 10 carbon atoms 6 carbon atoms in the alkyl moiety, - (CH ₂ ) q K- (CH ₂ ) _t aryl, - (CH ₂ ) q K- (CH ₂ ) _χ (cycloalkyl of 3 to 7 carbon atoms, containing 0, NR ² or S) and - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 3 -C 7 cycloalkyl) wherein K is O, S (O) _m , C (O) NR ² , CH = CH, C = C, N (R ² ) C (O), C (O) NR ² , C (O) 0 or OC (O), wherein alkyl, R, (CH ₂ ) q and (CH ₂ ) _t are optionally substituted with an alkyl group (C 1 -C 4) -hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 NH _2, or in the form of a C 1 -C 4 carboxylate alkyl ester and aryl means phenyl, naphthyl, pyridyl, 1H-tetrazole -5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiophenyl, quinolinyl, pyrazinyl or isothiazolyl, optionally substituted with 1-yl up to 3 halogen atoms, 1 to 3 -OR ² , -C (O) OR ² , -C (O) N (R ² ) (R ² ), nitro, cyano, benzyl, 1 to 3 alkyl groups of 1 up to 4 carbon atoms, -S (O) _m R ² or 1H-tetrazol-5-yl, provided that X represents a hydrogen atom, Y has a meaning different from that of a hydrogen atom, R ⁴ and R ⁵ independently represent hydrogen, alkyl of 1 to 6 atoms 394 carbon, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy, 1 to 3 alkanoyloxy of 1 to 10 carbon atoms, 1 to 3 alkoxy of 1 to 6 carbon atoms, phenyl, phenoxy, 2-furyl, alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety or S (O) _m -alkyl having 1 to 6 carbon atoms in the alkyl moiety, or R ⁴ and R ³ together may form - (CH 2) j L ³ · (CH 2) _e -, where L ^a is C (R ² ) ₂ , O, S (O) _m or N (R ² ), d and e are independently the integer 9 number 1 to 3 and R is as defined above, A means one of the groups R ⁷ R ⁷ - (CH ₂ ) _x -C "(CH ₂ ) - or -Z - (CH ₂ ) _x -C - (CH ₂ ) - Ŕ ₇ and R ^7a where x and y independently represent an integer of 0, 1, 2 or 3, Z is NR or 0 ^and wherein R ^a is H or alkyl of 1 to 6 carbon atoms, R ⁷ and R ^{7a are} independently hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , cycloalkyl of 3 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or ⁷ and R ^{7a may} be joined to one or both R ⁴ and R ⁵ groups to form alkylene bridges between the terminal nitrogen atom and the alkyl moiety of R ⁷ or R ^7a , wherein the bridges contain 1 to 5 carbon atoms or R 1 and R 7 ^and together form a cycloalkyl ring having from 3 to 7 carbon atoms, as defined in claim 1, m is 0, 1 or 2, n is 1, 2 or 3, 395 q is 0, 1, 2, 3 or 4, t is 0, 1, 2 or 3, as well as pharmaceutically acceptable salts of these compounds and their individual diastereomers. The piperidine, pyrrolidine and hexahydro-1H-azepine derivatives of claim 13, wherein: R ¹ is selected from alkyl of 1 to 10 carbon atoms, aryl (alkyl of 1 to 4 carbon atoms) -, (cycloalkyl of 3 to 6 carbon atoms) (alkyl of 1 to 4 carbon atoms) -, (alkyl of 1 to 4 carbon atoms) (C 1 -C 2 alkyl) -K- (C 1 -C 2 alkyl) -, aryl (C 2 -C 2 alkyl) -K- (C 1 -C 2 alkyl) - or (C 3 -C 7 cycloalkyl) (alkyl of 0 to 2 carbon atoms) -K- (alkyl of 1 to 2 carbon atoms), wherein K is O, S (O) _m , OC (O), C (O) O, wherein the alkyl groups are optionally substituted with 1 to 7 halogen atoms, S (O) _m R ² , 1 to 3 OR ² or C (O) OR ² and aryl means phenyl, naphthyl, indolyl, azaindolyl, pyridyl, benzothienyl or benzofuranyl, optionally substituted with 1 to 7 2 alkyl groups having 1 to 4 carbon atoms, ABOUT 1 or 2 halogen atoms, 1 or 2 -OR groups, S (O) _m R ² or C (O) OR ² , o R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 4 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing O, s or NR ^a, wherein R ^a is hydrogen or C 1 -C 4 alkyl, X is selected from hydrogen, - _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH ₂ ) _q N (R ² ) SO ₂ (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH 2) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) O (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) R ² , 396 - (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q S (O) _m R ² and - (CH ₂ ) S (O) _m (CH ₂ ) _t -aryl, wherein R is optionally substituted by hydroxyl, carboxyl, CO ₂ H, S (O) _m CH 3, in the form of a C 1 -C 4 carboxylate alkyl ester or tetrazole group, and aryl is phenyl, naphthyl, pyridyl or 1H-tetrazole- 5-yl, optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR ² , -CO ₂ NH, -C (O) OR ² , 1 to 3 C 1 -C 4 alkyl, -SCO 4 R 6 groups, or 1H-tetrazol-5-yl, Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms, - (CH ₂ ) _t -aryl, - (CH ₂ ) _q - (C 5 -C 6 cycloalkyl), - (CH ₂ ) _q -C 1 -C 6 alkyl in the alkyl moiety, - (CH _{2) q-} K- (CH ₂ ) _t aryl, - (CH ₂ ) _q -K- (CH ₂ ) _χ (cycloalkyl of 3 to 7 carbon atoms containing 0, NR ² or S) and - (CH ₂ ) _q -K- (CH ₂ ) _t - (C 5 -C 6 cycloalkyl) wherein K is O, S (O) _m and the alkyl groups are optionally substituted with a hydroxyl group, a carboxyl group, -CO ₂ NH _2, or in the form of a 1-carboxylate alkyl ester up to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl, aryl means phenyl, naphthyl, pyridyl, ΙΗ-tetrazolyl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl or thiophenyl, optionally substituted with 1 up to 3 halogen atoms, 1 to 3 -OR ² , -C (O) OR ² , -C (O) N (R ² ) (R ² ), cyano, 1 to 2 C 1 -C 4 alkyl groups, benzyl, -S (O) _m R or 1H-tetrazol-5-yl provided that when X is a hydrogen atom, Y has a meaning different from that of a hydrogen atom, R ⁴ and R 5 independently represent hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted with 1 to 5 halogen atoms, 1 to 3 hydroxy groups, S (O) _m- alkyl of 1 to 6 carbon atoms in the alkyl moiety or phenyl, 397 A represents a group R ⁷ (CH ₂ ) X -CR ^7a wherein x represents 0 or 1, R ⁷ and R ^7a independently represent hydrogen, C 1 -C 6 alkyl, trifluoromethyl, phenyl, substituted C 1 -C 6 alkyl wherein the substituents are selected from imidazolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , cycloalkyl of 5 to 7 carbon atoms, N (R ² ) (R ² ), C (O) N (R ² ) (R ² ) or ⁷ and R ^{7a may} be joined to one or both R ⁴ and R ³ groups to form alkylene bridges between the terminal nitrogen atom and the alkyl part of R ⁷ or R ^7a , wherein the bridges contain 5 to 6 atoms or R ⁷ and R ^{7a may} together form a cycloalkyl ring of 3 carbon atoms, provided that claim 1 m means about, 1 or 2, n means 2 q means about, 1, 2 or 3 T means about, 1, 2 or 3 as well as pharmaceutically acceptable salts thereof and their individual diastereomers. 15. The piperidine, pyrrolidine and hexahydro-lH-azepine compound according to claim 13, of formula CI b _x? I ¹ / ^r4 r ¹ —c'-ncan i Λ r ⁵ c = o ⁰ (on) I 398 where R ¹ is selected from the group consisting of alkyl of 1 to 10 carbon atoms, aryl (alkyl of 1 to 3 carbon atoms), (cycloalkyl of 3 to 7 carbon atoms) (alkyl of 1 to 3 carbon atoms), or aryl (alkyl of 1 to 3 carbon atoms) (C 1 -C 2 alkyl) -K- (C 1 -C 2 alkyl) - wherein K is O, S (O) _m and aryl is phenyl, naphthyl, indolyl, azaindolyl, pyridyl or benzimidazolyl, optionally substituted with 1 to 2 alkyl groups of 1 to 4 carbon atoms, 1 or 2 halogen atoms, 1 or 2 -OR ² groups, S (O) _m R ² or C (O) OR ² , R represents a hydrogen atom, an alkyl of 1 to 6 carbon atoms or a cycloalkyl of 3 to 7 carbon atoms, and may be taken together to form a ring of 5 to 7 members when two alkyl groups of 1 to 6 carbon atoms are attached to one atom optionally containing an oxygen, sulfur or NR ^3a group, wherein R ^3a represents a hydrogen atom or a C 1 -C 4 alkyl group, X is selected from hydrogen, - _{(CH2) q} N ^(R2) C (0) R ^2, - (CH 2) q N (R ²⁾ C (O) (CH 2) _t -aryl, - (CH ₂ ) _q N (R ² ) SO ² (CH 2) t -aryl, - (CH ₂ ) _q N (R ² ) SO ² R ² , - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (CH ₂ ) _t -aryl, - (CH ₂ ) _q N (R ² ) C (O) N (R ² ) (R ² ), - (CH ₂ ) _q C (O) N (R ² ) (R ² ), - (CH ₂ ) _q N (R ² ) C (O) OR ² , - (CH 2) q C (O) N (R ² ) (CH 2) _t -aryl, - (CH ₂ ) _q C (O) OR ² , - (CH ₂ ) _q C (O) 0 (CH ₂ ) _t -aryl, - (CH ₂ ) _q OC (O) R ² , - (CH ₂ ) _q OC (O) (CH ₂ ) _t -aryl, - (CH ₂ ) _q S (O) _m R ² and - (CH 2) q S (O) m (CH 2) t -aryl, wherein R ² is optionally substituted by hydroxyl, carboxyl, CONH 2, S (O) _m CH ₃ , in the form of a carboxylate alkyl ester of 1 to 4 carbon atoms in the alkyl moiety or a tetrazole group and aryl means phenyl, naphthyl or pyridyl, optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR ² , -C (O) OR ² groups , 1 to 3 alkyl groups having 1 to 4 carbon atoms, -S (O) _m R or 1H-tetrazol-5-yl, Y represents a hydrogen atom, an alkyl of 1 to 8 carbon atoms, 399 - (CH _{2) t} -aryl, - _(CH2) - (C 5 -C 7 cycloalkyl), - (CH _O) -K-C 1 -C 6 atoms in the £. q of the keel moiety, - (CH ₂ ) q K- (CH ₂ ) _t -aryl or - (CH ₂ ) q K (CH ₂ ) (C 5 -C 6 cycloalkyl), wherein K is S (O) _m and alkyl groups are optionally substituted by hydroxyl, carboxyl, -CONH ₂ or in the form of a carboxylate alkyl ester of 1 to 4 carbon atoms in the alkyl moiety or 1H-tetrazol-5-yl, aryl means phenyl, naphthyl, pyridyl, thiazolyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl or imidazolyl, optionally substituted with 1 to 2 halogen atoms, 1 to 2 -OR ² , -C (O) OR ² , -N (R ² ) (R ² ), 1 to 2 C 1 -C 4 alkyl groups, -S (O) _m R or 1H-tetrazol-5-yl provided that when X is a hydrogen atom, Y has a meaning different from that of a hydrogen atom, R ⁴ and R ⁵ independently represent hydrogen, alkyl of 1 to 4 carbon atoms, optionally substituted alkyl of 1 to 3 carbon atoms, wherein the substituents may be 1 to 2 hydroxy groups, A stands for ' R ⁷ (CH ₂ ) X -O-r ⁷ and wherein x is 0 or 1, R ⁷ and R ^7a independently represent hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, substituted alkyl of 1 to 6 carbon atoms in which the substituents are selected from imidixolyl, phenyl, indolyl, p-hydroxyphenyl, OR ² , S (O) _m R ² , C (O) OR ² , or R ⁷ and R ^7a together may form a cycloalkyl ring of 3 carbon atoms, m means about, 1 or 2, q means about, 1 , 2, or 3 T means 0 1 , 2, or 3 as well as pharmaceutically acceptable salts thereof and their individual diastereomers. 400 Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 13, having the general formula C18-C-n-c-a-nC R (CIc) wherein r 1; is selected from groups or regioisomers of these compounds, unless specifically specified, 401 X represents a hydrogen atom or one of the groups: 402 Y represents a hydrogen atom or one of the groups: or regioisomers of these groups, unless specifically specified, provided that when X is a hydrogen atom, Y has a meaning different from that of a hydrogen atom, 403 is selected from the following groups: H ₃ C ^ jdh ₃ h ₃ c CH ₃ 9 ^ 3 ch ₃ h ₃ c ch ₃ y Y * y vV W Ay Ax H, C CH, .CH, <\ \ NH R 5 and R 5 are independently selected from groups CH, CH ₂ OH - H - CH _{3 -} CH ₂ CH ₃ OH OH as well as pharmaceutically acceptable salts and diastereomers thereof. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 13, stereospecifically defined by the general formula HH 0 r ⁴ R ¹ —j - NCAN C = 0 R ⁵ I X (CH ₂ ) _n \ Rx Wherein each symbol is as defined in claim 13. Piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 13 from the group of: 404 405 406 Ο And pharmaceutically acceptable salts and individual diastereomers thereof, unless specifically indicated. 19. A pharmaceutical composition for increasing endogenous production or release of growth hormone in a human or other animal, which comprises as its active ingredient piperidine, pyrrolidine or hexahydro-1H-azepine derivatives according to claim 1 together with an inert carrier. 408 20. A pharmaceutical composition for increasing endogenous production or release of growth hormone in a human or other animal, comprising the piperidine, pyrrolidine or hexahydro-1Hazepine derivatives of claim 1, and additionally a growth hormone secretagogue together with an inert carrier. 21. The pharmaceutical composition of claim 20, wherein the further growth hormone secretagogue is selected from the group consisting of GHRP-6 peptide, GHRP-2 peptide, or growth hormone releasing GHRP-1 peptide, factor B-HT920, which releases growth hormone. a hormone or analog thereof, IGF-1 and IGF-2. 22. A pharmaceutical composition for the treatment of osteoporosis comprising a combination of a bisphosphonate compound and a piperidine, pyrrolidine or hexahydro-1H-azepine derivative according to claim 1. The pharmaceutical composition of claim 22, wherein the bisphosphonate compound is alendronate. 24. A method of increasing the concentration of endogenous growth hormone in a human or other animal, comprising administering an effective amount of a compound of claim 1. 25. A method for increasing feed utilization, accelerating growth, increasing dairy production, and improving meat quality in domestic animals, comprising administering an effective amount of the compounds of claim 1. 26. A method of treating or preventing osteoporosis, catabolic diseases, immune system deficiency including reduced T ^ / Tg cell rate, femoral neck fracture, bone and skeletal muscle damage in the elderly, growth hormone deficiency in adults and children, obesity, tachexia and protein loss in chronic diseases such as AIDS and malignant tumors, treatment of conditions after surgery, trauma and burns, characterized in that an effective amount of the compounds of claim 1 is administered. 27. A method for treating osteoporosis, comprising administering a combination of the compounds of claim 1 and the bisphosphonate compounds. Method according to claim 27, characterized in that alendronate is used as the bisphosphonate. A process for the preparation of piperidine, pyrrolidine and hexahydro-1H-azepine derivatives according to claim 1, characterized in that the compound of formula 4 is reacted. R ^J N-H C = O (CH ₂ ) n 1 · 3 Y (4) with a compound of formula 5 or 6 ABOUT HO-C-A- or (θ) HO-C-A- to form a compound of formula I or 7 410 ^H ? 2 / N-C-A-N C = O ^R R R ^J H H O I I II N-C-A-N C-O R (CH ₂ ) _n or ^ 1 (CH ₂ ) _n W _x , 3 Y R0) (7) where R ^1, R ^3, R ^4, R 5, A, W, X, Y and n are as defined in Claim 1 and L is a protecting group, then optionally removing the protecting group L and optionally converting the free compounds into their salts. 30 Preparation of piperidine, pyrrolidine and hexahydro-lH-azepine derivatives, according to claim 1, characterized in that the reaction of a compound of formula 12, or HOR 12 ^H HH ⁴ 0 L R ¹ --NCA -N-R ⁵ R ¹ —f — NCANR ⁵ COOH or COOH (12) (12a) wherein L is a protecting group and the other symbols are as defined in claim 1 with a compound of formula 2 to form a compound of formula I or 7 411 Η Η Ο II-N-C-A-N c = o R ⁴ R ⁵ H H O L I II. —N-C-A-N « C = 0 R ⁵ J \ LW (CH ₂ ) _n y M-x R ³ , x ^Y or ✓N w (CH 3 JnY '™) M-x R ³ · ^Y (7) where L is a protecting group and the other symbols are as defined in claim 1, then optionally protecting group is removed and the free compounds obtained are optionally converted into their salts. A piperidine, pyrrolidine and hexahydro-1H-azepine derivative according to claim 13, of the formula and pharmaceutically acceptable salts thereof. 32. The piperidine, pyrrolidine and hexahydro-1H-azepine derivative according to claim 13, of the formula: NH ₂ HCl 412 A pharmaceutical composition according to claim 19, characterized in that it comprises as an active ingredient a derivative according to claim 31 together with an inert carrier.