LT3594B - Imidazole,triazole and tetrazole derivatives - Google Patents

Abstract

The class of changed imidazole, triazole and tetrazole compounds is a selective antagonist for receptors, similar to 5 Hti, hereby useful for treating clinical states, in particular migraine and disorders caused by it, where a selective agonist of such receptors is applicable.

Description

The present invention describes a class of substituted imidazole, triazole, and tetrazole derivatives that act on 5-hydroxytryptamine (5-HT) receptors as so-called 5-HT / 'receptor-selective agonists. As such, they are useful in the treatment of clinical conditions where selective agonists of these receptors are indicated.

5-HTf receptor-like agonists with selective vasoconstrictor activity, as recently described, are used in the treatment of migraine, such as A. Doenicke et al., The Lancet, 1988, Vol. 1, 1309-11). The compounds of the present invention being selective for 5-HT! receptor agonists / 'are therefore particularly used in the treatment of migraine and related conditions such as mixed headache, chronic paroxysmal migraine, headache associated with vascular disorders, tension headache and migraine in children.

EP no. A-0313397 describes a class of substituted five-membered heteroaliphatic ring-derived tryptamine derivatives that are considered specific for δ-ΗΤ / special type receptors and thus are considered effective therapeutic agents for the treatment of clinical conditions requiring such effects, particularly migraine. However, EP no. A-0313397 neither describes nor proposes the imidazole, triazole and tetrazole derivatives of the present invention.

The present invention provides a compound of formula I, or a salt or parenteral form thereof:

X; '· \ Y

-f (I) wherein the dotted ring represents two non-adjacent double bonds at any position on the pentagonal ring;

two, three or four of V, W, X, Y and Z are nitrogen and the remainder are carbon, provided that two of V, W, X, Y and Z are nitrogen and the rest are carbon, then said nitrogen atoms are not in adjacent positions in a five-membered ring;

A ¹ is hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, -OR ^X , -SR ^X ,

A is an unbound pair of electrons when four of V

W, X

Y and Z are nitrogen and the rest is carbon; or when two or three of V, W, X, Y and Z are nitrogen and the rest is carbon,

A ² is hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, -OR ^X , -SR ^X , -NR ^x R ^y '-NR ^X COR ^Y ' -NR ^X CO 2 R ^Y '-NR ^X SO 2 R ^Y or - NR ^Z CTNR ^X R ^Y ;

Ξ is a bond or a linear or branched alkylene chain containing from 1 to 4 carbon atoms;

_v . F is a group of formula

U is nitrogen or C-R;

is an oxygen

N-R;

rmu 1 ζ

wherein the dotted line is not necessarily a chemical bond;

R ^2, R ^3, R ^4, R ^5, R ⁶ and R ⁷ independently represent hydrogen or C _x _ ₆ alkyl;

R ^x and R ^y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y together represent a C ₂ _ ₆ alkylene group;

R ^z is hydrogen, hydrocarbon or heterocyclic;

T is oxygen, sulfur or a group of the formula = N.G; and

G is a hydrocarbon, heterocyclic group, or electron withdrawing group.

The present invention also provides compounds of formula I as mentioned above wherein three or four of V, W, X, Y and Z are nitrogen and the remainder are carbon;

A ² is an unbound pair of electrons where four of V, W, X, Y and Z are nitrogen and the rest is carbon; or when three of V, W, X, Y and Z are nitrogen and the remainder are carbon, A 'is hydrogen, hydrocarbon, heterocyclic group, halogen cyano, trifluoromethyl, -OR ^X , -SR ^X , -NR ^X R' - NR ^x COR ^y '-NR ^x CO 2 R ^y ' -NR ^x SO 2 R ^y or NR ^z CTNR ^x R ^y ; and

A ¹ , E, F, R ^x , R '' R ^z and T are as previously defined.

When used in medicine, the salts of the compounds of formula I will be non-toxic, pharmacologically acceptable salts. However, other salts may be useful in preparing the compounds of this invention or their non-toxic, pharmacologically acceptable salts. Suitable pharmacologically acceptable salts of the compounds of the present invention include those which may be obtained, for example, by mixing a solution of a compound of the invention with a solution of a pharmacologically acceptable non-toxic acid, namely hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid. , oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In particular, when the compounds of the present invention contain an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

The term hydrocarbon, as used herein, includes linear, branched or ring groups having up to 18 carbon atoms, more preferably up to 15 carbon atoms and most preferably up to 12 carbon atoms. Suitable hydrocarbon groups include CT.g alkyl, C ₂ . _{6 alkenyl,} C2 -6 alkynyl, C ₃ _ ₇ cycloalkyl, C ₃ _ ₇ cycloalkyl (Ο ₃ _ ₆₎ alkyl, aryl and aryl (Cj.g) alkyl.

As used herein, a heterocyclic group includes cyclic groups having up to 18 carbon atoms and at least one heteroatom, preferably selected from oxygen, nitrogen and sulfur. A more preferred heterocyclic group has up to 15 carbon atoms and most preferably carbon atoms, and fusion is preferred. Examples of suitable.heterocyclic groups up to 12. 3 ip yrs. C'3_7 heterocycloalkyl, C ₃ _ ₇ heterocycloalkyl (Ο ₃ _ ₆₎ alkyl, heteroaryl and heteroaryl (C?) Alkyl groups.

Suitable alkyl groups are straight chain and 5 branched alkyl groups having 1 to 6 carbon atoms. Typical examples are methyl and ethyl groups and linear or branched propyl and butyl groups. Particular alkyl groups include methyl, ethyl and t-butyl.

Suitable alkenyl groups are straight chain and branched alkenyl groups having from 2 to 6 carbon atoms. Typical examples are vinyl and alum groups.

Suitable alkynyl groups are straight chain and branched alkynyl groups having from 2 to 6 carbon atoms. Typical examples are ethynyl and propargyl groups.

Suitable cycloalkyl groups are those having from 3 to 7 carbon atoms. Particular cycloalkyl groups include cyclopropyl and cyclohexyl.

A particular aryl group is phenyl.

Particular aryl (C _i _ ₆₎ alkyl groups are benzyl, phenethyl and phenylpropyl.

Suitable heterocycloalkyl groups include azetidinyl, pi30 rolidyl, piperidyl, piperazinyl and morpholinyl.

Suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinium, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl.

Particular heteroaryl (C 1-6) alkyl groups are pyridylmethyl and pyrazinylmethyl.

The hydrocarbon and heterocyclic groups may in turn be optionally 5 substituted by one or more groups selected from Cį.g alkyl, adamantyl, phenyl, halogen, C _T _ ₆ haloalkyl, C ^ g aminoalkyl, trifluoromethyl, hydroxy, C _x _g alkoxy, aryloxy , keto,

C _{_ 3} alkylenedioxy, nitro, cyano, carboxyl, C ₂ _ ₆ AL10 koksikarbonilo C ₂ _ ₆ alkoxycarbonyl (C ^ g) alkyl, C ₂ _ ₆ alkylcarbonyloxy arilkarboniloksilo C ₂ _ ₆ alkylcarbonyl, arylcarbonyl, Ο ₄ _ ₆ alkylthio, Ci_ ₆ alkylsulfinyl, C ^ g alkylsulfonyl, arylsulfonyl, NP / R ^W

NR ^V COR ^W , -NR ^v CO 2 R ^w , -NR ^v SO 2 R ^w , CH 2 NR ^v SO 2 R ^w , -NHCONR ^v R ^w , 15 CONR ^V R ^W , ~ SO ₂ NR ^v R ^w, and -CH ₂ SO ₂ NR ^V R ^W in which R ^v . and R ^w independently represent hydrogen, C 1-6 alkyl, aryl, or aryl (O 3-6) alkyl, or R ^v and R ^w together represent C 2. ₆ alkylene group.

When R ^x and R ^Y or R ^v and R ^w together represent a C _{2 -} 8 alkylene group, this group may be an ethylene, butylene, propylene, pentamethylene or hexamethylene group, preferably butylene or pentamethylene.

When G is an electron withdrawing group, a suitable group is cyano, nitro, -COR ^X , -CO 2 R ^X or -SO 2 R ^X , wherein R ^x is as previously defined.

The term halogen as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine.

The present invention includes within its scope primary pharmaceutical formulations of the compounds of formula I above. In general, such primary dosage forms will contain compounds of Formula I, i

Km e switch to ductile compound of poor formula:

..ai c> <.

Lines selected and available as suitable daLT 3594 B primary dosage forms are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

When the compounds of the invention have at least one asi5 metric center, they may accordingly exist as enantiomers. When the compounds of the invention have two or more asymmetric centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the present invention.

It is understood that imidazole, dai of Formula I, may be in the form of forms. They will be properly formulated from IA to IT:

triazole and tetrazole may exist as a sequence expressing the following

(ID) (IE) (IF)

(IK) (IL) (IM)

The ¹ f.

The ^A

V, N- ^f - ^F

N - H

(IN) (IP) (IQ)

(IR) {j

TT where A ¹ is more appropriate

A ² , E and F are as previously defined, imidazole, 'triazole and tetrazolium

Fo rmu.l e s I: Spears are rings represented by the formulas IA, IC, IG, IH, IL, IM, IN, IP and IQ mentioned above, especially IH.

The alkylene chain E can be, for example, methylene, ethylene, 1-methylethylene, propylene or 2-methylpropylene. Alternatively, group E may represent a single bond such that group F in formula I is attached directly to a five membered heteroaromatic ring.

A suitable group F is an indole, benzofuran or benzothiophene moiety in formula FA or an indazole moiety in formula FB:

B R '(FA)

wherein B, R ¹ , R ² and R ³ are as previously defined.

it is preferable that group F is an indole particle in structure FC:

(FC) wherein R ¹ , R ² and R ³ are as previously defined, especially wherein R ³ and R ^{3 are} both hydrogen.

It is understood that when four of V, W, X, Y and Z are nitrogen and the remainder are carbon, e.g. when the ring of formula I is a tetrazole ring, then the group A ² will be an unbound pair of electrons. Otherwise, A and A independently represent hydrogen, hydrocarbon, heterocyclyl, halogen, cyano, trifluoromethyl, -OR ^X , -SR ^X , -NR ^x R ^y '-NR ^x COR ^y ' -NR ^X CO 2 R ^y '-NR ^x SO 2 R ^y or '-NR ^z CTNR ^x R ^y . "'

2

Suitable values for the groups A and / or A is C ^ g alkyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (C ₁ _ ₆₎ alkyl, C ₃ .. ₇ heterocycloalkyl, heteroaryl or heteroaryl (C ^ g) alkyl, any these groups may not necessarily be substituted; as well as hydrogen, halogen, cyano, trifluoromethyl, Ο ₃ _ ₆ alkoxy, C ^ alkylthio or -NR ^x R ^{y ',} wherein R ^x and R ^y are as defined before. Groups A ¹ and / or a suitable Examples of optional substituents is trifluoromethyl, Ci-g alkoxy, C ₂ _ ₆ alkoxycarbonyl, C _2-6 alkylcarbonyl, C _w alkylsulfonyl, arylsulfonyl, amino, mono- or di _(Ο χ _ ₆₎ alkylamino C ₂ _ ₆ alkylcarbonylamino, arylcarbonylamino, C ₂ _ _e alkoxycarbonylamino, _Ο χ _ ₆ alkylsulphonylamino onilamino, arilsulf oniiamino C -, _ ₆ alkylsulfonylaminomethyl, aminocarbonylamino, mono- or di (C ₁ _ ₆₎ alkylaminocarbonylamino, mono- or diarilaminokarbonilamino , piroiidiikarbonilamino, aminocarbonyl, monoar di (C _± _ ₆₎ alkylaminocarbonyl, Ο ₃ _ ₆ alkyl-aminosulfonilmetilas monoar and di (C ₁ _ ₆₎ alkilaminosulfoniimetilas.

Particular A and / or A methyl, methoxymethyl, methyl, acetylaminomethyl, 1-oxo-carbonylamine.

The term "sulfonyl" isopropylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl, methoxycarbonylaminoethyl. , aminokarbonilaminoetilas, metilaminokarbonilaminoetilas t-butilaminokarbonilaminoetilas, fenilaminokarbonilaminoetilas, pirolidilkarbonilaminoetilas, cyclopropyl, phenyl, metilsulfonilaminofenilas, aminocarbonyl, methylaminocarbonylphenyl, metilsulfonilaminometilfenilas, aminosulfonilmetilfenilas, metilaminosulfonilmetilfenilas, dimetilaminosulfonilmetilfenilas, benzyl, trifluoromethylbenzyl, methoxybenzyl, acetylaminobenzyl, metilsulfonilaminobenzilas, aminokarbonilaminobenzilas, aminokarbonilbenzilas, metilaminokarbonilbenzilas, metilsulfonilbenzilas, metilaminosulfonilbenzilas , pyridylmethyl, methoxypyridylmethyl, amino, meth ilamino, benzylamino, dimethylamino, t-butoxycarbonylaminoethylamine and methylsulfonylaminoethylamine.

2

Preferred values for A and / or A are hydrogen, methyl, ethyl, benzyl and amine.

Typical values for R ¹ are aminoethyl, N-methylaminoethyl, N, N-dimethylaminoethyl, 4-piperidyl, 1-methyl-4-piperidyl, 3-pyrrolidinyl and 1-methyl-3-pyrrolidinyl.

Preference is given to groups where R ² to R ⁷ are hydrogen and methyl.

A particular subclass of the compounds of the present invention is represented by the compounds of formula IIA and their salts and primary pharmaceutical forms:

(HA)

Oh where

X ¹ is nitrogen or A ¹² -C; n is zero, 1, 2 or 3;

B ¹ is oxygen, sulfur or NR ¹³ ;

A ¹¹ and A ¹² independently represent Ο ₇ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (Ο ₃ _ ₆₎ alkyl, C ₃ _ ₇ heterocycloalkyl, heteroaryl, or hete20 roaryl (C 1-8) alkyl, any of these groups may be optionally substituted; hydrogen, halogen, cyano, trifluoromethyl, C _1-6 alkoxy, C 1-6 alkylthio or -NR ^x R ^y ;

„12„ 13 „14„ 16. '17. . .

R, R, R, R and R independently or Ci_ ₆ alkyl; and represents hydrogen

R ^x and R ^y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y together represent a C ₂ _ ₆ alkylene group.

Suitable groups A ¹¹ and A ¹² Examples of optional substituents are trifluoromethyl, C ^ g alkoxy, C ₂ _ ₆ alkoxycarbonyl, C ₂ _6 alkylcarbonyl, C _{_ s} alkilsuif Onil as, arylsulfonyl, amino, mene- or di (C ^ g) alkylamino, C _{? Talking} aikilkarbonilamino, arylcarbonylamino, C ₂ _ ₆ alkoksikarbcnilamino, Cj.g alkilsuifonilamino, ariis'ulfcnilLT 3594 B amino, Cj_ ₆ alkylsulfonylaminomethyl, aminocarbonylamino, mono- or di (C ₁ _ ₆₎ alkylaminocarbonylamino, mono- or diarilaminokarbonilamino, pirolidilkarbonilamino, aminocarbonyl mono- or di _(χ 0 _ ₆₎ alkylaminocarbonyl, C3_g alkylaminosulfonyl, aminosulfonilmetilas and mono or di (C _x _ ₆₎ alkilaminosulf onylmethyl.

Particular values of A and A in Formula IIA are hydrogen, methyl, ethyl, benzyl and amine. When XI A ¹² C, it is better that the group A ¹¹ is hydrogen or methyl.

Preferably, R, R and R each represent hydrogen. Preferably, the values of R ¹⁶ and R ^{17 in} formula IIA are hydrogen or methyl.

Another subclass of the compounds of the present invention are compounds of formula IIB, their salts and primary pharmaceutical forms:

in which

Y ¹ is nitrogen or A ²² -C;

n is zero, 1, 2 or 3;

2 3

B is oxygen, sulfur or N-R;

A ²¹ and A 'independently represent ² _Ο χ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C _2-6 alkynyl, C _{3rd 7} -cycloalkyl, aryl, ARRL (C _x _ ₆₎ alkyl, C ₃ _ ₇ heterocycloalkyl, heteroaryl or heteroaryl (C _x _ ₆₎ alkyl, any of which groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, C _{x- 6} alkoxy, C _{x- 6} alkylthio or -NR ^x R ^y ;

R ^22, R ^23, R ^24, R ²⁶ and R ²⁷ independently represent hydrogen or C _x _ _c alkyl; and

R ^x and R ^y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y together represent a C ₂ _ ₆ alkylene group.

2122

Examples of optional substituents for groups A and A correspond to those 11 for those given for groups A and A in formula IIA above. Particular values for A ²¹ and A ^{22 in} Formula IIB are hydrogen, methyl, ethyl and benzyl.

Preferably, R, R and R each represent hydrogen.

^ 7

Preferred values of R and R 'in formula IIB are hydrogen and methyl.

A further subclass of the compounds of the invention comprises compounds of the formula IIC, their salts and primary pharmaceutical forms:

in which

Y ¹ is nitrogen or A ¹ -C;

Z ¹ is nitrogen or CH;

n is zero, 1, 2 or 3;

. · 33

B is oxygen, sulfur or N-R;

A ³¹ and A ³² independently represent a C ^ g alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (C ₇ _ ₆₎ alkyl, C ₃ _ ₇ heterocycloalkyl, heteroaryl or heteroaryl (Ci.g) alkyl, any of these groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, C ₁ _ ₆ alkoxy, C ^ alkylthio or -NR ^x R ^y;

R ³¹ is -CH ₂ CHR ³⁴ NR ³⁶ R ³⁷ or a group of formula

- (κ! · \ / or -C NR ³ ”»

R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ and R ³⁷ independently represent hydrogen or alkyl; and

R ^x and R ^y independently represent hydrogen, hydrocarbon or heterocyclic group or R ^x and R ^y both represent

C _2-6 alkylene group.

Examples of optional substituents are those given by the group .; net j'e in formula HA. ·· - Ypa * in formula II-C is hydrogen in the form A ³ ′ and · A ³² corresponds to. 1 12

A * and A were previously migo s values A '' and A '' '' ethyl and amine.

Preferably R ³² , R ³³ and R ³⁴ each represent hydrogen. Preferred values are when R ³⁵ , R ³⁶ and R ³⁷ are hydrogen and methyl.

Yet another subclass of the compounds of the present invention include compounds of formula IID, their salts, and primary pharmaceutical forms:

when

42

W is nitrogen or C-A; n is zero, 1, 2 or 3;

B ⁴ is oxygen, sulfur or NR ⁴³ ;

A ⁴¹ and A ⁴² independently represent Ο ₃ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C _2-6 alkynyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (C ^ g) alkyl, C ₃ _ ₇ heterocycloalkyl, heteroaryl or heteroaryl (C _x- g) alkyl, any of these groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, Ο ₃ _ ₆ alkoxy, C _g _x alkylthio or -NR ^x R ^y;

4 4 4 F 4 7

R is -CH ₂ , CHR, NR R or a group of the formula

43 44 45 46. 47

R, R, R, R, R and R independently represent hydrogen or C _x _ ₆ alkyl; and

R ^x and R ^y independently represent hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y are both a C ₂ _ ₆ alkylene group.

Examples of optional substituents for groups A and A correspond to the substituents given for groups A ¹¹ and A ^{12 in} the aforementioned formula HA. Particular values for A ⁴¹ and A ^{42 in} Formula IID are hydrogen and methyl.

Preferably R ⁴² and R ⁴³ and R ^{44 are} each hydrogen. Preference is given to R ⁴⁵ , R ⁴⁶ and R ⁴⁷ being hydrogen and methyl.

Specific compounds within the scope of the present invention are:

2- [5- (2-Benzyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; 2- [5- (1-Benzyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; N-dimethyl-2- [5- (1-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (2-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (1,1,1,2-triazol-1-ylmethyl) -1H-indol-3ii] ethylamine;

N, N-dimethyl-2- [5- (tetrazol-2-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (tetrazol-1-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (1-methyl-1,2,4-triazol-5-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (1-methyl-1,2,4-triazol-3-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (1,2,3-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine;

3- (2-aminoethyl) -5- (1-methyltetrazol-5-yl) benzo [b] thiophene;

3- (2-aminoethyl) -5- (2-methyltetrazol-5-yl) benzo [b] thiophene;

3- [2- (N, N-dimethylamino) ethyl] -5- (2-methyltetrazol-5-yl) benzo [b] thiophene;

N, N-dimethyl-2- [5- (2-methylimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (imidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (2-ethyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (1-ethyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (1,2,4-triazol-1-yl) -1H-indol-3-yl] ethylamine;

1-methyl-4- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] piperidine;

1-methyl-4- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] piperidine;

4- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] piperidine;

4- [5- (1,2,4-Triazol-1-ylmethyl) -14 indol-3-yl] piperidine

3- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] pyrrolidine;

1-methyl-3- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] pyrrolidine;

4- [5- (imidazol-1-yl) -1H-indol-3-yl] piperidine;

4- [5- (1,2,3-Triazol-1-yl) -1H-indol-3-yl] piperidine;

1-methyl-4- [5- (imidazol-1-yl) -1H-indol-3-yl] piperidine;

1-methyl-4- [5- (1,2,3-triazol-1-yl) -1H-indol-3-yl] piperidine;

1-methyl-3- [5- (1,2,3-triazol-1-yl) -1H-indol-3-yl] pyrrolidine;

1-methyl-3- [5- (2-methylimidazol-1-ylmethyl) -1H-indol-3-yl] pyrcidin;

1-methyl-3- [5- (imidazol-1-yl) -1H-indol-3-yl] pyrrolidine;

1-Methyl-3- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] pyrrolidine;

1-methyl-3- [5- (imidazol-1-ylmethyl) -1H-indol-3-yl] pyrrolidine;

N, N-dimethyl-2- [5- (2-aminoimidazol-1-yl) -1H-indol-3-yl] ethylamine;

N, N-dimethyl-2- [5- (2-aminoimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine;

N-Methyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine;

and their salts and primary forms.

The invention also provides pharmaceutical compositions comprising one or more compounds of the invention in association with a pharmacologically acceptable carrier. Preferably, the compositions are in unit dosage forms, namely, tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, aerosols or pulverulent liquids, drops, ampoules, auto-injections or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for inhalation and infusion. For the preparation of solid compositions, namely tablets, the main active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tablet ingredients, namely, corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium srearate, dicalcium phosphate or resins, and other pharmacological diluents, e.g. water to form a solid preformulation composition comprising a homogeneous mixture of a compound of the invention or a non-toxic pharmacologically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is distributed so uniformly throughout the composition that the composition can be readily subdivided into uniform active unit dosage forms, namely tablets, pills, and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the invention. Tablets or pills of the new formulation may be coated or otherwise processed to provide a dosage form that provides the advantage of prolonged action. For example, a tablet or pill may have an internal and external dose component when the latter is in the form of a shell over the former. The two components can be separated by an enteric layer that allows resistance to gastric disintegration and allows the inner component to pass intact into the duodenum or subsequently relax. Various materials may be used for such enteric coatings or coatings, and such materials include a range of polymeric acids and polymeric acid mixtures with materials such as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the present invention for oral or injection administration may be formulated include aqueous solutions, suitable aromatic syrups, aqueous or oily suspensions, and aromatic emulsions with edible oils, namely, cotton oil, sesame oil, coconut oil, or peanut oil. , as well as elixirs and other pharmaceuticals. Suitable dispersing or suspending agents for aqueous suspensions are synthetic and natural resins, namely tragacanth, acacia, alginate, dextran, carboxymethylcellulose sodium, methylcellulose, polyvinylpyrrolidone or gelatin.

For the treatment of migraine, a suitable dosage level is about 0.01 to 250 mg / kg / day, preferably about 0.05 to 100 mg / kg / day, and more particularly about 0.05 to 5 mg / kg / day. The compounds may be administered 1 to 4 times daily.

The 1,2,4-triazole compounds of the present invention may be prepared by reacting an active carboxylic acid derivative of formula R ^a -CO ₂ H with a compound of formula III or formula IV, or a salt thereof:

NHR ^b

N

II

C

N

(III) (IV) wherein one of R ^a , R ^b and R ^c is a group of formula A, the other is a group of formula A and the third is a group of formula -EF as previously described in the description attached to formula I.

Suitable active acid derivatives of R ^a -CO 2 H are esters, for example alkyl esters; thioesters such as pyridylthioesters; acid anhydrides such as (R ^a -CO) 2 O; acid halides, such as acid chlorides; orthoesters; and primary, secondary and tertiary amines.

The preferred active derivative of the acid R ^a -CO ₂ H is the imine ether derivative of formula V:

(V) wherein R is C _{x 4} alkyl.

The reactant of formula III may be prepared in situ in the reaction mixture. For example, the reaction may be carried out by treating a compound of formula V above with an alkylhydrazine such as methylhydrazine followed by a suitable carboxylic acid such as formic acid.

The reaction is usually carried out by heating the reactants together, not necessarily in a solvent such as tetrahydrofuran, dimethylformamide or a lower alcohol such as ethanol, propanol or isopropanol, for about 1 to about 6 hours for about 20 to 100 ° C.

When R ^a is a group of formula -EF and group F is an indole moiety of structure FC above, the reactive carboxylic acid derivative of formula HO ₂ CEF can be obtained by reacting a compound of formula VI:

ę-F

(VI) wherein Q represents a reactive carboxylate moiety and E is as defined above; with a compound of formula VIII or a form thereof wherein the carbonyl is protected:

wherein R ² is as defined above and E ^{11 is} a group R ^{1 as} defined above or represents a group of formula -CH ₂ . CHR ⁴ D ⁴ wherein R ⁴ is as defined above and D ¹ represents an easily substituted group; followed, if necessary, by N-alkylation by standard methods to introduce the R moiety.

Suitable forms of the compounds of formula VII with protected carbonyl include dimethylacetal or ketal derivatives.

The readily displaceable group D ¹ in the compounds of Formula VII, respectively, represents a halogen atom, preferably chlorine. When a particle of R ¹¹ in the compounds of formula VII is a group having the formula 4 1 1 -CH ₂ . In CHR D, the substituent D is replaced by m situ under the reaction conditions to form a product of formula I, wherein R ¹ represents a group of formula -CH 2. CHR ⁴ . NH2. The terminal amino group may subsequently be further treated, if necessary, using art-known procedures for the preparation of a compound of formula I wherein R ¹ is the desired group of formula -CH ₂ . CHR ⁴ . NR ⁶ R ⁷ .

The reaction between compounds VI and VII can be carried out in one step (Fisher indole synthesis) or in the initial non-cyclization step at low temperature to give the compound of formula VIII:

Q-E

(VIII) wherein Q, E, R and R are further cyclized as defined above; using a suitable reagent, namely a phosphate ester, to form a compound of formula Q-E-F.

The hydrazines of formula VI may be obtained from the corresponding anilines of formula IX:

Q-E

(IX) wherein Q and E are as previously defined; diazotizing and then reducing. Diazotization is usually performed using sodium nitrite / conc. HCl, and the resulting diazoproduct is reduced in situ using, for example, tin (II) chloride / conc. HCL or Sodium Sulfite / Conc. HCL.

Anilines of formula IX may be obtained by refluxing the corresponding nitro compounds of formula X:

(XI wherein Q and E are as previously defined; typically by catalytic hydrogenation using tin (II) chloride.

If not commercially available, nitro compounds of formula X may be synthesized by known standard methods.

Where R ^a is a group of formula -EF and F is, as previously described, an indazole moiety of structure FB, a reactive derivative of a carboxylic acid of formula HO ₂ CEF can be obtained by cyclizing a compound of formula XI:

2 · · * · wherein Q, E and R are as defined above; and D represents an easily substituted group; further, if necessary, N-alkylation is followed by standard methods to introduce R ³ .

The cyclization of compound XI is generally carried out in a suitable organic solvent at elevated temperature, for example, in a mixture of m-xylene and 2,6-lutidine at a temperature near 140 ° C.

Easily displaceable group D ² compound of formula XI, respectively _L represents a C ₄ _ alkanoiloksilo group, preferably acetoksilą. When D ^{2 in the} required compound of formula XI represents acetoxyl, such a compound can generally be prepared by the action of a carbonyl compound of formula XII:

(XII) wherein R ¹ , E and Q are as previously defined: or a protected derivative thereof; with hydroxylamine hydrochloride, more preferably pyridine, at boiling point of the solvent; followed by acetylation with acetic anhydride, more preferably in the presence of a catalytic amount of 4-dimethylamino pyridine, in dichloromethane at room temperature.

The N-formyl protected intermediate of formula XII can conveniently be obtained by ozonolysis of the indole derivative of formula XIII:

(XIII i wherein R ¹ , E and Q are as previously defined, followed by reductive treatment, more preferably using dimethylsulfide.

The indole derivative of formula XIII may be prepared using methods analogous to those described in the examples below or by methods well known in the art.

In an alternative process, the triazole compounds of the present invention may be obtained by reacting a compound of formula XIV:

wherein A ¹ , E and F are as defined above, Hal represents halogen, and two of V ^a , W ^a , X ^a , Y ^a and Z ^a , to which one Hal group is attached, represent carbon and the remaining represents 2 nitrogen; with a reagent having an anion -A, where A is as defined above.

Reagents which may contain the anion -A are Grignard reagents A MgHal (where Hal = halogen); organic ku2 prato reagents, namely LiA ₂ Cu; organic lithium rea2 genera ALi; or compounds which stabilize the anion with the aid of a neighboring activating group such as an ester or an enolized ketone functional group. In this case, the adjacent ester or ketone functional group may remain at the end of the process or may be removed. For example, the ester moiety may be hydrolyzed or decarboxylated.

The 1,2,3-triazole compounds described in the present invention may be obtained by the cycloprocessing reaction of an alkyne of formula R ^a -CCR ^b with an azide of formula R ^c -N ₃ when R ^a , R ^b and R ^c are defined earlier.

The cyclopropionic reaction can proceed well in a suitable solvent such as tetrahydrofuran, preferably by autoclaving for 8 hours.

The tetrazole compounds of the present invention may be prepared by a cycloprecipitation reaction between a nitrile of formula NCR ^d and an azide of formula R ^e -N ₃ where one of R ^d or R ^e is a group of formula A ¹ and the other is a group of the formula -EF as depicted above in Scheme 15.

The cycloprocessing reaction proceeds well by heating the reactants together at elevated temperature, i. y. a temperature of about 150 ° C, and a suitable solvent, viz

N-methylpyrrolid-2-one; works favorably in the presence of triethylamine hydrochloride. The product obtained in the cycloprecipitation reaction will generally be a mixture of isomers substituted at the 1 and 2 positions of the A ¹ group at the tetrazole ring which correspond to the structures IL and IM ati 25, respectively, as previously defined. These isomers may conveniently be separated by conventional techniques, notably chromatography.

Alternatively, the tetrazole compounds of the invention may be prepared by reacting a compound of formula R ^e -L with a tetrazole derivative of formula XV:

Yeah

wherein one of R ^d and R ^e is a group of formula A ¹ and the other is a group of formula -EF as defined above and L is a suitable leaving group; when a base is present, namely triethylamine.

A suitable leaving group L is halogen, i.e. bromine or iodine, or a sulfonate derivative, namely tosylate or mesylate.

The reaction proceeds well in a suitable organic solvent, i.e. acetonitrile at room temperature.

Tetrazolium derivatives of formula XV may be prepared by cycloprecipitation of formula NCR ^d and reaction between nitrile, sodium azide;

favorable conditions have been described previously for nitrile N = CR ^d and azide

R ^e -N, reaction; it is then acidified with a mineral acid, namely hydrochloric acid

Further, the compounds of the present invention wherein the group F is an indole moiety of structure FC as defined above can be obtained by reacting a compound of formula

XVI:

(XVI) wherein V, W, X, Y, Z, A ¹ , A ² and E are as previously defined; with a compound of formula VII as defined above, or a carbonyl-protected form thereof, i.e. dimethylacetal or ketal; followed, if necessary, by N-alkylation in known manner to introduce R ³ .

As with the reaction between the compounds VI and VII, the reaction between the compounds XVI and VII can be carried out in a single step (Fischer indole synthesis) or an initial non-cyclization step at a lower temperature to give the compound of formula XVII:

wherein V, W, Y, Z, A ' ¹ , A ² , E, R ² and R ¹¹ are as previously defined; followed by cyclization with the appropriate reagent, namely the polyphosphate ester.

Hydrazines of formula XVI may be obtained from the corresponding anilines of formula XVIII:

wherein V, W, X, Y, Z, A ¹ , A ² and E are as previously defined; analogous to those previously described, based on the compounds of formula IX.

Anilines of formula XVIII can be obtained from the corresponding nitro compounds of formula XIX:

(XIX) wherein V, W, X, Y, Z, A ^x , A and E are as previously defined; analogous to those described above, based on the compounds of formula X.

Nitro compounds of formula ΧΓΧ may be prepared by a number of routes known to those skilled in the art: For example, when V is a nitrogen atom, the corresponding compounds of formula XIX may be prepared by reacting an anion of a compound of formula XX with a compound of formula of formula XXI:

d ³ .

'NO (XXI) • 1 2 wherein W, X, Y, Z, A, A and E are as previously defined and D ³ is an easily substituted group.

When compound XX is a triazole or tetrazole derivative, its anion can be obtained by reaction in the base, namely triethylamine. When compound XX is an imidazole derivative, its anion can be readily obtained by reaction with sodium hydride using N, N-dimethylformamide as solvent. When the salts of the compounds of formula XX are obtained commercially, e.g. 1,2,4-tria20-sol salt, preferably used in a solution of N, N-dimethylformamide in place of the compounds of formula XX itself; in this case there is no need to have an additional base in the reaction mixture.

The easily substituted group D ^{3 in the} compounds of formula XXI is, respectively, a halogen atom, preferably bromine; except when particle D is directly attached to the aromatic ring, when E represents a bond, then D ^{3 is} preferably fluorine.

Unless commercially available, the above nitro compounds of Formula XXI may be prepared using methods analogous to those described in the Examples below or by known methods.

5

In view of the 1,2,4-triazole derivatives on the other hand, the nitro compounds of formula XIX may be obtained from the compounds of formula X described above by appropriate modification of the Q moiety using, for example, methods analogous to those described above of formulas III and IV. Thus, for example, when Q in the compound of formula X represents a reactive carboxylate moiety, the compounds of formula XIX can be obtained from them by reaction with a compound of formula A ² -C (= NNHA ¹ ) NH 2 or A ² (= NNH ² ). NHA ¹ .

In a further process, the compounds of the present invention wherein the group F is an imidazole moiety of structure FB of the foregoing can be obtained by a cyclization of a compound of formula XXII:

wherein V, W, X, Y, Z, A ¹ , A ² , E, R ¹ and D ² are as previously defined; followed, if necessary, by N-alkylation by standard methods to introduce R ³ .

When considering the cyclization of compound XI, the latter is conveniently carried out on compound XXII in a suitable organic solvent at elevated temperature such as a mixture of m-xylene and 2,4-lutidine at a temperature close to 140 ° C.

Compounds of formula XXII may, for example, be obtained from the corresponding compound of formula XXIII:

(XXIII) wherein V, W, X, Y, Z, ^{1 1} , A,, E and R ¹ are as previously defined; or a protected derivative thereof; which may be obtained in turn from the corresponding compound of formula XXIV:

(XXIV) wherein V, W, X, Y, Z, A ¹ , A ¹ , E and R ¹ are as previously defined; using methods analogous to those previously described for the compounds of formulas XII and XIII. Therefore, for example, if Q in the compounds of formula XIII represents a reactive carboxylate moiety, the 2,4-triazole derivatives of formula XXIV of Formula XXIV may be obtained from them by reaction with a compound of formula A '-C (= NNHA ¹ ) NH 2 or A ² -C (= NNH 2) NHA ¹ .

Still further, the compounds of the invention further encompassed by this process, Group F, is a benzofuran or benzothiophene moiety, obtainable by a process comprising the cyclization compound of formula XXV:

in which V, W, X, Y, Z, A

A ² ,

E and R (XXV) are as previously defined, B 'represents oxygen or sulfur and R ²¹ represents R ¹ as defined above or represents a precursor of a group as discussed below; followed, if necessary, by a transfer by conventional means of the group R '.

The cyclization is usually carried out at acid or polyphosphate ester, at temperature.

to the desired group R more advantageously in polyphosphoric enhancement

Compounds of formula XXV may be prepared by reacting a compound of formula XXVI with a compound of formula XXVII:

(XXVI) (XXVII 'where V, W,. X, Y,

A *, A \

R ^-1 has the values previously defined, and Hal

B, R 'and represents halogen.

The reaction is usually carried out in the presence of a base, namely sodium hydroxide.

The hydroxy and mescapto derivatives of formula XXVI can be obtained by various known means. In one of the following ways, the anion of a compound of formula XX as defined above reacts with a compound of formula XXVIII:

(XXVIII) wherein D ³ , E and Ba ^a have the above meanings; to yield an intermediate of formula XXVI wherein V is nitrogen.

Compounds of formulas XXVII and XXVIII, if not commercially available, may be prepared by standard techniques known in the art.

It will be appreciated that any compound of Formula I, initially obtained by any of the foregoing, may, where appropriate, be subsequently transferred to a further compound of Formula I in a known manner. Indeed, it is understood that the aforementioned compound of formula XV wherein R ^d is a group of formula -EF is itself a compound of formula I wherein A ¹ is 2 hydrogen and A represents an unbound electron pair. In particular, there is initially obtained a compound of formula I wherein R ³ is water. may be converted to a compound of formula I wherein R ³ represents alkyl, C ₂ . ₆ alkenyl or C _; . ₆ alkynyl, in a standard manner, in particular by alkylation, for example by reaction with an alkyl iodide such as methyl iodide,

-at least under basic conditions such as sodium hydride dimethylformamide or triethylamine acetonitrile. There is also initially obtained a compound of formula I and wherein R ¹ represents a group of formula -CH 2. CHR ⁴ . NH2 can be transferred to a compound of Formula wherein R ¹ represents a group of formula -CH ₂ .CHR ^4th NR ⁶ R ⁷ wherein R ⁶ and R ⁷ have the previously defined meanings other than hydrogen, for example using a conventional N-alkylation or N-arylation technique, for example, with the appropriate aldehyde in the presence of a reducing agent such as sodium cyanoborohydride.

When the above processes for the preparation of the compounds of the present invention result in the formation of mixtures of stereoisomers, the latter isomers may be separated by conventional techniques such as preparative chromatography.

The novel compounds may be obtained in racemic form or individual enantiomers may be obtained by either enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their enantiomeric components in a standard manner such as the formation of diastereomeric pairs by formation of a salt with an optically active acid such as (-) -di-p-toiu.ild-tartaric acid and / or (+) - di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The novel compounds may also be isolated by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

In each of the synthesis sequences described above, it may be necessary and / or desirable to protect sensitive or reactive groups on each molecule of interest. This can be achieved using conventional protecting groups, specifically described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and

T.W. Greene, Protective Groups in Organic Synthes, John Wiley Sons, 1981. Protective groups may be removed at a later stage using known methods.

Optionally, in the desired products, certain functional groups may be retained in the reaction sequence as group precursors and subsequently recovered from these group precursors in the final step of all synthesis. For example, where R ^{1 in the} desired compound of formula I represents a group of the formula - (CH ₂ ) ₂ NH ₂ , this group may be derived from the cyano precursor -CH ₂ CN by reduction using, for example, borane / tetrahydrofuran. This cyano precursor can be sequentially maintained throughout the reaction as the methyl group -CH ₃ , which can readily be converted to -CH ₂ CN under N-bromosuccinimide and benzoyl peroxide under bright light followed by the resulting bromine intermediate reaction with sodium cyanide in dimethylsulfoxide.

The following examples illustrate the preparation of the compounds of the present invention.

Ability of test compounds to bind to similar 1 5-HT! receptor was measured on membranes derived from mumps (pig caudate) using the method described in J. Neurosci., 1987, 7, 894. Binding was determined using 2 nM 5-hydroxytryptamine creatinine sulfate and 5- [1,2-3H ( N)] as a radioligand. Cianopindololis (100 nM) and mezulerginas (lOOnM) was used for assessment of corresponding 5-HT _1A and 5-HT _lc The port blocking. The concentration of the compounds of the Examples required to transfer 50% specific binding (IC ₅₀ ) is less than 1 μΜ in each case.

The activity of the test compounds as a 5-HT 1R agonist-like receptor was measured by their ability to induce shrinkage of the New Zealand white trtuLT 3594 B in these subjects using the method described in Arch. Pharm., 1990, 342, 111. Agonistic properties were calculated as -log ₁₀ EC ₅₀ (pEC _S0 ) values, plotted against 5-HT (1 m) as a function of agonist concentration. The sample compounds were found to have a pEC _{50 of} at least 5.0 in each case.

EXAMPLE

2- [5- (2-Benzyltetrazol-5-ylmethyl) -1H-indol-3-yl] -ethylamine. The oxaate

1. 4-Hydrazinobenzyl cyanide. Hydrochloride

A solution of NaNO ₂ (80 g, 1, 16 mol) was added dropwise to a cooled (-10 ° C) stirred mixture of 4-aminobenzyl cyanide (153.5 g,

1.16 mol) in concentrated hydrochloric acid (1500 ml) at a rate such that the temperature does not rise above -10 ° C. The mixture was stirred at -10 ° C for 0.25 h, then filtered rapidly under vacuum into a separatory funnel. The solution was added in portions every 0.25 h to a rapidly stirred mixture of SnCl ₂ .2H ₂ O (1.05 kg, 4.64 mol) in concentrated HCL (800 mL) while maintaining the temperature below -5 ° C. The mixture was allowed to cool to room temperature and stirred for 0.25 h, then the brownish precipitate was filtered off with suction and rinsed with ether (5 x 500 mL). The resulting solid was dried over P ₂ O _{5 in a} vacuum oven (80 ° C) for 16 h to give the title compound (213 g, 100%), mp 181-183 ° C; ³ H NMR δ (360ΜΗζ, D ₂ O) δ 3.90 (2H, s, CH ₂ ); 7.06 (2H, d, J = 8.7Hz, Ar-H); 7.40 (2H, d,

J = 8.7Hz, Ar-H).

2- (5-Cyanomethyl-1H-indol-3-yl) ethylamine.

Hydrochloride

4-Chlorobutanal dimethylacetal (37.07 g, 0.24 mol) was added to a stirred solution of 4-hydrazinobenzyl cyanide hydrochloride (47.0 g, 0.26 mol) in EtOH / H ₂ O (5: 1; 21) and refluxed for 4 hours. , 5h. The reaction mixture was evaporated to dryness in vacuo, taken up in MeOH (150 mL) and left at 0 ° C for 10 h. The resulting yellowish precipitate was filtered off with suction, washed with Et ₂ O / MeOH (5: 1; 2 x 100 mL) and dried. The product was used without further purification (24, lg, 40%), en 239241 ° C; R _f 0.4 CH ₂ Cl ₂ / EtOH / NH ₃ (40: 8: 1); ¹ H NMR (360MHz, D ₂ O) 3.18 (2H, t, J = 7.1Hz, CH ₂ ); 3.36 (2H, t, J = 7.1Hz,

CH ₂ ); 4.02 (2H, s, CH ₂ ); 7.22 (1H, dd, J = 1.5 and 8.4Hz,

Ar-H); 7.36 (1H, s., Ar-H); 7.56 (1H, d, J = 8.4Hz, ArH); 7.66 (1H, s, Ar-H).

3. 2- (5-Tetrazol-5-ylmethyl-1H-indol-3-yl) -ethylamine

Solution of 2- (5-cyanomethyl-1H-indol-3-yl) ethylamine hydrochloride (2.5 g, 10.6 mmol), triethylamine hydrochloride (2.2 g, 16.0 mmol) and sodium azide (2.1 g, 32.3 mmol) of l-methylpyrrolidin-2-one (30 mL) was heated at 140 ° C for 8 h. 5N hydrochloric acid (3 ml) was added and the solvents were removed by distillation in vacuo. The residue was chromatographed on silica gel eluting with EtOH / Et ₂ O / H ₂ O / NH ₃ (20: 30: 8: 1) to give the title tetrazole (1.76 g, 69%); δ (360ΜΗζ, CD ₃ OD) 3.06 (2H, t, J = 7.2Hz, CH _2); 3.19 (2H, t, J = 7.2Hz, CH ₂ ); 4.29 (2H, s, CH ₂ ); 7.07 (1H, d, J = 8.4Hz, Ar-H); 7.13 (1H, s, Ar-H); 7.29 (1H, d, J = 8.4Hz, Ar-H); 7.44 (1H, s, Ar-H).

. N-tert-Butyloxycarbonyl-2- (5-tetrazol-5-ylmethyl-1H-indol-3-yl) -ethylamine to stirred 2- (5-tetrazol-5-ylmethyl-1H-indol-3-yl) -ethylamine (1,76) g (7.27 mol) in dry CH ₂ Cl ₂ (40 mL) was added triethylamine (1.5 g, 14.9 mmol) and (BOC) ₂ O (1.9 g, 7.3 mmol) and the mixture stirred for 16h,

The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with EtOH / Et ₂ O / H ₂ 0 / NH ₃ (20: 60: 8: 1) to give the title product (l, 6g, 64%); δ (360ΜΗζ, CD ₃ OD) 1.41 (9H, s, 3 of CH _3); 82.87 (2h, t, J = 7.4Hz, CH ₂ ); 3.3 (2H, t, J = 7.4Hz, CH ₂ ); 4.32 (2H, s, CH ₂ ); 6.99 (1H, d, J = 8.3 Hz, Ar-H); 7.04 (1H, s, Ar-H); 7.26 (1H, d, J = 8.3 Hz, Ar-H); 7.49 (1H, s, Ar-H).

5. N-tert-Butyloxycarbonyl-2- [5- (2-benzyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine and N-tert-butyloxycarbonyl-2- [5- (1-benzyltetrazol-5-ylmethyl) ) -1H-Indol-3yl] -ethylamine.

Benzyl bromide (0.31 g, 1.8 mmol) was added to a solution of tetrazole from Step 4 (0.62 g, 1.8 mmol) and triethylamine (0.37 g, 3.6 mmol) in dry acetonitrile (20 mL). The mixture was stirred at room temperature for 2h, heated at 70 ° C for 1h and stirred at room temperature for 16h. The solvent was removed in vacuo and the residue chromatographed on silica gel, eluting with CH ₂ Cl ₂ / MeOH (97: 3), to give 2-separate benzyltetrazoles. The less polar isomer was identified as 2-benzyltetrazole (0.17 g, 22.4%); δ (360ΜΗζ, CDC1 ₃₎ 1.43 (9H, s, 3 of CH _3); 2.90 (2H, t, J = 6.8Hz, CH ₂ ); 3.41 (2H, pi t, CH ₂ ); 4.32 (2H, s, CH ₂ ); 5.70 (2H, s, CH ₂ Ph); 7.00 (1H, s, Ar-H); 7.15 (1H, d, J = 8.4Hz, Ar-H); 7.28 (1H, d. J-8.4Hz, Ar-H); 7.34 (5H, s, Ar-H); 7.50 (1H, s,

Ar-H); 7.96 (1H, pi s, NH).

The more polar component was identified as 1-benzyltetrazole (0.2 g, 26.4% δ (360ΜΗζ, CDCl ₃ ) 1.43

(9H, s, 3 from CH ₃ ); 2.88 (2K, t, J = 7, OHz, CH _2); 3.40 (1H, P ¹ -1, CH,); 4.26 (2H, s, CH ₂ ); 5.29 (2H, s, CH ₂ -Ph); 6, 92 (1H, d, J = 8.4Hz, Ar-H); 7.01-7.05 (3H, m, Ar-H); 7.27 · - 7, 30 (5H, m, Ar-ΗΪ; 8.08 (1H, pi-s, NH).

2- [5- (2-Benzyltetrazol-5-ylmethyl) -1H-indol-3-yl] -ethylamine. Oxalate

Trifluoroacetic acid (1.5 mL) was added to a less polar component isolated in step 5 (0.17 g, 0.4 mmol) in CH ₂ Cl ₂ (5 mL) and stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was chromatographed on silica gel eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (40: 8: 1) to give the title tetrazole. Oxalate (65 mg) was prepared; mp 169-171 ° C; (Found: C, 59.23; H, 5.07; N, 19.60. C ₁₉ H ₂₀ N _6. 1.05 (C ₂ H ₂ O ₄ ) is C, 59.36; H, 5, 22; N, 19.68%); δ (360ΜΗζ, D ₂ O) 3.09 (2H, t, J = 6.9Hz, CH ₂ ); 3.29 (2H, t, J = 9Hz, CH ₂ ); 4.30 (2H, s, CH ₂ ); 5.77 (2H, s, CH ₂ ); 5.77 (2H, s, CH ₂ ); 7.11 (1x4, dd, J = 1.6, and 8.4Hz, Ar-H); 7.28 (1H, s, Ar-H); 7.32-7.34 and 7.39-7.41 (5H, m, Ar-H);

7.43 (1H, d, J = 8.4Hz, Ar-H); 7.51 (1H, s, Ar-H).

EXAMPLE

2- [5- (1-Benzyltetrazol-5-yl-ethyl) -1H-indol-3-yl] -ethylamine. Hydrochloride. Hemihydrate

Made from the more polar component isolated in Example 1, Step 5 using the method described in Example 1, Step 6. The hydrochloride hemihydrate salt was prepared; mp 210-213 ° C; (Found: C, 60.39; H, 5.88; N, 22, 14. C ₁₉ H ₂₀ N _6. HCl. 0.5H, O is C, 60.39; H, 5.87; N, 22.24%); δ (250ΜΗζ, D ₂ O) 3.02 (2H, t, J = 6.8Hz,

CH ₂ ); 3.19 (2H, t, J = 6.8Hz CH ₂ ); 4.44 (2H, s, CH ₂ ); 5.60 (2H, s, CH ₂ ); 6.95-7.02 (3H, m, Ar-H); 7.16-7.25 (4H, m, Ar-H); 7.28 (1H, s, Ar-H); 7.40 (1H, d, J = 8.4Hz, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (2-methyl-tetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

N-tert-Butyloxycarbonyl-2- [5- (2-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine and N-tert-butyloxycarbonyl-2- [5- (1-methyltetrazol-5) -ylmethyl) -1H-indol-3yl] -ethylamine

Methyl iodide (0.44 g, 3.1 mmol) was added to the stirred tetrazole solution (0.95 g, 2.78 mmol) described in Example 1, Step 4, and triethylamine (0.56 g, 5.5, mmol). in dry acetonitrile (15 mL). After 10 h, another equivalent amount of methyl iodide was added and stirred for 16 h. The solvent was removed in vacuo and the residue chromatographed on silica gel eluting with CH ₂ Cl ₂ / MeOH (97: 3) to give the title mixture of 1- and 2-methyltetrazoles (0.6 g, 61%); δ (360ΜΗζ, CDCl ₃ ) 1.43 (9H, m, 3 of CH ₃ ), * 2.89-2.92 (2H, m, CH ₂ ); 3.38-3.48 (2H, m, CH ₂ ); 3.83 (2H, s, CH ₂ ); 4.28 and 4.40 (total 3H, s, CH ₃ ); 6.98 and 7.17 (total 1H, d, J = 8.4Hz, Ar-H); 7.02 and 7.06 (total 1H, s, Ar-H); 7.30 and 7.31 (total 1H, d, J = 8.4Hz, Ar-H); 7.43 and 7.54 (total 1H, s, Ar-H); 8.00 and 8.10 (total 1H, pi, s, NH).

2. 2- [5- (2-Methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine and 2- [5- (1-Methyltetrazol-5-ylmethyl) -1H-indol-311] -ethylamine

Derived from the above methyl tetrazoles using the method described in Example 1, Step 6. The crude product was chromatographed on silica gel, eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (40: 8: 1); 2 separate components were obtained. The less polar product (0.1 g, 24%) was identified as 2-methyltetrazole; δ (360ΜΗζ, CDC1 ₃₎ 1.38 (9H, s, 3 of CH _3); 2.88 (2H, t, J = 6.6Hz, CH ₂ ); 3.00 (2H, t,

J = 6.6Hz, CH ₂ ); 4.28 (3H, s, CH ₃ ); 4.33 (2H, s, CH ₂ );

7.00 (1H, d, J = 8.4Hz, Ar-H); 7.06 (1H, d, J = 2, ± Hz, Ar-H);

7.17 (1H, d, J = 8.4Hz, Ar-H); 7.56 (1H, s, Ar-H); 8.04 (1H, pi, s, NH).

The more polar product (0.13 g, 31%) was identified as 1-methyltetrazole; δ (360ΜΗζ, CDC1 ₃₎ 1.38 (9H, s, 3 of CH _3); 2.86 (2H, t, J = 6.6Hz, CH ₂ ); 3.00 (2H, t, J = 6.6Hz, CH ₂ ); 3.82 (3H, s, CH ₃ ); 4.40 (2H, s, CH ₂ );

6.98 (1H, dd, J = 1.6 and 8.3 Hz, Ar-H); 7.06 (1H, d,

J = 1.6Hz, Ar-H); 7.31 (1H, d, J = 8.3 Hz, Ar-H); 7.41 (1H, s, Ar-H); 8.18 (1H, pi, s, NH).

N, N-Dimethyl-2- [5- (2-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

A solution of formaldehyde (80 mg in 30% solution) in methanol was added to a stirred solution of 2- [5- (2-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine (0.1 g, 0.4 mmol). , NaCNBH ₃ (60 mg) and glacial acetic acid (0.12 g) in methanol (15 mL). The solution was stirred for 2 h, basified with K ₂ CO ₃ solution and removed in vacuo with MeOH. The crude product was obtained after extraction with ethyl acetate and the solvent removed by chromatography on silica gel eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (40: 8: 1) to give the desired N, N-dimethyltryptamine (96 mg, 87%). The oxalate was obtained: 1.t.185-187 ° C (MeOH / Et ₂ O); (Found: C, 54.42; H, 5.74; N, 22.53. C ₁₅ H ₂₀ N _6. C ₂ H ₂ O ₄ is C, 54.54; H, 5.92; N, 22 , 45%); δ (360ΜΗζ, D ₂ O) 2.91 (6H, s, 2 of CH ₃ ); 3.21 (2H, t, J = 7.4Hz, CH ₂ ); 3.47 (2H, t, J = 7.4Hz, CH ₂ ); 4.30 (3H, s, CH ₃ ); 4.34 (2H, s, CH ₂ ); 7.17 (1H, dd, J = 1.5 and S, 4Hz, Ar-H); 7.33 (1H, s, Ar-H); 7.48 (1H, dd,

J = 8.4Hz, Ar-H); 7.59 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (1-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

Obtained from 2- [5- (1-methyltetrazol-5-ylmethyl) -1H-indol-3'-yl] ethylamine (0.125 g, 0.49 mmol) using the procedure described in Example 3, Step 3. Free base obtained (0.11 g,

80%) was transferred to oxalate and recrystallized from MeOH / Et ₂ O; mp 176-177 ° C; (Found: C, 54.21 '; H, 5.84; N, 22.36. C ₅ H ₂₀ N _6. C ₂ H ₂ O ₄ is C, 54.54; H, 5.92; N , 22, 45%); δ (360ΜΗζ, D ₂ O); 2.91 (6H, s, 2 of CH ₃ ); 3.21 (2H, t,

J = 7.4Hz, CH ₂ ); 3.40 (2H, t, J = 7.4Hz, CH ₂ ); 4.00 (3H, s, CH ₃ ); 4.43 (2H, s, CH ₂ ); 7.13 (1H, dd, J = 1.5 and 8.4Hz,

Ar-H); 7.35 (1H, s, Ar-H); 7.50 (1H, d, J = 8.4 Hz, Ar-H); 7.54 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate Hydrate

1- (4-Nitrophenyl) methyl-1,2,4-triazole

4-Nitrobenzyl bromide '(21.6 g, 0.1 mol) was added to the rapidly stirred sodium salt of 1,2,4-triazole (9.1 g,

O, 1 mol) in anhydrous DMF (100 mL) and the mixture was stirred. at room temperature for 16h. Ethyl acetate (.400 mL) was added followed by water (250 mL) and the layers were then separated. The organic phase was washed with water (3 x 250 mL), dried (MgSO ₄ ) and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate to give the title product (10.6 g, 52%); mp 98-100 ° C. δ (360ΜΗζ, CDC1 ₃₎ 5.47 (2H, s, CH _2), 7.40 (2H, d, J = 9 Hz, Ar-H); 8.02 (1H, s, Ar-H), 8.13 (1H, s, Ar-H), 8.23 (2H, d, J = 9Hz,

Ar-H).

2. 1- (4-Aminophenyl) methyl-1,2,4-triazole. Hydrochloride '

A solution of 1- (4-nitrophenyl) methyl] -1,2,4-triazole (10.0 g, 49 mmol ') in ethanol (50 mL), ethyl acetate (50 mL), 5N HCl (10 mL) and water (10ml) was hydrogenated on 10% Pd / c (1.0g) _f . 40 psi on a Parr machine until 138 psi - (approx. 10 minutes). The catalyst was removed by filtration through hyflo and the solvent evaporated in vacuo. The residue was aceotroped with ethanol (x2) to give the title amine hydrochloride (10.6 g, 100%). δ (360ΜΗζ, D ₂ O), 5.53 (2H, s, CH ₂ ), 7.377.48 (4H, m, Ar-H), 8.12 (1H, s, Ar-H), 8.66 (1H, s,

Ar-H).

1- (4-Hydrazinophenyl) methyl-1,2,4-triazole

A solution of sodium nitrite (3.28 g, 48 mmol) in water (20 mL) was added to a solution of the above amine hydrochloride (10.0 g, 48 mmol) in concentrated HCl (40 mL) at a rate not exceeding -10 °. C. After the addition was complete, the solution was stirred at 0 ° C for 0.25 h and then added portionwise to a rapidly stirred solution of SnC ₂ 2.2H ₂ O (40 g) in concentrated HCl (40 mL). The solution was warmed to room temperature and basified with 20% aqueous NaOH. The solution was extracted with ethyl acetate (3 x 250 mL) and the combined extracts dried (MgSO ₄ ) and filtered through hyflo. The solution was evaporated to dryness to give the required hydrazine (5.0 g, 56%)

M.p. 109-112 ° C. δ (360ΜΗζ, D ₆ -DMSO) 3.93 (2H, br, s, NH ₂ ),

5.20 (2H, s, CH ₂ ), 6.73 (2H, d, J = 8Hz, Ar-H), 7.08 (2H, d, J = 8Hz, Ar-H), 7.72 ( 1H, s, Ar-H), 8.57 (1H, s, Ar-H).

4. 2- [5- (1,2,4-Triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine

4-Chlorobutanal dimethylacetal (3.22 g, 21.1 mmol) was added to a stirred mixture of the above hydrazine (5.0 g,

26.4 mmol) in ethanol / water (5: 1, 180 mL) and 5N HCl (4.5 mL) and the solution was refluxed for 4 h. The solvents were removed in vacuo and the residue chromatographed on silica gel eluting with the required tryptamine.

CK ₂ Cl ₂ / EtOH / NH ₃ (2.4 g, 38%). CHO, 2.99 (2I-1, (30: 8: 1), β (360MHz, t, J - 7Hz,

CDCl ₃ ), 2.90 (2H, t, J = 7H:

+ U. t

CH _2), 5.43 (2H, s, _CH? J '10 (1H, s, Ar-H), 7.11 (1H, d, J = 8Hz, Ar-H), 7.39 ( 1H, d,

J = 8Hz, Ar-H), 7.57 (1H, s, Ar-H), 7.94 (1H, s, Ar-H),

8.08 (1H, s, Ar-H).

N, N-Dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate hemihydrate

A solution of formaldehyde (37% v / v, 0.19 g) in methanol (10 mL) was added to a mixture of the above tryptamine (0.36 g, 1.5 mmol), NaCNBH ₃ (0.225 g,

3.6 mmol) and glacial acetic acid (0.45 g) in methanol (10 mL). After stirring at room temperature for 2 h, saturated K ₂ CO ₃ (50 mL) was added and methanol was evaporated. The residue was extracted with ethyl acetate (3 x 100ml) and the combined extracts were washed with ink (100ml), dried (K ₂ CO ₃ ) and evaporated. The crude product was chromatographed on silica gel eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (20: 8: 1) to give the free base of the title compound (0.21 g, 52%). Obtained oxalate hemihydrate salt, m.p. 165-167 ° C (MeOH / Et ₂ O); (Found: C, 55.53; H, 6.04; N, 18.59. C ₁₅ H ₁₉ N _5. C ₂ H ₂ O ₄ .0.55H ₂ O is C, 55.29; H, 6 , 03; N, 18.96%); m / e 269 (M ⁺ ); δ (360ΜΗζ,

D ₂ O) 2.91 (6H, s, NMe ₂ ), 3.22 (2H, t, J = 7Hz, CH ₂ ), 3.47 (2H, t, J = 7Hz, CH ₂ ), δ, 52 (2H, s, CH ₂ ), 7.21 (1H, dd,

J = 1.6 and 8.4Hz, Ar-H), 7.36 (1H, s, Ar-H), 7.52 (1H, d, J = 8.4Hz, Ar-H), 7.65 (1H, s, Ar-H), 8.06 (1H, s, Ar-H), 8.56 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (1,2,3,4-tetrazol-2-ylmethyl) -1H-indol3-yl] ethylamine. Oxalate.

1- (4-Nitrophenyl) methyl-1,2,3,4-tetrazole and 2- (4-nitrophenyl) methyl-1,2,3,4-tetrazole.

4-Nitrobenzyl bromide (15.42 g, 71.3 mmol) was added to a stirred solution of 1H-tetrazole (5.0 g, 71.3 mmol) and triethylamine (7.9 g, 78.0 mmol) in acetonitrile (100 mL). The mixture was stirred at room temperature for 16 h, the solvent removed in vacuo and the residue chromatographed on silica gel eluting with dichloromethane to give

2-isomers. The 2nd alkylated product was a less polar product (2.47 g, 17%); 0 (360MHz, CDCl ₃ ) 5.92 (2H, s, CH ₂ ), 7.53 (2H, d, J = 8.7Hz, Ar-H), 8.25 (2H, d, J = 8, 7Hz, Ar-H), 8.56 (1H, s, Ar-H). The more polar predominant isomer was identified as the 1st alkylated product (II, 75g, 75%); (360MHz, CDCl ₃ ) 5.73 (2H, s, CH ₂ ), 7.46 (2H, d, J = 8.7Hz, Ar-H), 8.64 (1 H, s, Ar-H).

2- (4-Aminophenyl) methyl-1,2,3,4-tetrazole. Hydrochloride

2- (4-Nitrophenyl) methyl-1,2,3,4-tetrazole (2.47 g, 12.1 mmol) was hydrogenated as described in Example 5, Step 2. The product (2.55 g, 100%) was obtained as the hydrochloride; δ (250ΜΗζ, D ₂ O) 5.86 (2H, s, CH ₂ ), 7.40 (2H, d, J = 8.7Hz, Ar-H), 7.36 (2H, d, J = 8 , 7Hz, Ar-H),

8.74 (1H, s, Ar-H).

N, N-Dimethyl-2- [5- (1,2,3,4-tetrazol-2-ylmethyl) -1K-indol-3-yl] methylamine. Oxalate.

Said amine was converted to the title compound using conventional techniques described in Example 5, Steps 3-5. Oxalate was obtained and recrystallized from MeOH / Et ₂ O; mp 198-199 ° C; (Found: C, 53.38; H, 5.55; N, 22, 63. C ₄ H ₁₈ N _6. CH ₂ O _4. 0.2 (EtOH) is C, 53.30; H, 5). 78; N, 22.74%); δ (360ΜΗζ, D ₂ O) 2.91 (6H, s, NMe ₂ ), 3.23 (2H, t, J = 7.4Hz, CH ₂ ), 3.48 (2H, t, J = 7, lHz, CH _2), 6.01 (2H, s, CHO, ^7, 30 (1H, dd, J = l and 6 8,1Hz,

Ar-H), 7.37 (1H, s, Ar-H), 7.53 (1H, d, J = 8.4Hz, Ar-H),

7.76 (1H, s, Ar-H), 8.74 (1H, s, Ar-H).

EXAMPLE

N, N, -Dimethyl-2- [5- (1,2,3,4-tetrazol-1-ylmethyl) -1H-indol-3-yl] methylamine. Succinate

1- (4-Nitrophenyl) methyl-1,2,3,4-tetrazole was converted to the title compound using the methods described in Example 5. 5556 ° C (isopropyl alcohol) was obtained; (Found C: 57.08; H, 6.14; N, 23.34. C ₁₄ H ₁₈ N _6. 0.75 (C ₄ H ₆ O ₄ ) is C, 56.89; H, 6.32 ;

N, 23.42%); δ (360ΜΗζ, D ₂ O) 2, 93 (6H, s, NMe ₂ ), 3.23 (2H, t, J = 7.5Hz, CH ₂ ), 3.48 (2H, t, J = 7, 5Hz, CH ₂ ), 5.81 (2H, s, CH ₂ ), 7.28 (1H, dd, J = 1.7 and 8.4Hz, Ar-H) 7.39 (1H, s, Ar- H), 7.56 (1H, d, J = 8.4Hz, Ar-H), 7.75 (1H, s, Ar-H),

9.20 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (1-methyl-1,2,3,4-triazol-5-ylmethyl) -1H-indol-3-yl] ethylamine. Bisoxalate

1. Ethyl 3- [2- (dimethylamino) ethyl] -1H-indole-5-methylcarboximidate. Hydrochloride

A solution of N, N-dimethyl-2- (5-cyanomethyl-1H-indol-3-yl) ethylamine (5 g, 22.01 mmol) in ethanol was saturated with HCl gas and the solution was stirred at room temperature for 16 h. The solvent was removed in vacuo to give the title product (6 g, 92%); δ (360ΜΗζ, D ₆ -DMSO) 1.29 (3H, t, J = 7.0Hz, CH,); 2.83 (6H, s, NMe ₂ ), 3.13 (2H, t, J = 7.5Hz, CH ₂ ), 3.31 (2H, m, CH ₂ ), 4.04 (2H, s) , CH ₂ ), 4.42 (2H, kv, J = 7.0Hz, CH ₂ ), 7.08 (1H, dd, J = 1.5 and 3.4Hz, Ar-H), 7.27 ( 1H, s, Ar-H), 7.37 (1H, d, J = 8.4Hz, Ar-H), 7.48 (1H, pi, s, NH), 7.71 (1H, s, Ar) -H).

N, N-Dimethyl-2- [5- (1-methyl-1,2,3,4-triazol-5-ylmethyl) -1H-indbl-3-yl] ethylamine. Dioxalate

A mixture of the said imidate ester (3 g, 10.15 mmol), methylhydrazine (0.8 mL) and triethylamine (3.54 mL) in ethanol (30 mL) was stirred at room temperature for 3 h.

The solvent was removed in vacuo and the product was dissolved in formic acid (98%, 3.3 mL) and the solution was stirred at room temperature under reflux for 2 h. The solution was cooled to room temperature, poured into aqueous K ₂ CO ₃ (75 mL) and extracted with ethyl acetate (4 x 200 mL). The combined extracts were dried (MgSO ₄ ) and evaporated, the residue chromatographed on silica gel eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (40: 8: 1) to give 2 components. The less polar isomer was identified as the title 1-methyl-1,2,3,4-triazole (360 mg). Dioxalate was obtained; mp 135-134 ° C; (Found: C, 50.91; H, 5.38; N, 13.86. C _ie H ₂₁ N _5. 0.25 (ethanol) is

C, 50.70; H, 5.47; N, 14.08%); δ (360ΜΗζ, D ₂ O) 2.91 (6H, s, NMe ₂ ); 3.23 (2H, t, J = 7.3Hz, CH 2), 3.48 (2H, t, J = 7.3Hz, CH ₂ ), 3.95 (3H, s, Me), 4.48 (2H, s, CH ₂ ), 7.13 (1H, dd, J = 1.5 and 8.4Hz, Ar-H), 7.37 (1H, s, Ar-H), 7.53 (1H , d, J = 8.4Hz, Ar-H), 7.57 (1H, s, Ar-H), 8.32 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (1-methyl-1,2,3,4-triazol-3-ylmethyl) -1H-indol-3-yl] ethylamine. Trihydrochloride

D A

The more polar isomer from Example 8, Step 2 was identified as the title zriazole (180 g). Trihydrochloride, m.p. <-2C (hygroscopic) - was obtained; Ra: C, 49, 80; H, 6.56; N, 16.69.

C- ₆ H ₂₁ N ₅ .3HCl. 0.35 (Et, O) is C, 49.91; H, 5.62; M,

16.73%); δ (360ΜΗζ, D, O) 2.91 (6H, s, XMe,); 3.23 (2H, t,

J = 7.4Hz, CH _2), 3.49 (2H, t, J = 7.4Hz, CH,), 3.95 (3H, s,

Me), 4.27 (2H, s, CH ₂ ), 7.17 (1H, dd, J = 1.5 and 8.5Hz,

Ar-H), 7.34 (1H, s, Ar-H), 7.50 (1.H, d, J-8.5Hz, Ar-H),

7.60 (1H, s, Ar-H), 8.88 (1H, s, Ar-H).

EXAMPLE 10

N, N-Dimethyl-2- [5- (1,2,3-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

1- (4-Nitrophenyl) methyl-1,2,3-triazole

4-Nitrobenzyl bromide (25.4 g, 0.12 mol) was added to a solution of 1H-1,2,3-triazole (8.12 g, 0.12 mol) and triethylamine (11.88 g, 0.12 mol). anhydrous acetonitrile.

The mixture was refluxed for 1 h, cooled to room temperature, and precipitated with NEt ₃ . The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with CH ₂ Cl ₂ (100) and CH ₂ Cl ₂ / MeOH (95.5) to give 2 products.

The more polar product was identified as the title 1-isomer (13g, 54%); lt114116 ° C δ (250ΜΗζ, CDC1 ₃₎ 5.72 (2H, s, CH _2), 7.38 (2H, d,

J = 9Hz, Ar-H), 7.64 (1H, s, Ar-H), 7.78 (1H, s, Ar-H),

8.12 (2H, d, J = 9Hz, Ar-H). The less polar product, the minor isomer, was identified as 2 alkylated product (2.25 g, <9%), m.p. 112-113 ° C. (250MHz,

CDCl ₃ ), 5.72 (2H, s, CH ₂ ), 7.40 (2H, d, J = 9Hz, Ar-H),

7.66 (2H, s, Ar-H), 8.18 (2H, d, J = 9Hz, Ar-H).

0

N, N-Dimethyl-2- [5- (1,2,3-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

1- (4-Nitrophenyl) methyl-1 _z 2, 3-triazole was converted to the unmodified mole using known techniques as described in Example 5. Oxalate was obtained, en 210]

1.1 (C ₂ H ₂ O ₄ ) 0.15H ₂ O; is C, 55.67; H, 5.84, N, 18.87%) δ (360ΜΗζ, D ₂ 0). -2.90 (6H, .s, NMe ₂ ) ·, 3.22 (2H, t,

J = 7.4Hz, CH ₂ ), 3.46 (2H, t, J = 7.4Hz, CH ₂ ), 5.7.2 (2H, dd, J = 1.6 and 8.4Hz, Ar-H) , 7.24 (1H, dd, J = 1.6, 8.4Hz,

Ar-H), 7.36 (1H, s, Ar-H), 7.52 (1H, d, J = 8.4Hz, Ar-H),

7.66 (1H, s, Ar-H), 7.79 (1H, s, Ar-H), 8.00 (1H, d,

J = 1Hz, Ar-H).

EXAMPLE

3- (2-Aminoethyl) -5- (2-methyl-tetrazol-5-yl) benzo [b) -thiophene. Oxalate.

stage 15

4- Bromophenylmercaptopropanone

To a stirred solution of 4-bromothiophenol (5.09g, 26.9 mmol)

NaOH (1.08 g, 26.9 mmol) and water (32 mL) were added chloroacetone and then the mixture was stirred under nitrogen for 45 min then extracted with ether, washed with water, dried (Na ₂ SO ₄ ) and evaporated in vacuo to leave 6.89 g (100%) of the title compound as a white solid. Δ (CDCl ₃ ) 2.27 (3H, s), 3.65 (2H, s), 7.20 (2H, d, J = 8.5Hz), 7.41 (2H, d,

J = 8.5Hz).

stage

5-Bromo-3-methylbenzo [b] thiophene

Refluxed polyphosphoric acid (4, -47 g) and chiorbenzene (100 mL) were added portionwise to bromophenylmercaptopropanone (2.24 g, 9.14 mmol ·) over 1 h and then the mixture was refluxed for 3 days. . After cooling, the organic phase was decanted and the residue was partitioned between H ₂ O (ii 10 mi), extracted with CH ₂ Cl ₂ ( ₂ x 75 mL, dried (MgSO ₄ ), and combined with the decanted organic phase. oil. Kugelrohr distillation apparatus obtained 1.83 g (88%) of pale yellow liquid title compound, vt100110 ° C / O, 35 mbar. 5 (CDC1 ₃₎ 2.41 (3H, s), 7.10 (1 H , dd,

J = 8.5 and 1.9Hz), 7.69 (1H, d, J = 8.5Hz), 7.64 (1H, d,

J = 1.9Hz).

stage

5-Cyano-3-methylbenzo [b] thiophene

6.35 mmol) was added (1.179 g, 5.19 mmol) then the mixture was replaced with copper (I) cyanide (0.569 g,

5-Bromo-3-methylbenzo [b] thiophene in N-methylpyrrolidone (10 mL) and stirred at 180-190 ° C for 17 h. The mixture was fractionated with ether (75 mL) and ammonia solution (75 mL). The ether layer was separated, washed with more ammonia solution (2 x 50 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 0.81 g of a white solid. Purification by flash chromatography on silica eluting with 10% ethyl acetate / petroleum ether afforded 0.76 g (85%) of the title compound as a white solid. 0 (CDCl ₃ ) 2.47 (3H, s), 7.23 (1H, s), 7.55 (1H, dd, J = 8.3 and 1.5Hz), 7.93 (1H, d, J = 8.4Hz), 8.03 (1H, d,

J = 1.4Hz).

stage

3-Methyl-5- (tetrazol-5-yl) -benzo [b] thiophene

To a solution of 5-cyano-3-mecibenzo [b] thiophene (0.194 g, 1.12 mmol) in N-methylpyrrolidone (5 mL) under nitrogen was added triethylamine hydrochloride (0.231 g, 1.68 mmol) followed by sodium azide (0.234). g, 3.59 mmol) and the mixture

I was extracted with ether (4x50 mL). The combined ethereal extracts were dried (MgSO ₄ ) and evaporated in vacuo to give 0.78 g of a solid white solid. The latter was purified by flash chromatography on silica eluting with CH ₂ Cl ₂ / MeOH / NH ₃ (aq) (40: 8: 1 to 30: 8: 1) to give 0.246 g (100%) of a white solid. product in the form of the name. Δ (DMSO) 2.46 (3H, s), 7.41 (1H, s), 7.98 (1H, d, J = 8.4Hz), 8.03 (1H, dd, J = 8.4 and 1). , 5Hz), 8.36 (1H, d, J = 0.9Hz). m / z (CI ', NH ₃ ) 215 (M-H) -, 160.

stage

3-Methyl-5- (2-methyltetrazol-5-yl) benzo [b] thiophene and 3-methyl-5- (1-methyltetrazol-5-yl) benzo [b] thiophene

To 3-methyl-5- (tetrazol-5-yl) benzo [b] thiophene (0.241 g,

To a mixture of 1.12 mmol) in acetonitrile (5 mL) was added triethylamine (0.28 mL, 2.01 mmol), then iodomethane (0.486 mL, 7.81 mmol) followed by DMF (3 mL) until the solution became clear. The solution was stirred overnight under nitrogen, then evaporated in vacuo and the residue partitioned between water (50 mL) and ether (25 mL). The aqueous layer was separated and extracted with more ether (2x25 mL), the combined ethereal extracts dried (MgSO 4) and evaporated in vacuo to give 0.24 g of a yellow solid. Purification by flash chromatography on silica eluting with 25-40% ethyl acetate / petroleum ether yielded 0.168 g (65%) of the title compound as a white solid, 2-isomer and 0.063 g (24%) of a white solid. 1-isomer of the product as named. 2-isomer 5 (CDCl ₃ ) 2.52 (3H, s), 4.42 (3H,

s), 7.14 (1H, s), 7.94 (1H, d, J = 8.4Hz), 8.10 (1H, dd,

J = 8.4 and 1.5Hz), 8.51 (1H, s), m / z (Cl ⁺ , NH ₃ ) 231 (M + H) ⁺

1-isomer (CDCl ₃ ) 2.50 (3H, s), 4.22 (3H, s), 7.23 (1H, s), 7.64 (1H, dd, J = 8.3 and 1, 5Hz), 8.03 (lh, ow,

I ι

J = 8.4Hz), 8.12 (1H, d, J = 1.6Hz). m / z (Cl ⁺ , NH ₃ ), 231 (M + H) ⁺ , 202, 172.

stage

3-Cyanomethyl-5- (2-methyltetrazol-5-yl) benzo [b] thiophene

Reflux a mixture of 3-methyl-5- (2-methyltetrazol-5-yl) benzo [b] thiophene (0.162 g, 0.703 mmol) and benzoyl peroxide (10.6 mg) under carbon tetrachloride (10 mL). two table lamps (2x60 W) were charged with Nbromosuccinimide (0.126 g, 0.707 mmol) in small portions. When all was added, the mixture was refluxed for another 90 min, then filtered and the filtrate evaporated in vacuo to give an oil / solid mixture. Purification by flash chromatography on silica eluting with dichloromethane gave the crude 3-bromomethyl-5- (2-methyltetrazol-5-yl) benzo [b] thiophene as a colorless oil.

The crude 3-bromomethyl-5- (3-methyl-tetrazol-5-yl) benzene b] thiophene (0.145 g) in DMSO (0.3 mL) was added to a mixture of sodium cyanide (29.9 mg, 0.61 mmol). DMSO (0.2 mL) and the mixture was stirred at 100 ° C for 2h. After cooling, the mixture was poured into water (10 mL) and the brown solid was filtered off, washed with water and dried in a vacuum gun to give 73.5 mg. The filtrate was extracted with dichloromethane (3x30 mL) and the combined extracts dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 44.7 mg. This was combined with the starting solid and purified by flash chromatography on silica eluting with 20-50% ethyl acetate / petroleum ether to give 61.5 mg (38%) of the title product as a white solid. 0 (CDCl ₃ ) 3.99 (2H, s), 4.43 (3H, s), 7.59 (1H, s), 8.00 (1H, d, J = 8.5Hz), 8.19 (1H, dd, J = 8.5 and 1.5 Hz), 8.47 (1H, s).

stage 5

3- (2-Aminoethyl) -5- (2-methyl-tetrazol-5-yl) bis [b] -3-thiophene. The oxaate

To a solution of 3-cyanomethyl-5- (2-methyl-tetrazol-5-yl) -benzo [b] thiophene (0.434 g, 1.70 mmol) in THF (16 mL) under nitrogen was added dropwise a 1.0 M borane-tetrahydrofuran complex THF (5.10 mL, 5.10 mmol) and then the mixture was refluxed for 6h. After cooling in an ice bath, the mixture was quenched with 2N HCl (22 mL) and refluxed for 1h. THF was then removed in vacuo and the residue basified with 50% sodium hydroxide solution (4 mL), followed by extraction with dichloromethane (3x75 mL). The combined extracts were dried (K ₂ CO ₃ ) and evaporated in vacuo to give 0.45 g.

Purification by flash chromatography on silica eluting with CH ₂ Cl ₂ / MeOH / NH ₃ (aq) (60: 8: 1) gave 0.383 g (87%) of the title compound as a white solid. The oxate is prepared using oxalic acid in methanol / ether to give the oxide of the title product as a white solid, en 204-209 ° C. Found: C, 47.75; H, 4.28; N, 19.28%. C ₁₂ H ₁₃ N ₅ S. 1,1C ₂ H ₂ O ₄ ; Found: C, 47.59; H, 4.28; N, 19, o4. 0 (DMSO) 3.17-3.21 (4H, m), 4.46 (3H, s), 7.72 (1H, s),

8.06 (1H, dd, J = 8.4 and 1.4Hz), 8.52 (1H, s), m / z (Cl ⁺ ,

NH ₃ ) 260 (M + N) ⁺ , 230.

EXAMPLE .35 3- (2-Aminoethyl) -5- (1-methyltetrazol-5-yl) benzofb] -thiophene. The oxaate

I

Stage I

3-Cyanomethyl-5- (1-methyltetrazol-5-yl) benzo [b] thiophene

According to Example 11, Step 6, 0.666 g (2.89 mmol) of 3-methyl-5- (1-methyltetrazol-5-yl) benzo [b] thiophene was reacted with 0.515 g, (2.89 mmol) of N-bromosuccinimide and , 1 mg benzoyl peroxide in 30 ml carbon tetrachloride. The reaction mixture was evaporated and purified by flash chromatography on silica eluting with 0-3% methanol / dichloromethane to give 0.532 g of crude 3-bromo-5- (1-methyltetrazol-5-yl) benzo [b] thiophene. .

Crude 3-bromo-5- (1-methyltetrazol-5-yl) benzo [b] thiophene (0.504 g) was reacted with 97.7 mg (1.99 mmol) of sodium cyanide in 1.5 mL of DMSO at 100 ° C for 2h. After cooling, the reaction mixture was poured into water (25 mL) and extracted with dichloromethane (6 x 50 mL). The combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 0.37 g. Purification by flash chromatography on silica eluting with 30-60% ethyl acetate / petroleum ether gave 28.0 mg (4%) of the title product. Δ (CDCl ₃ ), 4.00 (2H, s), 4.23 (3H, s), 7.63 (1H, s), 7.73 (1H, dd), 8.08 (1H, d) , 8.15 (1H, d).

stage

3- (2-Aminoethyl) -5- (1-methyltetrazol-5-yl) benzo [b] -thiophene. Oxalate

According to the procedure described in Example 11, Step 7, 26.1 mg (0.102 mmol) of 3-cyanomethyl-5- (1-methyltetrazol-5-yl) benzo [b] -thiophene was treated with 2 ml of THF with 0.36 ml (0.36). mmol) with 1.0 M boranotetrahydrofuran complex in THF. Purification by flash chromatography on silica eluting with CH ₂ Cl ₂ / MeOH / NH ₃ (aq) (60: 8: 1),

17.7 mg (67%) of the product is obtained in the form of a colorless oil. Oxalate is produced using oxalic acid in methanol / ether to give the product as a white solid. mp 206-212 ° C. Found: C, 47.55; H, 4.05; N, 19.65%. C ₁₂ H ₁₃ N ₅ S. 1.1 C ₂ H ₂ O ₄ ; Found: C, 47.59; H, 4.28; N, 19.5%. δ (ϋ ₂ Ο) 3.32-3, 35 (2H, m), 3.40-3.44 (2H, m), 4.22 (3H, s), 7.64 (1H, s), 7.73 (1H, d,

J = 8.4Hz), 8.19 (1H, s), 8.22 (1H, d, 8.5Hz).

EXAMPLE

3- [2-N, N-Dimethylamino) ethyl) -5- (2-methyltetrazol-5-yl) benzo [b] thiophene. Oxalate

To a mixture of - (2-aminoethyl) -5- (2-methyltetrazol-5-yl) benzo [b] thiophene (0.372 g, 1.43 mmol) and sodium cyanoborohydride (0.136 g, 2.15 mmol) in methanol (3 ml) and acetic acid (0.247 ml, 4.30 mmol) cooled in an ice bath were added a 38% (w / v) formaldehyde solution (0.453 ml, 5.74 mmol) in methanol (3 ml) dropwise over 5 min. and the mixture was stirred at room temperature for 3 h. After this time, a saturated solution of potassium carbonate (30 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined extracts were evaporated in vacuo to give 0.53 g. Purification by flash chromatography on silica eluting with 1030% methanol / dichloromethane gave 0.335 g (81%) of the title compound as a colorless oil. Oxalate is prepared using oxalic acid in methanol / ether to give the oxalate of the title product as a white solid, m.p. 214-218 ° C. Found: C, 50.58; H, 4.80; N, 18.28%.

C ₁₄ H ₁₇ N ₅ SC ₂ f f ₂ O ₄ is: C, 50.92; H, 5.07; N, 18.56%.

Δ (DMSO) 2.84 (6H, s), 3.30-3.42 (4H, m), 4.46 (3H, s),

7.69 (1H, s), 8.06 (1H, dd, J = 8.4 and 1.4Hz), 8.20 (1H, d, J = 8.4Hz), 8.56 (1H, s) m / z (Cl ⁺ , NH ₃ ) 288 (M + H) ⁺ .

I

I

EXAMPLE

N, N-Dimethyl-2- [5- (2-methylimidazol-1-ylmethyl) -1H-indol3-yl] ethylamine. Trioxalate

1- (4-Nitrophenyl) methyl-2-methylimidazole

Sodium hydrate (2.45g, 61.0 mmol, 60% dispersion in oil) was added to a solution of 2-methylimidazole (5.0 g, 0.9 mmol) in DMF (100 mL). The mixture was stirred at room temperature for 0.25 h, then was treated with 4-nitrobenzyl bromide (13.2 g, 61.0 mmol) and heated at 110 ° C for 2 h, then stirred at room temperature for 16 h. Water (200 mL) and ethyl acetate (500 mL) were added, the aqueous layer was separated and extracted with ethyl acetate (2x500 mL). The combined extracts were washed with water (3 x 250 mL), dried (MgSO ₄ ) and evaporated. The crude product was chromatographed on silica gel eluting with CH ₂ Cl ₂ / MeOH (4%) to give the title product (1.58 g, 10.5%); δ (360ΜΗζ, CDCl ₃ ) 2.34 (3H, s, Me), 5.16 (2H, s, CH ₂ ); 6.67 (1H, d, J = 1.3Hz, Ar-H); 7.03 (1H, d, J = 1.3Hz, Ar-H), 7.19 (2H, d, J = 9.5Hz, Ar-H); 8.22 (2H, d, J = 9.5Hz, Ar-H).

N, N-Dimethyl-2- [5- (2-methylimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Trioxalate

Derived from the above 4-nitrobenzylimidazole using the conventional route described in Example 5. Mp 160-163 ° C (MeOH / Et ₂ O); Found: C, 50.57; H, 5.25; N, 10.60. C ₁₇ H ₂₂ N ₄ . 2.8 (C ₂ H ₂ O ₄ ) is C, 50.79; H, 5.21; N, 10.48%); m / e 282 (M ⁺ ); δ (360ΜΗζ, D ₂ O) 2.65 (3H, s, Me); 2.92 (6H, s, NMe ₂ ); 3.25 (2H, t, J = 7.3Hz, CH ₂ );

3.50 (2H, t, J = 7.3 Hz, CH ₂ ); 5.42 (2H, s, CH ₂ ); 7.18 (1H, d, J = 8.4Hz, Ar-H); 7.31-7.40 (2H, m, Ar-H); 7.40 (1H, s,

Ar-H); 7.56 (1H, d, J = 8.4Hz, Ar-H); 7.66 (1H, s, Ar-H).

I

EXAMPLE

N, N, -Dimethyl-2- [5-imidazol-1-ylmethyl-1H-indol-3-yl] ethylamine .'- Dioxalate

Derived from imidazole and 4-nitrobenzyl bromide using the method described in Example 5. Dioxalate prepared, 165-166 ° C in MeOH / Et ₂ O); Found: C, 53.30; H, 5.34; N, 12.18. C ₁₆ H ₂₀ N ₄ . 2.05 (C ₂ H ₂ O ₄ ) is C, 53.30; H, 5.36; N,

12.37%); δ (360MHz, - J ₂ O) 2.92 (6H, s, NMe ₂ ); 3.24 (2H, t,

J = 7.7Hz, CH ₂ ); 3.48 (2H, t, J = 7.7Hz, CH ₂ ); 5.50 (2H, s,

CH ₂ ); 7.27 (1H, dd, J = 1.5 and 8.4 Hz, Ar-H); 7.37 (1H, s,

Ar-H); 7.45 (1H, s, Ar-H); 7.49 (1H, s, Ar-H); 7.56 (1H, d, J = 8.4Hz. Ar-H); 7.75 (1H, s, Ar-H); 8.78 (1H, s,

Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] ethylamine. Sesquioxalate

1- (4-Nitrophenyl) -2-methylimidazole

Sodium hydride (4.87 g, 122.0 mmol, 60% dispersion in v / v) was added to 2-methylimidazole (10 g, 122.0 mmol) in DMF (100 mL) and stirred at room temperature for 0.25 h. 1-Fluoro-4-nitrobenzene (17.18 g, 122.0 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. Water (150 mL) and ethyl acetate (250 mL) were added, the aqueous layer was separated and extracted with ethyl acetate (3 x 150 mL). Combined extracts were washed with water (.3x150 mL), dried (Na ₂ SO ₄₎ and evaporated to give the desired product (11.5 g 4 ¹ *); δ (360ΜΗζ, CCC1 ₃₎ 2.24 (3H, s, Me); 7.06 (1H, d, J = 1.5Hz,

Ar-H); 7.10 (1H, d, J = 1.5Hz, Ar-H); 7.50 (2H, 1,

J = 9.5Hz, Ar-H); 3.38 (2H, d, J = 9.5Hz, Ar-H).

I

N, N, -Dimethyl-2- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] ethylamine. Sesquioxalate

Derived from the above 4-nitrophenylimidazole using the method described in Example 5. Made sesquioxalate. mp 185-186 ° C (iPA / MeOH); (Found: C, 56.17; H, 5.99; N, 13.46. C ₁₆ H ₂₀ N _4. 1.55 (C ₂ H ₂ O ₄ ). 0, 10OH is C, 56.19; H, 5.79; N, 13.58%); δ (360MHz, D ₂ 0) 2.55 (3H, s, Me); 2.93 (6H, s, NMe ₂ ); 3.26 (2H, t, J = 7.4Hz, CH ₂ ); 3.51 (2H, t, J = 7.4Hz, CH ₂ ); 7.30 (1H, dd, J = 2.0 and 8.7Hz, Ar-H);

7.48 (1H, d, J = 2.1 Hz, Ar-H); 7.51-7.53 (2 H, m, Ar-H);

7.70 (1H, d, J = 8.7Hz, Ar-H); 7.79 (1H, d, J = 2.0Hz, ArH).

EXAMPLE

N, N-Dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Succinate. Method B

A solution of 1- (4-hydrazinophenyl) methyl-1,2,4-triazole dihydrochloride (2 g, 7.6 mmol, Step 5 in Example 5) and 4-N, N-dimethylaminobutanaldimethylacetal (1.8 g, 11.2 mmol) ) In 4% aqueous sulfuric acid (70 mL) was refluxed for 2h. The reaction mixture was then cooled to room temperature, ethyl acetate (200 mL) was added and the aqueous layer was basified with K ₂ CO ₃ . The aqueous layer was separated and further extracted with ethyl acetate (2 x 150 mL). The combined organic phases were dried (Na ₂ SO ₄ ) and evaporated, and the residue was chromatographed on silica gel eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (30: 8: 1) to give the title triazole (610 mg, 30%). . The succinate was prepared by adding a solution of succinic acid (0.27 g, 2.3 mmol) in methanol (3 mL) to the triazole. (0.61 g, 2.3 mmol) in methanol (5 mL).

I

The solvent was removed in vacuo and the product recrystallized from isopropyl alcohol, mp 118-120 ° C; (Found: C, 58.76; H, 6.27; N, 17.79. C ₁₅ H ₁₉ N _3. C ₄ H ₆ O ₄ is C, 58.90; H, 6.50; N, 18 , 08%).

EXAMPLE

N, N-Dimethyl-2- [5-1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Benzoate

N, N-Dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine benzoate was prepared by combining a solution of benzoic acid in diethyl ether with a free base solution in ethanol / diethyl ether ( 1: 4). The precipitated salt was recrystallized from ethanol, mp 178-180 ° C; (Found: C, 67.28; H, 6.55; N, 17.66. C ₁₅ H ₁₉ N _3. C ₆ H ₅ CO ₂ H is C, 67.50; H, 6.44; N, 17.89%); ³ Η NMR (360MHz, D ₂ O) δ 2.92 (6H, s, NMe ₂ ); 3.22 (2H, t, J = 7.3 Hz, CH ₂ ); 3.46 (2H, t, J = 7.3 Hz, CH ₂ ); 5.52 (2H, s, CH ₂ ); 7.22 (1H, dd, J = 1.6, 8.4 Hz,

Ar-H); 7.36 (1H, s, Ar-H); 7.44-7.58 (4H, m, Ar-H);

7.65 (1H, s, Ar-H); 7.87-7.91 (2 H, m, Ar-H); 8.06 (1H, s, Ar-H); 8.54 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (2-ethyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

Obtained as described in Example 3 using ethyl iodide. M.p. 140-142 ° C; (Found: C, 55.71; H, 6.26; N, 21.35. C ₁₆ H ₂₂ N _6. C ₂ H ₂ O ₄ is C, 55.66; H, 6.23 N, 21.64% ); ^: Η NMR (360MHz, D ₂ O) δ1.54 (3H, t,

J = 7.4Hz, CH ₃ ); 2.91 (6H, s, NMe ₂ ); 3.21 (2H, t, J = 7.4Hz, CH ₂ ); 3.47 (2H, t, J = 7.4Hz, CH ₂ ); 4.34 (2H, s, CH ₂ ); 4.64 (2H, q, J = 7.4Hz, CH ₂ CH ₃ ); 7.17 (1H, dd, J = 1.5 and 8.4Hz, Ar-H); 7.33 (1H, s, Ar-H); 7.48 (1H, d, J = 8.4Hz, Ar-H); 7.59 (1H, s, Ar-H).

n

EXAMPLE

N, N-Dimethyl-2- [5- (1-ethyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

Obtained in the same manner as in Example 4 using ethyl iodide. M.p. 179 ° C (MeOH / Et ₂ O); (Found: C, 55.59; H, 6.23; N, 21.49. C ₁₆ H ₂₂ N _6. C ₂ H ₂ O ₄ is C, 55.66; H, 6.23; N, 21). , 64%); ¹ H NMR (360MHz, D ₂ O) δ 1.32 (3H, t, J = 7.4Hz, CH ₃ ); 2.90 (6H, s, NMe ₂ ); 3.21 (2H, t, J = 7.4Hz, CH ₂ ); 3.46 (2H, t, J = 7.4Hz, CH ₂ ); 4.38 (2H, kv, J = 7.4Hz, CH ₂ ); 4.47 (2H, s, CH ₂ ); 7.14 (1H, dd, J = 1.5 and 8.4Hz,

Ar-H); 7.35 (1H, s, Ar-H); 7.50 (1H, d, J = 8.4Hz, Ar-H); 7.53 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (1,2,4-triazol-1-yl) -1H-indol-3-yl] ethylamine. Dioxalate

Obtained as described in Example 16 from 1,2,4-triazole sodium derivative and 1-fluoro -4-nitrobenzene. Dioxalate produced en 210 ° C (MeOH / Et ₂ O); (Found: C, 50.11; H, 4.78; N, 16.35. C ₁₄ H ₁₇ N _5. 1.9 (C ₂ H ₂ O ₄ )?) C, 50.14; H, 4.92; N, 16.43%); ^Χ Η NMR (360MHz, D ₂ O) δ 2.92 (6H, s, NMe ₂ ); 3.25 (2H, t, J = 7.4Hz, CH ₂ ); 3.50 (2H, t, J = 7.4Hz, CH ₂ ); 7.44 (1H, s, Ar-H); 7.47 (1H, dd, J = 2.0 and 8.7Hz, Ar-H); 7.63 (1H, d, J = 8.7Hz, Ar-H); 7.88 (1H, d,

J = 2.0 Hz, Ar-H); 8.36 (1H, s, Ar-H); 9.05 (1H, s, Ar-H).

EXAMPLE

4- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] -N-methyl-piperidine. Dioxalate sesquihydrate

N-methyl-4- (formylmethyl) piperidine (0.25 g, 1.8 mmol) and 4- (2-methylimidazolyl) phenylhydrazine hydrochloride (0.48 g,

I

A solution of 2.1 mmol) in 4% H ₂ SO ₄ (25 mL) was refluxed for 16h. The mixture was cooled to room temperature, basified with K ₂ CO ₃ solution and extracted with CH ₂ Cl ₂ (3x75 mL). The combined extracts were dried (Na ₂ SO ₄ ) and evaporated, and the residue was purified by silica gel chromatography eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (60: 8: 1) to give the title compound (0.12 g). Dioxalate sesquihydrate prepared at 65-70 ° C (hygroscopic); (Found: C, 52.97; H, 5.51; N, 11.07. C ₁₈ H ₂₂ N _4. 2 (C ₂ H ₂ O ₄ ). 1.5 H ₂ O is C, 52.69; H, 5.83; N, 11.17%); Έ NMR (360MHz, D ₂ O) δΐ, 96-2.08 (2H, m, CH ₂ ); 2.31-2.40 (2 H, m, CH ₂ ); 2.56 (3H, s, CH ₃ ); 2.95 (3H, s, CH ₃ ); 3.20 to 3.27 (3H, m, CH and CH _2); 3,643.68 (2H, m, CH ₂ ); 7.28 (1H, dd, J = 2 and 8.7Hz, Ar-H); 7.44 (1H, s, Ar-H); 7.48 (1H, d, J = 2Hz, Ar-H); 7.53 (1H, d, J = 2Hz, Ar-H); 7.69 (1H, d, J = 8.7 Hz, Ar-H); 7.81 (1H, d, J = 2 Hz, Ar-H).

EXAMPLE

4- [5- (1,2,4-Triazol-1-ylmethyl) -1H-indol-3-yl] -N-methylpiperidine. Oxalate

N-Methyl-4- (formylethyl) piperidine (0.1 g, 0.71 mmol) and 4- (1,2,4-triazolylmethyl) phenylhydrazine dihydrochloride (0.185 g, 0.71 mmol) in 4% H ₂ SO ₄ was refluxed for 2 h. The mixture was cooled to room temperature, basified with K ₂ CO ₃ solution and extracted with CH ₂ Cl ₂ (2x100 mL). The crude product was chromatographed on silica gel with CH ₂ Cl ₂ / EtOH / NH ₃ (40: 8: 1) to give the title compound (60 mg). Mp 218-220 ° C; (Found: C, 58.61; H, 6.03; N, 17.94; C, ₁₇ H ₂₁ N ₅ , 1.02 (C ₂ H ₂ O ₄ ) is C, 58.96; H,

6.38; N, 17.56%); ¹ H NMR (360MHz, D ₂ O) δ 1.88-2.02 (2H, m, CH ₂ ); 2.20-2.34 (2H, m, CH ₂ ); 2.92 <3H, s, CH _3); 3,103.24 (3H, m, CH and CH ₂ ); 3.60-3, 64 (2H, m, CH ₂ ); 5.51 (2H, s, CH ₂ ); 7.21 (1H, dd, J = 1.5 and 8.4Hz, Ar-H); 7.26 (1H, s, Ar-H); 7.51 (1H, d, J = 8.4Hz, Ar-H); 7.69 (1H, s, Ar-H); 8.05 (1H, s, Ar-H); 8.55 (1H, s, Ar-H).

EXAMPLE 1H-4- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] -piperidine. Dioxalate dihydrate

1. 4- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] -N-benzylpiperidine

Obtained from N-benzyl-4- (formylmethyl) piperidine using the method described in Example 22; ^{Χ Η} NMR (360MHz, CDC1 ₃₎ δ 1.80 to 1, 94 (2H, m, CH _2); 1.98-2.06 (2H, m, CH ₂ ); 2.142.24 (2 H, m, CH ₂ ); 2.33 (3H, s, CH ₃ ); 2.76-2.85 (1H, m,

CH); 3.02-3, 08 (2H, m, CH ₂ ); 3.60 (2H, s, CH ₂ ); 7,037.10 (4H, m, Ar-H); 7.26-7.38 (5H, m, Ar-H); 7.41 (1H, d,

J = 8.5Hz, Ar-H); 7.52 (1H, d, J = 1.8 Hz, Ar-H); 8.30 (1H, pi, s, NH).

2. 1H-4- [5- (2-Methylimidazol-1-yl) -indol-3-yl] piperidine. Dioxalate dihydrate (30 mL) fed with ethyl acetate ammonium formate (0.32 g, 5.07 mmol) and 4- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] -N-benzylpiperidine A solution of (0.4 g, 1.08 mmol) in methanol (40 mL) was added with Pd / C (10%; 0.4 g) and the mixture was stirred at 60 ° C for 3 h. The catalyst was separated by filtration through celite and the solvent removed in vacuo. The residue was taken up in H ₂ O with NH ₃ solution and extracted (3 x 100 mL). The combined extracts were dried (Na ₂ SO ₄ ) and evaporated, and the residue was chromatographed on silica gel eluting with CH ₂ / MeOH / NH ₃ (30: 8: 1) to give the desired piperidine (0.2 g). Prepared from dioxalate dihydrate

80 ° C (hygroscopic); (Found: C, 50.53; H, 5.54; N, 10.87. C ₁₇ H ₂₀ N ₄ .2 (C ₂ H ₂ O ₄ ). 2.2 H ₂ O is C, 50.43; H, 5.72; N, 11.20%); NMR (360MHz, D ₂ O) δ 1.91-2.03 (2H, m,

I

CH ₂ ); 2.30-2.34 (2H, m, CH ₂ ); 2.55 (3H, s, CH ₃ ); 3,193.36 (3H, m, CH and CH ₂ ); 3.55-3.62 (2H, m, CH ₂ ); 7.28 (1H, dd, J = 1.2 and 8.6Hz, Ar-H); 7.44 (1H, s, Ar-H); 7.47 (1H, d, J = 2.0Hz, Ar-H); 7.52 (1H, d, J = 2.0Hz, Ar-H);

7.69 (1H, d, J = 8.6Hz, Ar-H); 7.82 (1H, d, J = 1.2Hz, Ar-H).

EXAMPLE 1H-4- [5- (1,2,4-Triazol-1-ylmethyl) -1H-indol-3-yl] -piperidine. Oxalate

Obtained from N-benzyl-4- (formylmethyl) piperidine and 4- (1,2,4-triazolylmethyl) phenylhydrazine dichloride using the methods described in Examples 23 and 24. Mp 272 ° C; (Found: C, 58.27; H, 5.56; N, 18.79. C ₁₆ H ₁₉ N _5. C ₂ H ₂ O ₄ is C, 58.21; H, 5.70; N, 18). , 86%); ¹ H NMR (360MHz, D ₂ O) δ 1.86-1.98 (2H, m, CH ₂ ); 2.24-2.28 (2H, m, CH ₂ ); 3.15-3.36 (3H, m, CH and CH ₂ ); 3.52-3.56 (2H, M, CH ₂ ); 5.51 (2H, s, CH ₂ ); 7.21 (1H, dd, J = 1.6 and 8.5 Hz, Ar-H); 7.27 (1H, s, Ar-H); 7.52 (1H, d, J = 8.5Hz, Ar-H); 7.70 (1H, d, J = 1.6Hz, Ar-H); 8.09 (1H, s, Ar-H); 8.60 (1H, s, Ar-H).

EXAMPLE 1H-3- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] -pyrrolidine. Dioxalate

1. 3- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] -N-benzylpyrrolidine

Obtained from N-benzyl-3- (formylmethyl) pyrrolidine and 4- (2-methylimidazolyl) phenylhydrazine hydrochloride as described in Example 22; 1 H NMR (360MHz, CDCl ₃ ) δ 1.98-2.06 (1H, m, CH from CH ₂ ); 2.34 (3H, s, CH2); 2.34 to 2.44 (2H, m, 2 of CH of CH _2); 2.71 (1H, i, J = 7.4Hz, CH 'from CH ₂ ); 2.80 (1H, t, J = 6.9Hz, CH from CH2); 3.05 (IH, t, J = 8.7Hz, CH of CH _2), 3.61 to 3.73 (1H, m, CH); 3.72 (2H, AB kv, J = 13Hz,

CH ₂ ); 6.95-7.14 (4H, m, Ar-H); 7.22-7.41 (5H, m, Ar-H);

7.40 (1H, d, J = 8.5Hz, Ar-H); 7.66 (1H, s, Ar-H); 8.30 (1H, pi, s, NH).

2. 1H-3- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] -pyrrolidine. Dioxalate

Obtained from said N-benzylpyrrolidine using the method described in Example 24. Mp 210213 ° C (roethanol / ether); (Found: C, 53.93; H, 5.22; N, 12.50. C ₁₆ H ₁₈ N ₄ .2 (C ₂ H ₂ O ₄ ) is C, 53.81; H, 4.97; N, 12.55%); ¹ H NMR (360MHz, D ₂ O) δ 2.91-2.30 (1H, m, CH from CH ₂ ); 2.55 (3H, s, CH ₃ ); 2.55 to 2.60 (1H, m, CH of CH _2);

3, 35-3, 64 (3H, m, CH and CH _2); 3.80-3, 90 (2H, m, CH ₂ );

7.30 (1H, dd, J = 2 and 8.6Hz, Ar-H); 7.47 (1H, d, J = 2Hz,

Ar-H); 7.50 (1H, s, Ar-H); 7.53 (1H, d, J = 2Hz, Ar-H);

7.70 (1H, d, J = 8.6Hz, Ar-H); 7.80 (1H, d, J = 2Hz, Ar-H).

EXAMPLE

N-Methyl-3- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] -pyrrolidine. Dioxalate

To a cooled (0 ° C) stirred mixture of 1H-3- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] pyrrolidine (0.12 g, 0.45 mmol), acetic acid ( A solution of formaldehyde (89 mg, 38% v / v H ₂ O, 1.1 mmol) in methanol (10 mL) was added dropwise to a solution of 0.136 g, 2.3 mmol) and NaCNBN ₃ (71 mg, 1.1 mmol) in methanol (10 mL). ml). The mixture was stirred at 0 ° C for 0.1 h, then warmed to room temperature and stirred

1.5 h. A saturated solution of K ₂ CO ₃ (10ml) was added and the solvent removed in vacuo. The residue was extracted with ethyl acetate (3 x 100ml) and the combined extracts dried (Na ₂ SO ₄ ) and evaporated. The crude product was chromatographed on silica gel eluting with CH ₂ Cl ₂ / MeOH / NH ₃ (60: 8: 1) to give the title product (0.1 g).

M.p. 191-194 ° C (MeOH / Et ₂ O); (Found: C, 54.39; H, 5.30; N, 11.87. C ₁₇ H ₂₀ N ₄ .2 (C ₂ H ₂ O ₄ ). 0, 2H ₂ O is C, 54.36; H, 5.30; N, 12.07%); ⁴ H NMR (360MHz, D ₂ O) δ 2.26-2.45 (1H, m, CH from CH ₂ ); 2.55 (3H, s, Me); 2.625 2.75 (1H, m, CH from CH ₂ ); 3.02 and 3.03 (total 3H, s, Me);

3.23-3, 45 (2H, m, CH ₂ ); 3, 60-3, 68, from 3.77 to 4.1 and 4,124,15 (total 3H, each m, CH and CH _2); 7.30 (1H, d, J = 8.9Hz, Ar-H); 7.48 (1H, d, J = 2.2 Hz, Ar-H); 7.52 (1H, s, Ar-H); 7.53 (1H, d, J = 2.2 Hz, Ar-H); 7.70 (1H, d,

J = -0, 9Hz, Ar-H); 7.78 (1H, s, Ar-H).

EXAMPLE 1H-4- [5-Imidazol-1-yl-1H-indol-3-yl] piperidine. Diok15 Salad

Derived from N-benzyl-4- (formylmethyl) piperidine and 4- (imidazoyl) phenylhydrazine hydrochloride using the method described in Examples 22 and 24. Dioxalate produced

l.t. 155- 157 ° C: (Found: C, 54, 32 H, 5 , 50; N, 11, 66.C ₁₆ H _1E , N ₄ .2 (C ₂ H ₂ O ₄ ) .0.3 (Et ₂ O) is C, 54.33; H, 5.38; N, 11.96%) : ^Σ Η NMR (360MHz, D ₂ O) δ 1.90-2.04 (2H, m, ch ₂ : ); 2.32 (2H, pi, d, J = 13Hz, CH ₂ ); 3.20-3.32 (3H, m, CH and CH ₂ ) ; 3.55-3.60 (2 H, m, CH ₂ ); 7.41-7.44 (2H, m,

Ar-H); 7.64 (1H, s, Ar-H): 7.68 (1H, d, J = 8.7Hz, Ar-H);

7.85 (1H, s, Ar-H); 7.92 (1H, d, J = 2Hz, Ar-H); 9.06 (1H, s, Ar-H).

EXAMPLE 30 1H-4- [5- (1.2.3-Triazol-1-yl) -1H-indol-3-yl] piperidine. Hemioxalate

Obtained from N-benzyl-4- (formylmethyl) piperihine and 4- (1,2,3-triazole) phenylhydrazine hydrochloride using the methods described in Examples 22 and 24. M.p. 278 ° C (MeOH / Et ₂ O); (Found: C, 61.84; H, ι

6.10; N, 22.21. C ₁₅ H ₁₇ N ₅ .0, 5 (C ₂ H ₂ O ₄ ) is C, 61.53; H,

5.81; N, 22.42%); ¹ H NMR (360MHz, D ₆ -DMSO) δ 1.66-1.82 (2H, m, CH ₂ ); 1, 98 to 2.06 (2H, m, CH _2); 2.83-2.89 (2H, m, CH ₂ ); 2, 98-3.08 (1H, m, CH); 3.21 (2H, pi, d, J = 12.5Hz, CH ₂ ); 7.28 (1H, s, Ar-H); 7.51-7.56 (2 H, m, Ar-H); 7.93 (1H, s, Ar-H); 8.05 (1H, s, Ar-H); 8.73 (1H, s, Ar-H).

EXAMPLE

N-Methyl-4- [5-imidazol-1-yl-1H-indol-3-yl] piperidine. Sesquioxalate

Derived from N-methyl-4- (formylmethyl) piperidine and 4- (imidazolyl) phenylhydrazine hydrochloride as described in Example 22. Mp 217 ° C; (Found: C, -57.41; H, 5.83; N, 13, 30. C ₁₇ H ₂₀ N _4. 1.5 (C ₂ H ₂ O ₄ ). 0.14 (CH ₃ OH) is C, 57.61; H, 5.66; N, 13.34%); ¹ H NMR (360MHz, D ₂ O) δ 1.94-2.06 (2H, m, CH ₂ ); 2.34-2.38 (2 H, m, CH ₂ ); 2.94 (3H, s, CH ₃ ); 3.20 to 3.27 (3H, m, CH and CH _2);

3, 63 to 3.67 (2H, m, CH _2); 7.40-7.43 (2 H, m, Ar-H); 7.64 (1H, s, Ar-H); 7.68 (1H, d, J = 8.7Hz, Ar-H); 7.84- (1H, s,

Ar-H); 7.90 (1H, d, J = 1.3Hz, Ar-H); 9.07 (1H, s, Ar-H).

EXAMPLE

N-Methyl-4- [5-1,2,3-triazol-1-yl) -1H-indol-3-yl] piperidine. Hemioxalate

Obtained from N-methyl-4- (formylmethyl) piperidine and 4- (1,2,3-triazoloyl) phenylhydrazine hydrochloride as described in Example 22. M.p. 251254 ° C (MeOH / Et ₂ O); (Found: C, 62.21; H, 6.49; N, 21.21. C ₁₆ H ₁₉ N ₅ .0.5 (C ₂ H ₂ O ₄ ). 0.1 H ₂ O is C, 62; 22; H, 6.20; N, 21.34%); ₁ H NMR (360MHz, D ₂ O) δ 1.69-2.01 (2H, m, CH ₂ );

2.25-2.31 (2 H, m, CK ₂ ); 2.94 (3H, s, CH ₃ ); 3.04-3.20 (31-1, m, CH and CH ₂ ); 3.61-3.65 (2 H, m, CH 1); 7.32 (1H, s, Ar-H); 7.44 (IK, dd, J-1.9 and 8.7Hz, Ar-H); 7.58 (1H,

I d, J = 8.7Hz, Ar-H); 7.86 J = 8.7Hz (1H, d, J = 1.8Hz, Ar-H);

7.94 (1H, s, Ar-H); 8.29 (1H, s, Ar-H).

EXAMPLE

N-Methyl-3- [5- (1,2,3-triazol-1-yl) -1H-indol-3-yl] -pyrrolidine, Oxalate

Obtained from N-benzyl-3- (formylmethyl) pyrrolidine and 4- (1,2,3-triazolyl) phenylhydrazine hydrochloride as described in Examples 26 and 27. 154156 ° C (MeOH / Et ₂ O): (Found: C, 57.06; H, 5.39; N, 19.43. C ₅ H ₁₇ N _5. C ₂ H ₂ O ₄ is C , 57.14; H, 5.36; N, 19.60%): ² H NMR δ (360), D ₂ O) 2.23-2.38 (1H, m, CH from CH ₂ ); 2.55-2.69 (1H, m, CH from CH ₂ ): 3.01 (3H, s, Me); 3.13-3.42 and

From 3.55 to 3, 60 (total 2H. Each m, CH ₂₎ 3.70 to 4, 09 (3H, m, CH and CH ₂₎ 7.39 (1H, d, J = 8.7Hz, Ar-H); 7.42-7.46 (1H, m, Ar-H); 7.58 (1H, d, J = 8.7Hz, Ar-H); 7.62 (1H, s, Ar-H);

7.93 (1H, s, Ar-H); 8.30 (1H, s, Ar-H).

EXAMPLE

N-Methyl-3- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] -pyrrolidine. Dioxalate

Derived from N-benzyl-3- (formylmethyl) pyrrolidine and 4- (2-methyl) imidazol-1-ylmethyl) phenylhydrazine hydrochloride as described in Examples 26 and 27. Dioxalate produced

I. Vol. 152-153 ° C; (Found: C, 55.41; H, 5.51; N,

II, 61, C ₁₈ H ₂₂ N ₄ .2 (C ₂ H ₂ O ₄ ) is C, 55.69; H, 5.52; N,

11.81%); ³ H NMR (360MHz, D ₂ O) δ 2.22-2.46 (1H, m, CH from

CH ₂ ); 2.58-2.76 (1H, m, CH from CH ₂ ); 2.65 (3H, s, Me);

3.02 and 3.03 (total 3H, s, Me); 3.21-3, 44, 3.60-3, 67,

3.75 to 3.95 and 4.09 to 4.14 (total 5H, each m, CH and 2 of CH _2); 5.42 (2H, s, CH ₂ ); 7.17-7.19 (1H, m, Ar-H);

7.32 (2H, s, Ar-H); 7.39 (1H, d, J = 8.4Hz, Ar-H); 7.56 (1H, d, J = 8.4Hz, Ar-H); 7.67 (1H, s, Ar-H).

I

EXAMPLE

N-Methyl-3- [5-imidazol-1-yl-1H-indol-3-yl] pyrrolidine. Dioxalate

Derived from N-benzyl-3- (formylmethyl) pyrrolidine and 4- (imidazolyl) phenylhydrazine hydrochloride using the methods described in Examples 26 and 27. M.p. 173-175 ° C (MeOH / Et ₂ O); (Found: C, 53.94; H, 5.07; N,

12.51. C ₁₆ H ₁₈ N ₄ .24 (C ₂ H ₂ O ₄ ) is C, 53.81; H, 4.97; N,

12.55%); ³ Η NMR (360MHz, D ₂ O) δ 2.26–2.45 and 2.60–2.78 (each 1H, each m, CK ₂ ); 3.02-3.03 (total 3H, each s, Me); 3.23-3.45, 3, 61-3.66, 3, 78-3, 95 and

4.11 to 4.16 (total 5H, each m, 2 of CH ₂ and CH);

7.42-7.45 (total 1H, each s, Ar-H); 7.49 (1H, d,

J = 9.2 Hz, Ar-H); 7.65 (1H, s, Ar-H); 7.69 (1H, d,

J = 9.2 Hz, Ar-H); 7.86-7.89 (2H, m, Ar-H); 9.09 (1H, s,

Ar-H).

EXAMPLE 35

N-Methyl-3- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] pyrrolidine. Sesquioxalate. Hemihydrate

Derived from N-benzyl-3- (formylmethyl) pyrrolidine and 4- (1,2,4-triazolylmethyl) phenylhydrazine dihydrochloride as described in 26 and 27 vioxalate hemihydrate alcohol / Et ₂ O); (Found: 16.99.C ₁₆ H ₁₉ N ₅ .1.3 (C ₂ H ₂ O ₄ )). Prepared from m.p. 59-61 ° C (isopropyl 55.10; H, 5.79; N,

i.e.

C,

0.4H ₂ O is C, 55.08; H, 5.57;

N, 17.27%); 1 H NMR (360MHz. D ₂ O): δ 2.20-2.42 and 2,542.72 (each 1H, each m, CH ₂ ); 3.0 and 3.02 (total 3H, each, Me): 3.16-3.42, 3.56-3.62, 3,723.76, 3.82-3.94 and 3.98-4, 10 (total 5H, each m, 2 of CH ₂ and CH), 5.52 (2K, s, CH₃), 7.22 and 7.24 (total 1H, each

Ar-H).

d, J = 8.6Hz, Ar-H), 7.52

I (1H, d, J = 8.6Hz, Ar-H), 7.66 (1H, s, Ar-H), 8.06 (1H, s, Ar-H), 8.58 (1H, s) , Ar-H).

EXAMPLE

N-Methyl-3- [5-imidazol-1-ylmethyl-1H-indol-3-yl] -pyrrolidine. Oxalate. Hemihydrate

Derived from N-benzyl-3- (formylmethyl) pyrrolidine and 4- (imidazol-1-ylmethyl) phenylhydrazine hydrochloride as described in Examples 26 and 27. 101-104 ° C (Isopropyl alcohol / Et ₂ O); (Found: C, 59.51; H, 6.35; N, 14.54 C ₁₇ H ₂₀ N ₄ C ₂ H ₂ O ₄ 0,6H ₂ O, 0, l (iPrOH) is a C 59, 86; H, 6.25; N, 14.47%); ¹ H NMR (360MHz, D ₂ O) δ 2.26-2.42 (1H, m, CH from CH ₂ ), 2.60-2.74 (1H, m, CH from

CH ₂ ), 3.03 (3H, s, Me), 3.16-4.12 (5H, pi, m, 2 of CH ₂ and CH), 5.45 (3H, s, Me), 7, 27 (1H, dd, J = 1.6 and 8.5Hz, Ar-H), 7.31 (1H, s, Ar-H), 7.38-7.40 (2H, m, Ar-H). ,

7.58 (1H, d, J = 8.5Hz, Ar-H), 7.70 (1H, s, Ar-H), 8.39 (1H, s, Ar-H).

EXAMPLE

N, N-Dimethyl-2- [5- (2-aminoimidazol-1-yl) -1H-indol-3-yl] ethylamine. Dioxalate

Obtained from 2-aminoimidazole and 4-fluoronitrobenzene as described in Example 16. To prevent the reaction of the aminoimidazole with sodium nitrite under diazotization conditions, the amino group was protected as acetamide with Ac ₂ O / AcOH before hydrogenation and hydrazine formation. The Fischer reaction of 4- [2- (methylcarbonylamino) imidazol-1-yl] phenylhydrazine with N, N-dimethylaminobutanaldimethylacetal gave the title product. Dioxalate formed lt 199-200 ° C (MeOH / Et ₂ O) (Found: C, 50.35; H, 5.06; N, 15.05 C ₁₅ H _{i9 5} N, 2.1 (C ₂ H ₂ O ₄ ) is C, 50.31 H, 5.10; N, 15.28%); ⁴ H NMR (360MHz, D ₂ O); δ 2.91 (6H, s, i

3.50 (2H, t, (1H, dd, J = 1.8)

7.67 (1H, d,

EXAMPLE

N, N-Dimethyl-2- [5- (2-aminoimidazol-1-ylmethyl) -1H-indol3-yl] ethylamine. Sesquioxalate

1. 4-Cyanophenylhydrazine. Hydrochloride

Sodium nitrile (31.5 g, 457 mmol) was added dropwise to a cooled (-15 ° C) and stirred suspension of 4-aminobenzonitrile (50 g, 423 mmol) in concentrated hydrochloric acid (550 mL). solution in water (200 ml) at a rate such that the temperature is below -10 ° C. The reaction mixture was rapidly filtered to remove solids and the filtrate was added portionwise to a cooled (-20 ° C) and stirred solution of tin (II) chloride dihydrate (477 g, 2.1 mol) in concentrated hydrochloric acid (370 mL). ) at a temperature below -10 ° C. Changes from -10 to 0 ° C over 15 minutes. Filtration gave a white precipitate which was washed with diethyl ether (4 x 250 mL) and dried to give 56 g (78%) of the title compound; 235-237 ° C (1: 1 ethanol / water); ¹ H NMR (250MHz, DMSO-d _s) δ 10.50 (3H, br, s, -N + H _3), 9.10 (1H, br, s, -NH-), 7.71 (2H, d, J = 8.8Hz, Ar-H), 7.03 (2H, d, J = 8.8Hz, Ar-H); m / z (CI) 132 (M ⁺ -1).

2- [5-Cyano-1H-indol-3-yl] ethylamine. Hydrochloride

To a stirred suspension of 4-cyanophenylhydrazinc (50 g) in ethanol / water (5: 1; 21) was added 4-chlorobutanaldimethylacetal (45 g) and the resulting mixture was refluxed for 18 h. The solvents were removed in vacuo and the residue aceotroped with toluene to give a brown solid. This crude material was crystallisation in methanol (150 ml) gave 23 g (35%) a yellow solid the title compound lt 270-274 ° C: ³ H NMR (250MHz, DMSO-d6): δ 11.60 (1H, br, s, Indole NH), 8.17 (1H, d, J = 1.1Hz, Ar-H), 7.97 (3H, pi, s, -N ⁺ H3), 7.54 (1H, d, J = 8.5Hz, Ar-H), 7.46 (1H, s, Ar-H), 7.44 (1H, dd, J = 8.5 and 1.1Hz, Ar-H), 3.05 ( 4H, pi, s, -CH ₂ CH ₂ N-); m / z (CI) 184 (M ⁺ -1).

3. N-tert-Butyloxycarbonyl-2- [5-cyano-1H-indol-3-yl] ethylamine

The title compound is obtained in the form of a white substance with a yield of 58% of said tryptamine under the conditions described in Example 1 (Step 4); 132134 ° C (hexane-ethyl acetate); ¹ H NMR (250MHz, CDCl ₃ ) δ 8.42 (1H, br, s, indolo NH), 7.93 (1H, s, Ar-H),

7.41 (2H, s, Ar-H), 7.12 (1H, d, J = 2.2Hz, Ar-H), 4.71 (1H, br, s, -NH-), 3.44 (2H, q, J = 6.9Hz, -CH ₂ NH-), 2.94 (2H, t. J = 6.9Hz, Ar-CH ₂ -), 1.45 (9H, s, t-Bu ); m / z (CI) 286 (M ⁺ + 1).

4. N-tert-Butyloxycarbonyl-2- [5-aminomethyl-1H-indol-3-yl] ethylamine

A solution of the product of the preceding step (11.3 g) in a mixture of absolute ethanol (750 ml) and chloroform (22 ml) was hydrogenated at 50 psi on platinum (IV) oxide (1 g) for 28 hours. The catalyst was filtered off and the solvents removed in vacuo. The residue was purified by flash chromatography (silica gel, dichloromethane-methanol-ammonia 90: 10: 1) to give 9.5 g (82%) of the title compound as a white solid: mp 147-149 ° C; ¹ H NMR (360MHz, CDCl ₃ ) δ 8.04 (1H, br, s, indolo NH), 7.52 (1H, s, Ar-H), 7.33 (1H, d, J = 8.4Hz) , Ar-H), 7.16 (1H, il ·!

d, J = 8.4Hz, Ar-H), 7.03 (1H, s, Ar-H), 4.61 (1H, pi, s,

-NHBOC), 3.96 (2H, s, Ar ~ CH ₂ NH _2), 3.45 (2H, br, q, CH ₂ NHBoc), 2.95 (2H, t, J = 6,8Hz, Ar -CH ₂ -), 1.49 (9H, s, t-Bu); m / z (CI) 288 (M ⁺ -1).

5. N-tert-Butyloxycarbonyl-2- [5-dimethylaminomethyl-1H-indol-3-yl] -ethylamine

The title compound is obtained in the form of a colorless thick oil of the title compound (71%) from the product of the preceding step under the conditions described in Example 3 (step 3); 1 H NMR (250MHz, CDCl ₃ ) δ 8.07 (1H, pi, s, indole

N-H), 7.50 (1H, s, Ar-H), 7.31 (1H, d, J = 8.3 Hz, Ar-H),

7.16 (1H, d, J = 8.3Hz, Ar-H), 7.02 (1H, s, Ar-H), 4.61 (1H, pi, s, -NH-), 3.54 (2H, s, Ar-CH ₂ N-), 3.45 (2H, q, J = 6,2Hz, -CH ₂ NH-), 2.94 (2H, t, J = 6,2Hz, Ar- CH ₂ -),

2.27 (6H, s, -NMe ₂ ), 1.43 (9H, s, t-Bu).

N-tert-Butyloxycarbonyl-2- [5-trimethylammoniomethyl-20H-indol-3-yl] ethylamine. A solution of the product of the iodide step (2.9 g) in anhydrous diethyl ether (170 mL) and iodomethane (36 mL) was left to stand at room temperature for 16 h in the dark. The white solid was filtered, washed with diethyl ether and dried over phosphorus pentoxide at 50 ° C in vacuo to give 4.2 g (100%) of the title compound; i.e.

(360MHz, DMSO-d ₆₎ δ 11.09 (1H, s, Ar-H) (dec) H indole NH), 7.69 (1H,

NMR

199-202 C) 1H, br, s,

7.44 (1H, d, J = 8.3Hz, Ar-H), 7.26 s, Ar-H), 7.19 (1H, d, J = 8.3Hz, Ar-H), 6, 89 (1H, br t, -NH-), 4.57 (2H, s, Ar-CH ₂ N-), 3.23 (2H, q, J = 7.6Hz,

-CH _; NHCH ₂ -), 49.30;

3.01 (9H, s, 37. (9H, s, b, r

N,

-N Me ₃ ) 2.83 (2H, t, J = 7.6H; t-Bu); m / z (FAB) 332.

Ar8.79, .C ₁₉ H ₃₀ IN ₃ O ₂ vra: C, 49, 68;

. N-tert-Butyloxycarbonyl-2- [5-2-nitroimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine

Sodium hydride (0.6 g of 60% dispersion in oil) was added to a stirred solution of 2-nitroimidazole (1.6 g, 14.2 mmol) in DMF (65 mL) at room temperature. After half an hour, a solution of said methyl iodide (3.26 g, 7.1 mmol) in DMF (40 mL) was added and the mixture was refluxed for 2 h and then stirred at room temperature for 18 h. After treatment with water, the crude product was purified by flash chromatography to give the title compound (2.6 g); ¹ H NMR (360MHz, CDCl ₃ ) δ 1.43 (9H, s, t-Bu), 2.94 (2H, t, J = 7.0Hz, CH ₂ ), 3,403.48 (2H, m, CH ₂ ), 5.69 (2H, s, CH ₂ ), 7.01 (1H, s, Ar-H), 7.09 (1H, d, J = 8.4Hz, Ar-H), 7.10 (2H, s, Ar-H), 7.37 (1H, d, J = 8.4Hz, Ar-H), 7.54 (1H, s, Ar-H), 8.12 (1H, s, indolo-NH).

8. 2- [5- (2-Nitroimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine

A solution of said imidazole (2.6 g, 6.7 mmol) in 90% HCO ₂ H (150 mL) was stirred at room temperature for 1.25 h. The reaction was quenched by the addition of MeOH and the solvents removed in vacuo. The crude product was purified by flash chromatography on silica gel eluting with CH ₂ Cl ₂ / EtOH / NH ₃ (30: 8: 1). The resulting yellow oily product ^X H NMR (360MHz, d ₄ -MeOH) δ 2,87-2.94 (4H, m, 2 of CH _2), 5.71 (2H, s, CH _2), 7.05 ( 1H, d, J = 8.4Hz, Ar-H), 7.11 (1H, s, Ar-H), 7.12 (1H, s, Ar-H),

7.35 (1H, d, J = 8.4Hz, Ar-H), 7.39 (1H, s, Ar-H), 7.55 (1H, s, Ar-H).

9. N, N-Dimethyl-2- [5- (2-nitroimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine

I

Derived from said triptami under the conditions described in Example 3 (Step 3); ¹ H NMR (250MHz, CDCl ₃ ) δ 2.33 (6H, s, N (Me) ₂ ), 2.62 (2H, t, J = 7.4Hz, CH ₂ ), 2.92 (2H, t, J = 7.4Hz, CH _2), 5.68 (2H, s, CH _2), 7.00 (1H, d,

J = 1.0Hz, Ar-H), 7.07 (1H, dd, J 1.0 and 8.2Hz, Ar-H),

7.09 (1H, d, J = 2.4Hz, Ar-H), 7.10 (1H, d, J = 2.4Hz, Ar-H),

7.35 (1H, d, J = 8.2Hz, Ar-H), 7.53 (1H, s, Ar-H), 8.19 (1H, pi, s, indolo-NH).

N, N-Dimethyl-2- [5- (2-aminoimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Sesquioxalate

The title compound is obtained from the product of Step 9 under the conditions of Example 5 (Step 2). The sesame oxalate salt was obtained, m.p. 211-212 ° C (MeOH / Et ₂ O); (Found: C, 54.46; H, 6.08; N, 16.53; C ₁₆ H ₂₁ N _5. 1.5 (C ₂ H ₂ O ₄ ), 0.06 (MeOH) is C, 54.46 ; H,

5.81; N, 16.66%), ¹ H NMR (360MHz, D ₂ O) δ 2, 91 (6H, s, N (Me) ₂ ), 3.25 (2H, t, J = 7.4Hz, CH ₂ ), . 3.49 (2H, t, J = 7.4Hz, CH ₂ ), 5.16 (2H, s, CH ₂ ), 6, 77 (1H, d, J = 2.3Hz, Ar-H), 6.83 (1H, d, J = 2.3Hz, Ar-H) , 7.1 9 (1H, dd, J = 1.5 and 8.5Hz, Ar-H), 7.39 (1H, s, Ar-H) , 7.56 (1H, d,

J = 8.5Hz, Ar-H), 7.61 (1H, s, Ar-H).

EXAMPLE 39

N-Methyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

N-Benzyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine

Freshly distilled solution of 2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine (1.5 g, 6.2 mmol) in EtOH (30 mL) was added. benzaldehyde (0.66 g, 6.2 mmol;

and the solution was stirred at room temperature for 21h, NaBH ₄ (0.24g, 6.3mmol) was added portionwise over .10min at room temperature and the resulting mixture was stirred for 0.5h, then the solvent was removed in vacuo. The resulting residue was taken up in water (10 mL) and acidified with IN HCl (15 mL). The mixture was then basified with 2N NaOH and extracted with EtOAc (4x50 mL). The combined organic phases were washed with NaCl solution (30 mL), dried and concentrated. The residue was chromatographed on silica gel, eluting with CH ₂ Cl ₂ / MeOH (85:15), to give the title product (1.38 g, 67%); ¹ H NMR (360MHz, CDCl ₃ ) δ 2.94 (4H, s, 2 of CH ₂ ), 3.80 (2H, s, CH ₂ ), 5.38 (2H, s, CH ₂ ), 7, 04 (1H, d, J = 2Hz, Ar-H), 7.08 (1H, dd, J = 1.5 and 8.4Hz, Ar-H), 7.18-7.30 (5H, m, Ar-H), 7.32 (1H, d, J = 8.4Hz, Ar-H), 7.54 (1H, s, Ar-H), 7.94 (1H, d, J = 2Hz, Ar -H), 8.17 (1H, pi, s, indolo-NH).

2. N-Benzyl-N-methyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine

To a stirred solution of said amine (1.14 g, 3.4 mmol) in anhydrous DMF (45 mL) was added K ₂ CO ₃ (0.89 g,

6.4 mmol) and dimethyl sulfate (0.46 g, 3.7 mmol). The mixture was stirred at room temperature for 3.5 h, then taken up in H ₂ O (90 mL) and extracted with EtOAc (2 x 100 mL). The combined organic solutions were washed with NaCl solution (40 mL), dried and concentrated. The residue was chromatographed on silica gel eluting with CH ₂ Cl ₂ / MeOH (90:10) to give the desired product (0.69g); ¹ H NMR (360MHz, CDCl ₃ ) δ 2.34 (3H, s, CH ₃ ), 2.70-2.76 (2H, m, CH ₂ ),

2.94-3.00 (2H, m, CH ₂ ), 3.60 (2H, s, CH ₂ ), 5.38 (2H, s, CH ₂ ), 7.04 (1H, d, J = 2Hz, Ar-H), 7.08 (1H, dd, J = 2 and

8.4Hz, Ar-H), 7.20-7.36 (6H, m, Ar-H), 7.44 (1H, s, Ar-H),

7.94 (1H, s, Ar-H), 7.96 (1H, s, Ar-H), 8.18 (1H, pi, s, indolo-NH).

3. N-Methyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate

Ϊ

A solution of said benzylamine '(0.69 g, 2.0 mmol) in ethanol (100 mL) and 2N HCl (2 mL) was hydrogenated at 30 psi at 10% Pd / C (0.6 g) for 4 h. The catalyst was removed by filtration through hyflo, the solvent removed in vacuo and the residue chromatographed on silica gel, eluting with CH ₂ Cl ₂ / EtOH / NH 3 (40: 8: 1) to give the title N-methylamine (0.34 g, 68%). The oxalate produced was recrystallized from isopropyl alcohol; mp 149-150 ° C; (Found: C, 55.42; H, 5.72; N, 19.55; C ₁₄ H ₁₇ N _5. C ₂ H ₂ O ₄ ,

0.15 (iPA) is C, 55.72; H, 5.75; N, 19.76%); ¹ H NMR (360MHz, D ₂ O) δ 2.44 (3H, s, CH ₃ ), 2.87-2, 98 (4H, m, 2 of CH ₂ ), 5.41 (2H, s, CH) ₂ ), 7.05 (1H, s, Ar-H), 7.09 (1H, dd, J = 1.6 and 8.4Hz, Ar-H), 7.31 (1H, d, J = 8 , 4Hz,

Ar-H), 7.57 (1H, s, Ar-H), 7.96 (1H, s, Ar-H), 7.99 (1H, s, Ar-H).

EXAMPLE

Making tablets

Tablets containing 1.0, 2.0 25.0 26.0, respectively

50.0 and 100.0 mg of the following compounds are prepared as follows:

N, N-Dimethyl-2- [5- (2-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine. Oxalate.

N, N, -Dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3yl] -ethylamine. Benzoate.

N, N-Dimethyl-2- [5- (1,2,4-tetrazol-1-ylmethyl) -1H-indol-3-yl] ethylamine. Succinate.

N-Methyl-4- [5-imidazol-1-yl-1H-indol-3-yl] piperidine. Sesquioxalate.

N-Methyl-3- [5-1,2,3, -triazol-1-yl) -1H-indol-3-yl] pyrrolidine. Oxalate.

DOSAGE TABLE, 1.25 mg OF ACTIVE COMPOUND

Amount-mg

Active compound 1.0 2.0 25.0 Microcrystalline cellulose 49.25 48.75 37.25 Modified nutritional corn starch 49.25 48.75 37.25 Magnesium stearate 0.50 0.50 0.50 DOSAGE TABLE, 26-100mg ACTIVITY COMPOUND Active compound 26.0 Amount-mg 50.0 100.0 Microcrystalline cellulose 52.0 100.0 200.0 Modified nutritional 2.21 4.2 8.5 corn starch Magnesium stearate 0.39 0.75 1.5

All active compound, cellulose and a portion of corn starch are mixed and granulated into 10% corn starch paste. The resulting granules are sieved, dried and mixed with cornstarch residue and magnesium stearate. The resulting pellets are compressed into tab15 spears containing 1.0, 2.0, 25.0, 26.0, 50.0 and 100 mg of active ingredient per tablet.

• D p

Claims (10)

DEFINITION OF INVENTION 1 12 X is nitrogen or A -C; n is zero, 1, 2 or 3; B ¹ is oxygen, sulfur or NR ¹³ ; A ¹¹ and A ¹² are independently C _x _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (C ₁ _ ₆₎ alkyl, C ₃ _ ₇ heterocycloalkyl, heteroaryl or heteroaryl (C1-g) alkyl, any of these groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, C ^ g alkoxy, Ο ₃ _ ₆ alkylthio or ₇ or C _g alkyl; and R ^{17 is} independently hydrogen and I R ^x and R ^y are independently hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y taken together are C ₂ _ ₆ alkylene group. 1. A compound of formula I, or a salt or parenteral form thereof: wherein the dotted ring represents two non-adjacent double bonds at any position on the pentagonal ring; two, three or four of V, W, X, Y and Z are nitrogen and the rest is carbon provided two of V, W, X, Y and Z is nitrogen and the rest is carbon and said nitrogen atoms are not in adjacent positions on the pentagonal ring; A ¹ is hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, -OR ^X , -SR ^X , -NR ^X R ^Y '-NR ^x COR ^y ' -NR ^x CO 2 R ^y '-NR ^x SO 2 R ^y or -NR ^z CTNR ^x R ^y ; A is an unbound pair of electrons when four of V, W, X, Y and Z are nitrogen and the rest is carbon; or when two or three of V, W, X, Y and Z are nitrogen and the remainder are carbon, 2 A is hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, trifluoromethyl, -OR ^X , -S ^X , -NR ^x R ^y '-NR ^x COR ^y ' -NR ^x CO 2 R ^y '-NR ^X SO 2 R ^Y or -NR ^z CTNR ^x R ^y ; E is a bond or a linear or branched alkylene chain containing from 1 to 4 carbon atoms; . F is a group of formula In which U is nitrogen or CR ² ; B is oxygen, sulfur or NR ³ ; R ¹ is -CH ₂ . CHR ⁴ . NR ⁶ R ⁷ or a group of the formula wherein the dotted line is an optional chemical bond; 2- [5- (1-Benzyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (1-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (2-methyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (tetrazol-2-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (tetrazol-1-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (1-methyl-1,2,4-triazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (1-methyl-1,2,4-triazol-3-ylmethyl) -1H-indol-3-yl] ethylamine; I N, N-dimethyl-2- [5- (1,2,3-triazol-1-methyl) -1H-indol-3-yl] ethylamine; 2- [5- (2-Benzyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; Compound according to claim 1, characterized in that it has the formula IIA and its salts and primary pharmaceutical forms: (HA) in which 3- [5- (2-Methylimidazol-1-yl) -1H-indol-3-yl] pyrrolidine; 1-methyl-3- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] pyrrolidine; 3- [2- (N, N-dimethylamino) ethyl] -5- (2-methyltetrazol-5-yl) benzo [b] thiophene; N, N-dimethyl-2- [5- (2-methylimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (imidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (2-methylimidazol-1-yl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (2-ethyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (1-ethyltetrazol-5-ylmethyl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (1,2,4-triazol-1-yl) -1H-indol-3-yl] ethylamine; 1-methyl-4- {5- (2-methylimidazol-1-yl) -1H-indol-3-yl] piperidine; 1-methyl-4- [5- (1,2,4-triaza-1-methyl) -1H-indol-3-yl] piperidine; 3- (2-aminoethyl) -5- (2-methyltetrazol-5-yl) benzo [b] thiophene; 3- (2-aminoethyl) -5- (1-methyltetrazol-5-yl) benzo [b] thiophene; 3. A compound according to claim 1, characterized in that it has the formula IIB and its salts and primary pharmaceutical forms: A 25 _R 2 ₇ (IIB) in which Y ¹ is nitrogen or A ²² -C; n is zero, 1, 2 or 3; B ² is oxygen, sulfur or NR ²³ ; A ²¹ and A ²² is independently a C ^ g alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (Ο ₃ _ ₆₎ alkyl, C ₃ _ ₇ heterocycloalkyl, heteroaryl or heteroaryl (Cp.g) alkyl, any of these groups may be optionally substituted; or hydrogen, halogen, cyano, Trif luormetilas, Ο ₃ _ ₆ alkoxy, C _x _ ₆ alkylthio or -NR ^x R ^y; 22 23 24 ° 7 R, R, R and R are independently hydrogen or C 1-6 alkyl; and R ^x and R ^{y are} independently hydrogen, hydrocarbon or heterocyclic group, or R ^x and R ^y together are a C ₇ -C ₆ alkylene group. 4- [5- (1,2,3-Triazol-1-yl) -1H-indol-3-yl] piperidine; 1-Methyl-4- [5- - (imidazol-1-yl) -1H-indol-3-yl] piperidine; 1-Methyl-4- [5- - (1,2,3-triazol-1-yl) -1H-indol-3-yl] piperidine; din; 1-Methyl-3- [5- - (1,2,3-triazol-1-yl) -1H-indol-3-yl] pyrrole- din; 1-Methyl-3- [5- - (2-methylimidazol-1-ylmethyl) -1H-indol-3-yl] pyrrolidine; l-methyl-3-Γ 5- - (imidazol-1-yl) -1H-indol-3-yl] pyrrolidine; 1-Methyl-3- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] pyrrolidine; 1-methyl-3- [5- (imidazol-1-ylmethyl) -1H-indol-3-yl] pyrrolidine; N, N-dimethyl-2- [5- (2-aminoimidazol-1-yl) -1H-indol-3-yl] ethylamine; N, N-dimethyl-2- [5- (2-aminoimidazol-1-ylmethyl) -1H-indol-3-yl] ethylamine; I N-Methyl-2- [5- (1,2,4-triazol-1-ylmethyl) -1H-indol-3-yl] ethylamine; and their salts and primary forms. 4- [5- (imidazol-1-yl) -1H-indol-3-yl] piperidine; 4- [5- (1,2,4-Triazol-1-ylmethyl) -1H-indol-3-yl] piperidine; 4- {5- (2-methylimidazol-1-yl) -1H-; -. '. doi-3-yl piperidine; I 4. A compound according to claim 1, characterized in that it has the formula IIC and its salts and primary pharmaceutical forms: (UC) in which Y ² is nitrogen or A ³² -C; Z ¹ is nitrogen or CH; n is zero, 1, 2 or 3; B ³ is oxygen, sulfur or NR ³³ ; ^{20 * * * * 25 * * *} 20 A ³¹ and A ³² are independently C _x _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (C _x _ ₆₎ alkyl, C ₃ _ ₇ heterocycloalkyl, heteroaryl, or heteroaryl (C _{x 6} ) alkyl, any of these groups may be optionally substituted; or hydrogen, halogen, cyano, 25 trifluoromethyl, C _x _ ₆ alkoxy, C _x _ ₆ alkylthio or -NR ^x R ^y ; R ³¹ is -CH ₂ . CHR ³⁴ . NR ³⁶ R ³⁷ or a group of the formula: , 33, 34 R is independently hydrogen or C vra _x _ ₆ alkyl; I R * and R ^y are independently hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y taken together are C ₂ _ ₆ alkylene group. 5-HT 1 receptor agonist. 5. A compound according to claim 1 having the formula IID and its salts and primary pharmaceutical forms: in which W ⁴ is nitrogen or CA ⁴² ; n is zero, 1, 2 or 3; B ⁴ is oxygen, sulfur or NR ⁴³ ; A ⁴¹ and A ⁴² are independently C _x _ ₆ alkyl, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₇ cycloalkyl, aryl, aryl (Cj.g) alkyl, C _{3rd 7} heterocycloalkyl, heteroaryl or heteroaryl (C 1 -C) alkyl, any of these groups may be optionally substituted; or hydrogen, halogen, cyano, Trif luormetilas, 0χ_ ₆ alkoxy, alkylthio Ch.g or -NR ^x R ^y; 41 44 4fi47 R is -CH ₂ .CHR. NR R or a group of the formula or 42 43 44 45 46 47 R, R, R, R, R and R are independently hydrogen or C _1-6 alkyl; and R ^x and R ^Y are independently hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y taken together are C ₂ _ ₆ alkylene group. 6. A compound according to claim 1, which is selected from the following compounds: 7. A pharmaceutical composition comprising a pharmacologically acceptable carrier or inert excipient comprising a compound according to any one of the preceding claims. 7 3 4 5 6 7 R ', R, R, R, R and R are independently hydrogen or C 1-6 alkyl; R ^x and R ^y are independently hydrogen, hydrocarbon or a heterocyclic group, or R ^x and R ^y taken together are C ₂ _ ₆ alki ethylene group; R 'is hydrogen, hydrocarbon or heterocyclic group; T is oxygen, sulfur or a group of the formula = N.G; I have G is a hydrocarbon, heterocyclic group, or electron withdrawing group. A compound according to any one of claims 1 to 6 for use in therapy. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment and / or prevention of clinical conditions requiring a selective similar 10. A process for the preparation of a compound according to any one of claims 1-6, wherein: (A) Reacting an active carboxylic acid derivative of the formula R ^a -CO ₂ H with a compound of the formula III or formula IV, or a salt thereof: NHR ^b NHR ^b N (IV) (III) a b c 1 wherein one of R, R and R is a group of formula A, the other is a group of formula A and the third is a group of formula -E-F as defined in claim 1; or (B) a reacting compound of formula XIV: \ W ° r LT 3594 B (XIV) in which A ¹ , E and F is according to claim 1 , Hal is ha- logen and two of V ^a , W ^a , X ^a , Y ^a and Z ^a , to one from of which Hal group, is coal and the rest is nitrogen; with reagent, which has an anion -A ² , 'where A ² is defined in point 1; or (C) linking, by cyclization, an alkyne of formula R ^a -C = CR ^b with an azide of formula R ^c -N ₃ wherein R ^a , R ^b and R ^c are as previously defined; or (D) by cyclization, the nitrile of formula N = CR ^{d is} attached to the azide of formula R ^e -N ₃ , wherein one of R ^d and R ^e is a group of formula A ¹ and the other is a group of formula EF according to claim 1; or (E) reacting a compound of formula R ^e -L with a tetrazole compound of formula XV: d (XV) do wherein one of R and R is a group of formula A ¹ and the other is a group of formula -EF of claim 1 and L is a suitable leaving group; at base; or (F) cyclizing the nitrile of formula N = CEF, wherein E and F are as defined in claim 1, with sodium azide, followed by acidification with a mineral acid; or (G) a reacting compound of formula XVI: (XVI) wherein V, W, Y, Z, A ¹ , with a carbonyl compound: o A 'and E are as defined in claim 1; with / 11 or a protected form thereof wherein R "is a group R 'mole above -CH ₂ • CHR' ⁱ D, wherein R \ is defined and R ¹ * 'is or is a group of the formula according to claim 1 and D * is an easily substituted group; followed, if necessary, by N-alkylation by standard means to introduce R ³ ; or (H) cyclization of a compound of formula XXII: wherein V, W, X, Y, Z, A ¹ , A ² , E and R ¹ are as defined in claim 1, and D is an easily substituted group; followed, if necessary, by N-alkylation by standard means to introduce R ³ ; or (J) cyclization of a compound of formula XXV: wherein V, W, X, Y, Z, A ¹ , A ¹ E and R ² are as defined in Claim 1, Ba ^a is oxygen or sulfur, and R ²¹ is or is a precursor to R ^{1 as} defined in Claim 1; followed by, if necessary, a transfer of the group R to the desired group R; and (K) then transferring the starting compound of Formula I, where appropriate, to the compound of Formula I below, by conventional means.