FI105474B - Amines and alcohols which are used as intermediates - Google Patents

Description

105474 Intermediate amines and alcohols

The invention relates to novel intermediates and their salts having the compounds of formula III, 10-YH '

10 NH

and which may be used in the preparation of guanidines of the formula I,

15T

ö i O NH, I

NH

wherein R is aryl, heteroaryl or heterocyclyl 20, T is CH 2 or O, L is NH or O, and -N (X) -M is a group -N (SO 2 -R 0) -CH 2 - or isoquinolylene; · ·, · · And «·: 25 R ° is the same as R, or: X is H or -CH2C00H, and · · · ·: ··: M is the group R'- (CH2): .2CH =, R '- COCH 2 CH =,. R' - COCH 2 CH =,. ·. R 1 - (CO) 2 NHCH 2 CH =,. At least 1 - OCONHCH 2 CH =,. 'J ·. -CH 2 [R' - (CO) χ.2ΝΗ] CH -, -CH2 (benzyl-OCONH) CH- or -CH (CO-Q) CH2 -, R 'is aryl, heteroaryl, cycloalkyl or heterocyclyl;

«I

R 'is a tetra... Heptamethyleneimino which may have 1 or 2 substituents selected from oxo, -COO-C 1-4 alkyl- (t). - (CH 2) - (C 1 -C 10 -C 1 -C 4 alkyl and optionally mono- or di-C 1 -C 4 alkylated carbamoyl, and Q is benzylamino or an optionally substituted tetra ... heptamethylenimine imino group containing an O atom and optionally substituted with 1 or 2 of the following 5 substituents: C 1-4 alkyl, COOH, -COO-C 1-4 alkyl, -CH 2 OH and - CH 2 O-benzyl, where heteroaryl means mono- or bicyclic groups having from 3 to 9 C atoms and 1 or 2 heteroatoms, which may be substituted with methyl, halogen, carboxymethyl or 1-methyl-5 trifluoromethylpyrazole group, and heterocyclyl mean one or two ring groups wherein at least one ring is non-aromatic and contains 4-7 C atoms and 1 or 2 heteroatoms and which may be substituted by a methyl, halogen, oxy, carboxy or methoxycarbonyl group, and their hydrates or solvates and physiologically acceptable salts thereof.

Examples of the physiologically acceptable salts of the guanidines of formula I are salts of mineral acids such as hydrochloric acid, sulfuric acid, sulfuric acid or phosphoric acid, or organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid, , tartaric acid, succinic acid or salicylic acid. ·. salts. The guanidines of formula I having a free carboxyl group may also form salts with physiological *. ti with acceptable bases. Examples of such salts are alkali metal, alkaline earth metal, ammonium, ammonium and alkylammonium salts, such as N, K, Ca or tetramethylammonium salts. The compounds of the formula I may also be in the form of zwitterions.

> ip: The guanidines of the formula I may be solvated, especially hydrated. Hydration may occur during the manufacturing process or gradually as a result of the hygroscopic properties of the initially anhydrous compound of Formula I.

The guanidines of formula I contain at least two asymmetric C atoms and thus may exist as diastereomeric mixtures or as optically pure compounds.

In the context of the invention, C 1-4 alkyl means straight-chain (C 1-7 -alkyl) groups or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

Aryl means groups such as phenyl, naphthyl or anthryl groups which may have from 1 to 4 substituents, examples of which are NO2, NH2, CN, OH, CH3, isopropyl, tert-butyl, phenyl, phenylsulfonyl, OCH3, benzyloxy, formamido, COOH, COO-C 1-4 alkyl and optionally mono- or di-C 1-4 alkylated amino.

Other possible substituents on the phenyl group are -NHSO 2 -Ar or -NHCO-Ar (wherein Ar is phenyl which may have 1 to 3 substituents such as halogen, NO 2, CF 3, COOH and C 1-4 alkyl, e.g. CH 3), -NHCOCH 2 CH 2 COO. (H, C 1 -C 4 alkyl or benzyl), acetamido, -NHCOCH 2 OCH 2 CH 2 OCH 3, NHCOO (H or C 1 -C 4 alkyl, -NHCO 2 COO (H or C 1 -C 4 alkyl), -NHCH 2 COO-ethyl, -NHCO 2 COO iminocarbonyl.

Examples of cycloalkyl groups are cyclohexyl and decalyl. Heteroaryl groups contain one ring. ; 25 or two rings having 3-9 C atoms and 1 or 2 heteroatoms. Examples include imidazolyl, thienyl, benzylthienyl, quinolyl and indolyl. In them you can. be substituents, e.g., CH 3, halogen, -CH 2 CO 2 H, or • -? -? - 1-methyl-5-trifluoromethylpyrazolyl.

Heterocyclyl means 1- or 2-ring groups containing 4-7 C atoms and 1 or 2 heteroatoms, examples of which are tetrahydroquinolyl, azapinyl, piper *] *]: dinyl, pyrrolidinyl, benzodiazepinyl , benzoxat-; solyl and benzopyrrolidinyl, which may have 1 to 2 substituents, such as methyl, 9 to 9 9 9 9 9 9 9 9 9 9 99 99 9 9 9 9 4 105474 , halogen, oxo, COOH or COOCH 3.

Examples of tetra-heptamethyleneimino groups include piperidino, hexahydroazepine and heptahydroazoquin-5-ene. Examples of the substituents R "of such a group are acetoxy, acetoxymethyl, carbomethoxy, carboethoxy, diethylcarbamoyl, butyryloxymethyl and isobutyryloxymethyl.

Examples of optionally substituted tet-10 ra ... heptamethyleneimino groups Q having an O or S atom in the chain are carboxyhexahydrooxazepine and hexahydrotiazepine.

As substituents on the -N (X) -M phenyl ring of the isoquinolylene group, for example, Cl, NO 2, NH 2 and OH are possible. Examples of compounds of formula I are compounds of formula O .. T-v R-S-N-M'-C-U 1)

n I 11 \ _m IA

20 0 X '0

NH

Wherein N (X ') -M is optionally substituted on the phenyl ring with sub- «1 f! . A substituted isoquinolylene group, or '1 / X' is H, CH 2 CO 3 H, -CH 2 COO-C 1-4 alkyl, CH 2 CO- (tetra ... hepta- · · * ···] methyleneimino) or optionally N-mono- or N-di-C 1 -C 4 alkylated CH 2 CONH 2, and 1 i: M 'is a group R' - (CH 2) 1.2 CH =, R 1 -CO 2 CH 2 CH = or -CH (C 0 -Q ') CH 2 -, * · · V 1 Q 'is benzylamino, morpholino or tetra ... heptamethyleneimine imine, and: 1 ": R, R', L and T have the same meanings as defined above, as well as their hydrates or solvates and physiologically acceptable. grueling salts.

• «1 •« «• 1 · ·» Il • »•« • i «I I I •« • • 5 105474

Preferred compounds of formula IA are those wherein X? is H and R, M ', L and T have the same meaning as above.

Preferred compounds of formula I are compounds of formula I? / \ / T \ R-S-N-M "-C-l V)

OH O '-N NH 2 IB

10 H

NH

wherein M "is a group R" -COCH2CH =, R '- (CO) 1.2NHCH2CH =, benzyl-1-OCONHCH2CH =, -CH2 [R' - (CO3 ^ NH] CH-, -CH2 (benzyl). OCONH) CH- or -CH (CO-Q ") CH 2 -, Q" is optionally substituted in the O or S atom and optionally substituted with 1 or 2 of the following substituents selected from the group consisting of tetra ... heptamethylene-imino the group: C 1-4 alkyl, COOH, -COO-C 1-4 alkyl, CH 2 OH and -CH 2-20-20 benzyl, and R, R ', R 2, L and T have the same meanings as above.

Examples of aryl groups R are naphthyl, hydronaphthyl, 4-biphenyl, 2-anthryl, iodophenyl, nitrophenyl, yl, benzyloxyphenyl, dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl, 2,4,6- triisopropylphenyl, 's'' carboxyphenyl, methoxycarbonylphenyl, benzyloxy * 11 * 1. naphthyl, phenylsulfonylphenyl, hexahydroazepinoylphenyl or tert-butylphenyl.

Examples of heteroaryl groups R are 3-methyl-11,10,8-quinolyl, 5- (1-methyl-5-trifluoromethylpyrazol-3-yl) -2-yl) -2-thienyl, and benzothienyl.

• 1 1!> T4! As an example of heterocyclyl groups, R is 3-methyl-1,2,3,4-tetrahydro-8-quinolyl. When -N (X) -M is designated. sulfonamide -N (S0 2 -Rej-CH 2 - is exemplified by N-dimethyl-1 · 1 · 3 · 35 -ylaminonaphthylsulfonylaminomethylene).

• · • · «• · ·« · · 1 · • · 1 • · 6 105474

Further preferred compounds of formula I are those wherein X is H or -CH 2 COOH.

Examples of group M for R '- (CH 2) 12 CH = are 3-indolylethylidene, 2,3-dioxo-1-indolininylethyl-5-dene, phenylethylidene, 1,4-dioxo-5H-benzodiazepin-5-yl-ethylidene, (fluorine) , chlorine, iodine, cyano, nitro, amino, carboxy, C 1-4 alkoxycarbonyl or hydroxy) phenylethylidene, cyclohexylpropylidene, decalylethylidene, imidazolylethylidene, thienylethylidene, (methyl, bromo, fluoro or carboxymethyl) -3, (etoksikarbonyylikarbonyyliamino, meth-oxy ikarbonyylietyylikarbonyyliamino, bentsyylioksikar-bonyylietyylikarbonyyliamino, ethoxycarbonylamino, bent-soyylikarbonyyliamino, Carboxy, metoxymethoxyphenyl-15 sietoksiasetamido, acetamido, karboksikarbonyyliamino, karboksipropionyyliamino, tolyylisulfonamido, jodifenyy-lisulfonamido, karboksifenyylisulfonamido or etoksikar-bonyylimetyyliamino) -fenyylietylideeni, oksobentsoksatso-liinietylideeni or 5-bromo or 5-methyl-2,3-dioxo-1-20 indolinyl ethylidene .

Examples of the groups M in the meaning of (R 'or R ") - COCH 2 CH = are hexahydroazepinoylethylidene, (methoxycarbonyl or carboxy) pyrrolidinoylethylidene, 3,4-dihydroxy-2 (1H-isoquinolinoylethylidene, (nitro, amino, iodine) •, 25 or formamido) -benzoyl ethylidene, morpholinoethylidene, I k *, * heptahydroazoquinoylethylidene, (ethoxycarbonyl, acetyl, dimethyl, dimethylcarbamoyl, isobutyryloxymethyl * 'or butyryloxymethyl), methoxycarbonyl-4-oxopiperidinoylethylidene or 4-aceto- * · ·: oxy-3-ethoxycarbonylpiperidinoylethylidene.

Examples of groups M with the meaning R1 (CO) j. 2NHCH2CH = are benzoylcarboxamidoethylidene, thienoyl-l-carboxamidoethylidene, benzoylamidoethylidene or benzoyloxycarboxamidoethylidene.

t i «• * * • · · *« · «• *« · · * · · c · • • t • «· • 105474 7

Examples of groups M for -CH 2 [R '(CO) 2 NH] CH- are 2- (carboxybenzoylamido) ethylene, 2- (benzyloxybenzoylamido) ethylene, 2- (2-piperidinecarboxamido) ethylene, 2- (hydroxybenzoylamido) ethylene or 2- (aminobenzoylamido) ethylene.

Examples of the groups M in the meaning of -CH (CO-Q) include 1- (benzylaminocarbonyl) ethylene, 1-hexahydroazepinoyl) ethylene, 1- (morpholinoyl) ethylene, 1- (hexahydroazoquinoyl) ethylene, 1- [2- (benzyloxymethyl) -10 morpholinoyl)] ethylene, 1- [2- (hydroxymethylmorpholinoyl)] ethylene, 1- (2-ethoxycarbonyl-4-methylpiperidinoyl) ethylene, 1- (2-carboxy-4-methylpiperidinoyl) ethylene or 1- (3-karboksiheksahydro-1,4-oksatsepinoyyli) ethylene.

In the above formulas, R is preferably aryl, especially naphthyl or nitro or iodophenyl, L is NH and the C atom of the piperidine or morpholine ring preferably has the S configuration.

Preferred compounds of the formula I are those of the formula -R-S-N-C C-10YV * X CH2 S ^ -NWNH2.

Ϊ 25 k Y

wherein A is aryl, aroyl or heterocyclyl, especially phenyl, nitrophenyl, indolyl, 2,3-dioxo-1-indolinyl ··· V · 1 or aminobenzoyl.

Examples of preferred compounds are the following: (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) -2,3-dioxo-1-indoline propionamide, (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (2-naphthyl-1: 15: 35 lisulfonamido) -o-nitro-hydro-cinnamide.

I I

• I I

• · · • ·

I I I

105474 (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (o-nitro-benzenesulfonamido) -indole-3-propionamide, (R) -N - [( S) -1-amidino-3-piperidinylmethyl] -α- (p-iodo-benzenesulfonamido) -indole-3-propionamide, 5 (R) -N - [(S) -1-amidino-3-piperidinylmethyl] -α - (p-iodobenzenesulfonamido) -p-nitrohydro-cinnamide, (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -3- (o-amino-benzoyl) - (2-naphthylsulfonamido) -propionamide, (R) -N - [(S) -1-amidino-3-piperidinyl] methylcarbamoyl] -10-phenylethyl] -N- (2-naphthylsulfonyl) glycine, (R) -N - [(S) -1-amidino- 3-piperidinylmethyl] -1,2,3,4-tetrahydro-2- (2-naphthylsulfonyl) -3-isoquinolinecarboxamide, (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] hexahydro-β-15 (2-naphthylsulfonamido) -oxo-1H-1-azepine butyramide, (R) -N - [(S) -1-amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) - 2,3-dioxo-1-indolinepropionamide, 4 '- (R) -2 - [[[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] oksalii nic acid, 20 (S) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] hexahydro-β-2-naphthylsulfonamido-oxo-1 (2H) -azoquinobutramide, (2RS, 4R) -1 - [N 4 - [[(S) -1-amidino-3-piperidinyl] methyl] -N 2 - (2-naphthylsulfonyl) -L-asparticinyl] -4-methyl-2-piperidinecarboxylic acid,. 25 1 - [(R) -2 - [[[(S) -1-amidino-3-piperidinyl] methyl] -2- (2-

• I

** ** naphthylsulfonamido) ethyl] succinanilide acid.

The above compounds may be prepared by a) reacting an acid of the formula: R 30 SO 2 N (X) -M-COOH ; having a carboxy group in the group X, R, or M is an intermediate · · · .1 ··. temporarily protected, reacting with an amine or alcohol of the formula: · · · · · · · · · · · · · · · · · · · · • · 1 • · 9 105474

> —N NH2 HI

Y

NH

Or a salt thereof, or b) reacting a compound of formula o X 0 H '' 10 with an amidating reagent, or c) reacting an amine of formula

O

O Q T-V

15 O X nh2 \ -m NH2 V

Y

NH

reacting with an acid of formula R'COOH or a functional derivative thereof, and d) optionally converting a reactive group in group M of the compound of formula I into another, and e) optionally converting a compound of formula I into a physiologically acceptable salt or The salt of formula I into the free acid or base.

<r · '25 Purpose is to react the acid II with V »; in a land solvent such as dimethylformamide (DMF), J; in the presence of a base such as 4-ethylmorpholine or ethyl; ··· lidiisopropylamine of the formula III; with a salt of a compound, e.g. trifluoroacetate, bisul-? 30 with phite, nitrate, hydrochloride or hydroiodide, and benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate at room temperature. The carboxy group in X, R or M, e.g., protected as a tert-butyl ester, is then liberated.

• * • »· t» »IM ·

Ml · • · • t • «· i · i a» a a t • a • «a •» 10 105474

In process variant b), the compound of formula IV can be reacted in a solvent such as DMF, in the presence of a base such as triethylamine, with formamidine sulfonic acid or 3,5-dimethyl-1-pyrazolyl-5-formamidine nitrate, conveniently up to 50 ° C.

In process variant c), the amine V may be reacted with an acid R'-COOH or a functional derivative thereof, e.g. an acid anhydride, in a solvent such as 10 DMF, in the presence of a base such as 4-ethylmorpholine at elevated temperature, e.g. up to.

Among the functional changes of process variant d), the following may be mentioned: 1. reduction of the nitroaryl group in group M with a Pd / C catalyst to an aminoaryl group in a solvent such as ethanol; 2. saponification of an ester group such as an ethoxycarbonyl group eg in ethanol or methanol with a base such as aqueous sodium hydroxide; 3. saponification of an ester group such as a benzyloxycarbonyl group, e.g. in ethanol, with the aid of a Pd / C catalyst; 4. cleavage of benzyl ether with Pd / C catalyst; in ethanol, for example, an acid such as hydrochloric acid or acetic acid; 25 in the presence of acid.

t «I

'. * N-sulfonated amino acids of formula II can be · · ·' ·· *. can be prepared by reacting a corresponding reactive sulfonic acid derivative such as sulfochloride R-SO 2 Cl with the corresponding free amino acid HN (X) -M-COOH in the presence of a base such as an alkali metal hydroxide in a solvent such as ether or diethyl ether. : ***: in dioxane, and water.

• · · ** ': In one variant, the acid of formula II may be M ·. *. is prepared by oxidation of the corresponding alcohol of formula 35 with 105474

R'SO2'N {X ^ M-CP ^ OH VI

e.g. in a solvent such as acetone, an oxidizing agent such as Jones reagent. Thus, the 5 'heterocyclyl group R' in group M of alcohol VI, such as 2-oxo-1-indolinyl, is oxidized to 2,3-dioxo-1-indolinyl.

The alcohol of formula V may be prepared by reacting the corresponding α-amino alcohol HN (X) -M-CH 2 OH in the presence of aqueous sodium hydroxide and sodium hydrogen carbonate 10 with sulfur chloride R-SO 2 Cl in dioxane.

The amino alcohol HN (X) -M-CH 2 OH, where M is e.g. a group CH (CH 2 -R '), can be prepared by cleavage of the corresponding oxazolidine substituted at the 4-position with a protected N atom, e.g. (R) -2,2-Dimethyl-4- (CH 2 -R ') -15 3-oxazolidinecarboxylic acid tert-butyl ester with hydrochloric acid in methanol.

The above oxazolidine can be prepared in a manner known per se, e.g., when R 'is an N-attached heterocyclyl group such as 2-oxolin-20-dolinyl, by reacting the corresponding cyclic amine HR' with (S) -2,2-dimethyl-. 4- (p-tolylsulfonyloxymethyl) -3-oxazolidinecarboxylic acid tert-butyl ester in the presence of a DMF suspension of sodium hydride.

For the preparation of amino acid II wherein R is. , A hydroxyaryl group, may be the corresponding sulfochloride R-SO 2 Cl, /. which OH group is protected, for example as an acetoxy group, may be · · · I ”. first by reaction with acetone HN (X) -M-COOH in acetone. in the presence of aqueous sodium hydroxide, and then • 1 1 * · · · 1 cleave a protecting group, e.g., acetyl, with sodium hydroxide • · · * · 1 1 30 aqueous methanolic solution.

To prepare a guanidine of formula I where X is -CH2COOH, sulfur R-SO2Cl can be prepared. First reacting the H2N-M-COO benzyl ester of the ester; With a salt, e.g., p-toluenesulfonate in a solvent, in the presence of a base such as methylene chloride in the presence of a base such as triethylamine 9 · 9 · 9 · 1 · 9 9 · 105474. The resulting sulfonamide R-SO 2 NH-M-COO-benzyl is then reacted in a solvent such as THF at about -80 ° C in the presence of butyllithium with bromoacetic acid tert-butyl ester. The benzyl group 5 is then selectively cleaved, e.g. by catalytic hydrogenation with Pd / C catalyst in ethanol, from the diester of R-SO 2 N (CH 2 COO-tert-butyl) -M-COO-benzyl 10.

As previously described, the reaction of the resulting acid with a compound of formula III releases a side-chain protected carboxy group as a tert-butyl ester.

The acids R-SO2NHCH (CO-Q) -15 CH2 COOH used as starting materials can be prepared by a) reacting an aspartic acid derivative, e.g.

tert -butoxy-CONHCH (COOH) CH 2 COO-benzyl 20 with a corresponding Q group amine HQ in a solvent such as DMF in the presence of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, ·; ·, b) by formation of the amide formed. 25 ° 1 *. * Tert-Butoxy-CONHCH (CO-Q) -CH 2 COO-benzyl • · · · · · · ·: · Reaction in a solvent such as ethyl acetate with an acid such as hydrochloric acid and then in dioxane nat. aqueous solution of sodium hydroxide, sodium hydrogencarbonate, and sulfur chloride R-SO2Cl, and c) cleavage of the benzyl group of the resulting sulfonamide ··· i · · * R-SO2NHCH (CO-Q) -CH2COO-benzyl • · ·: 35 105474 13 in a solvent such as methanol with an aqueous solution of sodium hydroxide.

The compounds of formulas III, IV and V are novel and as such are subject to the invention. The piperidine derivatives of formula III can be prepared as described below in Examples 1, 2 and 3 from 3-picolylamine when L-NH, or 3-hydroxymethylpiperidine when L = O. Aminomethylmorpholine derivatives of formula III can be prepared by reacting 2-aminomethyl-10 4-benzylmorpholine (J. Med. Chem. 33, 1990, 1406-1413) with di-tert-butyl dicarbonate in dioxane by hydrogenation of the Boc-protected amine in ethanol in the presence of a Pd / C catalyst 2- (tert-butoxycarbonylaminomethyl) morpholine and amidating the latter compound. The hydroxymethylmorpholine derivatives of formula III can be prepared by amidating the corresponding 2-hydroxymethylmorpholine.

Compounds of formula IV are prepared by reacting the corresponding acid II with a compound of formula h-LAQ hi · w • I r! Where W is a protecting group such as Boc or Z, *> e.g. as described above for the reaction between compounds II and III, then removing the protecting group, '·,; / · e.g. with trifluoroacetic acid in methylene chloride, p-tolu -: T: 30 with ethylene sulfonic acid in acetonitrile or with ethyl acetate in hydrogen chloride.

·· .1. Alcohols of formula III1 may be prepared. as in Example 3a) by attaching a protecting group to the N-atom of 3-hydromo "-ylpiperidine, or starting from benzyloxymethyloxy- as described in Example 19a) -c). 1 * · · 14 105474 14 siran to give 2-benzyloxymethylmorpholine and hence e.g. Boc-protected 2-benzyloxymethylmorpholine As described in Examples 6a) -d) and 19d) and e), the resulting alcohol can be converted to the corresponding amine 5 III '.

The amines V can be obtained by cleavage of a benzyloxycarbonyl group, e.g. in ethanol, in the presence of hydrochloric acid with a Pd / C catalyst, to give the corresponding compound of formula I wherein M is, for example, -CH 2 (benzyl-10 OCONH) CH-.

The guanidines of the formula I, their solvates and their salts, inhibit both thrombin-induced platelet aggregation and thrombin-induced plasma fibrinogen clotting. These compounds affect both platelet-induced and plasma coagulation. Thus, in particular, they prevent the formation of thrombosis, but also platelet-rich thrombi, and can be used in the prevention and treatment of diseases such as thrombosis, stroke, myocardial infarction, inflammation and arteriosclerosis. In addition, these compounds have an effect on tumor cells and inhibit metastasis. They can thus also be used as anti-tumor agents.

; In order to obtain the highest specificity • .1 and thus to avoid possible side effects, it is necessary to aim for a different inhibitory effect of the compounds of the invention on the one hand on thrombin and on the other serine proteases. Other tested • • · V; The ratio of trypsin inhibitory activity to thrombin inhibitory activity was taken as a measure of the overall specificity of the compound (q in the table below), in addition to the protease inhibitors, because a variety of inhibitors readily inhibit the non-specific serine protease. trypsin. In order to be able to directly compare the 35 inhibitory effects of thrombin and trypsin with those of various substrates, the inhibitory effect the inhibition constant KA was determined independent of substrate and enzyme concentration.

Specific chromogenic peptide substrates may be used to demonstrate inhibition of the catalytic activity of the above proteases. Inhibition of the amidolytic activity of thrombin and trypsin by the guanidines of the invention was demonstrated as described below.

Measurements were made on microtiter plates at room temperature. 150 µl of buffer (50 mM tris, 100 mM NaCl, 0.1% polyethylene glycol; pH 7.8) and 50 μΐ of DMSO dissolved in 15 buffer and 25 μΐ of human thrombin were added per well of the plate. (0.5 nM final concentration). After 10 minutes of incubation, the reaction was initiated by addition of chromogenic substrate S-2238 (HD-Phe-Pip-Arg-Paranitroanline, Kabivitrum; 10 or 50 μΜ final concentration) and hydrolysis of the sub-20 strate was followed spectrophotometrically on a kinetic microtiter plate reader. For 5 minutes. Ki values were determined from the graphs of the inhibition curves in Biochem. J. 55, 1955, 170-171. The inhibitory effect of trypsin was determined in

I I I

. However, however, the substrate S-2251 I li '.1 (H-D-Val-Leu-Lys-Paranitroaniline) was used at a final concentration of ·200 and 750 μΜ.

The results are shown in the following table: «• · · ...

• · f ...... _____ • · • 1 1 • · 1 1 * 1 1 • a a a I <* «« «• I 1 I 1 ψ • 1 1 • 1 1 ψ ψ 1. «·» • · · 105474 16 5 Product from example 8 9 13a 14i 17b

K i (nM) thrombin 8.55 135 20.8 25 20.7

Kj (nM) trypsin 20075 168700 29200 38000 6300 q 2350 1250 1400 1520 304 10

Product from Example 17c 17f 17j 18f

Ki (nM) thrombin 58 41.3 26.1 16 15 Ki (nM) trypsin 10000 18300 14800 18850 q 172 455 565. 1180 20

The guanidines of the formula I are of low toxicity. Thus, the products of Examples 8, 13a, 14i and 18f, when administered intravenously to mice, have a toxicity (30-50 mg / kg).

Medicaments containing a guanidine, a solvate thereof or a 'salt thereof of the formula I are prepared by a process wherein one or more of these compounds are combined, if desired together with one or more other therapeutically valuable substances, into a galenic formulation. The pharmaceutical formulations may be in the form of a gastrointestinal tract, e.g., in the form of tablets, lacquers, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. na, or rectal suppositories form to take «· · · ;; / 35 cigars, or spray form to take. However, the uplift of the drug can also be performed outside the digestive tract, e.g. in the form of injection solutions.

For the manufacture of tablets, lacquers, dragees and hard gelatine capsules, the active ingredient may be admixed with pharmaceutically inert, inorganic or organic excipients. As such excipients, tablets, lacquer tablets, dragees and hard gelatine capsules may be used. lactose, corn starch or derivatives thereof, talc, stearic acid or its salts. Suitable excipients for soft gelatine capsules include, for example, vegetable oils, waxes, fats, semi-solids and liquid polyols; however, depending on the properties of the active ingredient, the use of a filler is not always necessary. Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose, water, alcohols, polyols, glycerol and vegetable oils suitable for injection solutions, and natural or hardened oils, waxes, fats, semi-solids or liquid poly-20 ol. The pharmaceutical preparations may additionally contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, dyes, flavors, salts for varying the osmotic pressure, buffers, coatings or antioxidants.

• · »'m.'m For the prevention or treatment of the aforementioned diseases'' 1. The dosage of the active ingredient may vary within wide ····· _______ - - ranges, and will of course be determined in each individual case according to individual circumstances.

In general, for oral or parenteral administration, the adult human dose is 9 to 9 mg / kg, preferably about 0.1 to 20 mg / kg, preferably about 0.5 to 4 mg / kg / day; said upper limit may, where appropriate. '. also exceed or fall below.

The preparation of compounds of formula III is described in Examples 1-4 and 60A).

* · · • · · • «·« · · 1 105474 18

Example 1 a) To a solution of 3-picolylanine (30 g) in dioxane (300 ml) is added a solution of di-tert-butyl dicarbonate (66.6 g) in dioxane (200 ml) so that the temperature does not rise above 25 ° C. The reaction mixture is stirred at room temperature for 3 hours, then evaporated to dryness. The residue is filtered through silica gel eluting with ethyl acetate to give 55.5 g of 3-tert-butyloxycarbonyl-picolylamine.

B) 45.5 g of 3-tert-butyloxycarbonylpicolylamine are dissolved in 220 ml of methanol and hydrogenated at 10,000 kPa with a 5% ruthenium / aluminum catalyst (4.6 g) at 60 ° C. The catalyst is filtered off and the solvent is evaporated, yielding 46 g of ras-3-tert-butyloxycarbonylaminomethyl-piperidine.

c) Dissolve 38.8 g of the product obtained in b) in dimethylformamide (900 ml) and add 74.5 ml of triethylamine to the solution. 26.5 g of formamidine sulfonic acid are then added and the reaction mixture is stirred for 15 hours, then the mixture is filtered. The mother liquor is evaporated to dryness, the residue is dissolved in water and the solution is shaken with ethyl acetate. The aqueous phase is evaporated to dryness and the product is azeotroped with ethanol, toluene and diethyl chloroethane. The residue is slurried in ether and filtered. 44.0 g of ras-3-tert-butoxycarbonylaminomethyl-1-amidinopiperidine hemisulfite are obtained, MS: 257 ··· * (M + +1), 201, 157, 126, 96.

(d) Dissolve 27.8 g of the product obtained in (c) in 70 µl of 30 ml of methylene chloride and add 70 ml of trifluoroacetic acid and the mixture at 0 ° C. stir for one hour. The reaction mixture is evaporated to dryness. and evaporating the residue azeotropically with toluene and ethanol. 27.6 g of ras-3-aminomethyl-1-amine are obtained (4 m).

Ml * · I I I I · · • * f 19 105474 Dinopiperidine Sulphite, MS: 156 (M1), 126 (M1 -CH2NH2), 69, 45.

Example 2 To a solution of ras-3-hydroxymethylpiperidine (5.3 g) in dimethylformamide (100 mL) is added 19 mL of triethylamine. 6.8 g of formamidine sulfonic acid are then added and the reaction mixture is stirred for 15 hours. The suspension is filtered, the precipitate washed with ether and dried. 10.3 g of ras-3-hydroxymethyl-1-amidinopiperidine-hemi-10 sulfite are obtained, MS: 158 (M + 1), 143, 116, 102; mp. 100 eC.

Example 3 a) To a solution of ras-3-hydroxymethylpiperidine (92.9 g) in dioxane (1500 ml) is added a solution of di-tert-butyl dicarbonate (211.2 g) in 500 ml of dioxane so that the temperature does not rise above 25 ° C. eC. The reaction mixture is stirred at room temperature for 15 hours, then evaporated to dryness. The residue is slurried in 800 ml of hexane and filtered. 120.7 g of ras-N-tert-butyloxycarbonyl-3-hydroxymethylpiperidine are obtained, m.p. 78 ° C.

B) To a solution of the product obtained in (a) (100 g) in methylene chloride (4000 ml) is added 56.2 pyridine and the mixture is cooled to 0 ° C. Then 58.3 ml of butyric chloride is added dropwise so that the temperature does not rise above 10 ° C. The reaction mixture is then stirred for 15 hours at room temperature. The suspension is filtered, the filtrate is evaporated and ethyl acetate is added to the residue. The organic phase is washed with 10% aqueous CuSO4, dried and evaporated. The residue is filtered through silica gel eluting with hexane / ethyl acetate (8: 2). 119.7 g of ras-3- (butyroxymethyl) -1-piperidinecarboxylic acid tert-butyl ester are obtained.

. ·· 1. c) 116.6 g of the product of b) is emulsified in 0.1m ··· _ ___

NaCl solution (2 L) and 0.1 M sodium phosphate buffer (pH 3)

7.0, 80 mL). The pH is adjusted with 1.0 M NaOH solution: 1: 1 ·: 35 to 7.0 and the reaction is initiated by adding 1.00 g of Pseudo-1 · 1 · 1 · 1 · 1 · 1 · 2 · 105754 monas fluorescens lipoprotein lipase (Lipase P-30, Amano) in 10 ml of 0.1 ml NaCl solution. The pH is maintained at 7.0 by the addition of 2.0 M NaOH solution while stirring. After 14 hours, the reaction is quenched with 500 mL of methylene chloride, the reaction mixture is extracted with methylene chloride, and the organic phase is dried and evaporated. Chromatography of the residue on silica gel eluting with hexane / ethyl acetate gives 36.6 g of [S] -3-hydroxymethyl-1-piperidinecarboxylic acid tert-butyl ester, m.p. 89-90 ° C, [α] 3655 - + 53.5 ° (c = 1.0,

EtOH).

d) The ester fraction of c) is emulsified in a mixture of 0.1 M NaCl solution (1.15 L) and 0.1 M sodium phosphate buffer (pH 7.0, 45 mL) and 0.50 of Lipase P is added to the emulsion. -30 in 5 ml of 0.1 M NaCl solution. The pH is maintained at 7.0 by the addition of 2.0 M NaOH solution with stirring. After 40 hours, the reaction is quenched by the addition of 400 ml of methylene chloride, the reaction mixture is extracted with methylene chloride and the organic phase is dried and evaporated. Chromatograph the residue on silica gel, eluting with hexane / ethyl acetate, to give 49.5 g of [R] -3- (butyryloxymethyl) -1-piperidinecarboxylic acid tert-butyl ester. It is dissolved in 250 ml of ethanol, 88 ml of 2M NaOH solution are added to the solution and the reaction mixture is stirred for 1 hour; After 25 nights, the mixture is evaporated to dryness. The residue is taken up in 200 ml of methylene chloride and washed with water, the aqueous siphase is extracted with methylene chloride and the organic phase is dried and evaporated. Chromatography of the residue on silica gel eluting with hexane / ethyl acetate 30 gives 33.7 g of [R] -3-hydroxymethyl-1-piperidinecarboxylic acid tert-butyl ester, [α] 36 = 5 - 60.7® .2 ·. (c-1.0, EtOH).

4 4 f e) A solution of the product of d) (5.0 g) in 20 ml of methylene chloride is cooled to 0 ° C and 15 L of solution are added. '35 ml of trifluoroacetic acid. After 2 hours, reaction mixture 1 · · »»

V

Evaporate, add water and sodium hydrogen carbonate to pH 7.5. The resulting aqueous phase is evaporated to dryness and the crystalline residue obtained is slurried in methylene chloride / ethanol (9: 1). The salts are filtered off and the filtrate is evaporated. The residue is dissolved in 30 ml of dimethylformamide and 9.7 ml of triethylamine are added. 3.5 g of formamidine sulfonic acid are then added and the reaction mixture is stirred for 15 hours. The precipitate is filtered off and the solvent is evaporated. The residue is purified by reverse phase chromatography on silylated silica gel RP-18 using water for elution. 2.6 g of (R) -3-hydroxymethyl-1-amidinopiperidine hemisulfate are obtained, FAB-MS: 158 (M + 1).

Example 4 In analogy to Example 3e), [S] -3-hydroxymethyl-1-piperidinecarboxylic acid tert-butyl ester is prepared from (S) -3-hydroxymethyl-1-amidinopiperidine hemisulfate, FAB-MS: 158 (M +). l).

Example 5 To a solution of N- (2-naphthylsulfonyl) -D-tryptophan (1.5 g) in dimethylformamide (30 mL) is added 1.5 mL of ethyl morpholine. Then 0.7 g of ras-3-aminomethyl-1-amidinopiperidine dihydrogen sulphite (Example 1) and 1.7 g of benzotriazol-1-yloxy-tris (dimethylamino) -phosphonium N-hexafluorophosphate are added and the reaction mixture is stirred for 15 hours. »; acetate. The solvent is evaporated, the residue is dissolved in 50 ml of water, and the solution is extracted with ethyl acetate (100 ml). The ethyl acetate phase is washed with water, dried and evaporated. The crude product is purified on a RP-18 column with water / acetonitrile mixtures (0-30%). 0.8 g of (R) -N- is obtained. ..

[(RS) -1-Amidino-3-piperidinylmethyl] -α- (2-naphthylsulphonamido) -indole-3-propionamide bisulphite, FAB-MS: 533 (μ + ηγ.

• *

IM

• · • I «• I i III» »* •» • • • • • • • • * m «* •« * • «f t * 105474 22

Example 6 a) To a solution of (S) -3-hydroxymethyl-1-piperidinecarboxylic acid tert-butyl ester (Example 3c) (5.0 g) in 100 ml of pyridine is added 5.4 g of p-chloro-sulfonyl chloride. The reaction mixture is stirred for 15 hours, the mixture is evaporated, the residue is taken up in 200 ml of ethyl acetate and washed with water and 10% aqueous CuSO4. The organic phase is dried and evaporated. The residue is filtered through silica gel eluting with hexane / ethyl acetate (8: 2). 6.5 g of (S) -3- (p-chlorophenylsulfonyloxymethyl) -1-piperidinecarboxylic acid tert-butyl ester are obtained.

b) To a solution of the product of a) in dimethylformamide (50 ml) is added 3.25 g of sodium azide. The reaction mixture is stirred at 50 ° C for 15 hours, then evaporated to dryness. Water and ether are added to the residue and the ether phase is washed with water, dried and evaporated. 4.0 g of (S) -3-azidomethyl-1-piperidinecarboxylic acid tert-butyl ester are obtained.

C) A solution of the product of b) in ethanol (100 ml) is hydrogenated under 100 kPa hydrogen in the presence of PtO catalyst (0.6 g). The reaction mixture is then filtered over silica gel using methanol for elution. 3.4 g of (R) -3-amino-n-methyl-1-piperidinecarboxylic acid tert-butyl ester are obtained, [α] D = + 23.0 ° (c = 0.4, EtOH). .

* · 1 · d) By the same method, (R) -3-hydroxy-4-dimethyl-1-piperidinecarboxylic acid tert-butyl ester is obtained from (S) -3- aminomethyl-1-piperidinecarboxylic acid: m.p. = tert-butyl ester, [α] D = -17.7 ° (c = 0.6, EtOH).

E) To a solution of N- (2-naphthylsulfonyl) -D-tryptophan (1.5 g) in 50 ml of dimethylformamide is added 0.8 ml of ethyldiisopropylamine. Then 1.0 g of d) · · · ··· is added. of the product and 1.7 g of benzotriazol-1-yloxytris (dimethyl • · · amino) phosphonium hexafluorophosphate and the reaction mixture are stirred for 15 hours. The solvent is evaporated and the residue is dissolved in water and extracted with ethyl acetate. The ethyl acetate acetate phase is washed with water, dried and evaporated. The residue is chromatographed on silica gel using ethyl acetate as the eluent to give 2.3 g of 5 (R) [(S) -1- (tert-butoxycarbonyl) -3-piperidinylmethyl] -α-naphthylsulfonamidoindole-3-propionamide.

f) To a solution of the product of e) in 10 ml of methylene chloride is added 3 ml of trifluoroacetic acid at 0 ° C. The reaction mixture is stirred for 1 hour at 0 ° C, the mixture is evaporated and the residue is azeotropically evaporated with ethylene chloride. Water and ethyl acetate are added to the residue, the pH is adjusted to 9 with 10% Na 2 CO 3 solution and the mixture is shaken. The organic phase is dried and evaporated. 2.5 g of (R) -α-naphthylsulfonamido-15 N - [(S) -3-piperidinylmethyl] indole-3-propionamide are obtained.

g) To a solution of the product of f) in 50 ml of dimethylformamide is added 1.7 ml of triethylamine. Then 0.7 g of formamidine sulfonic acid is added and the reaction mixture is stirred for 15 hours. The solvent is evaporated and ethyl acetate and methanol are added to the residue. The organic phase is washed with water, dried and evaporated. Purification of the product on a RP-18 column with water / acetonitrile gives 1.85 g of (R) -N - [(S) -1-amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) indole-3-propionamide bisulfite, V 25 FAB-MS: 533 (M + H) +.

EXAMPLE 7 * (a) To a solution of N- (2-naphthylsulfonyl) - (D) -tryptophan • · (1/0 g) in dimethylformamide (20 mL) is added • ___________________ 0.5 mL of ethyl diisopropylamine. Then 0.6 g of:: (S) -3-hydroxymethylpiperidine carboxylic acid tert-butyl ester (Example 3c) and 1.1 g of benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate are added. And the reaction mixture is stirred for 15 hours. Solvent haih- 0 ____________ ...

The solution is dissolved in 50 ml of water and the solution is extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, and evaporated. The crude product is purified on silica gel using ethyl acetate to give 1.0 g of N- (2-naphthylsulfonyl) -D-tryptophan (S) -1-tert-butoxycarbonyl-3-piperidinyl-5-methyl ester.

b) To a solution of the product of a) in acetonitrile (10 ml) is added 0.9 g of p-toluenesulfonic acid. The reaction mixture is stirred for 15 hours. The mixture is evaporated, the residue is dissolved in ethyl acetate and the solution is washed with saturated NaHCO 3 solution. The organic phase is dried and evaporated. Purification on an RP column eluting with water / acetonitrile gives 0.47 g of N- (2-naphthylsulfonyl) -D-tryptophan (S) -3-piperidinylmethyl ester.

c) To a solution of the product of b) in 20 ml of dimethylformamide is added 0.4 ml of triethylamine. 0.2 g of formamidine sulfonic acid are then added and the reaction mixture is stirred for 15 hours. The DMF is evaporated, ethyl acetate is added to the residue and the mixture is washed with water. The organic phase is dried and evaporated. Purification on an RP column using water / acetonitrile as eluent gives 0.27 g of N- (2-naphthylsulfonyl) -D-tryptophan (S) -1-amidino-3-piperidinylmethyl ester bisulfite, FAB-MS: 534 (M + l).

Example 8 25 a) (R) -4-Hydroxymethyl-2,2-dimethyl-3-oxazolidinecarboxylic acid tert-butyl ester (J. '**, Org. Chem. 5Z, 1987, Z36I-64) (10.7 g) ) to a solution of pyridine (107 mL) is added 9.7 g of p-toluenesulfonic acid chloride. The reaction mixture is stirred for 17 hours, then ethyl acetate is added and the mixture is washed with water, dried and evaporated. The residue is purified on silica gel eluting with hexane / ethyl acetate (3: 1). 15.1 g of (S) -2,2-dimethyl-4-p-tolylsulfonyloxy- (methyl) -3-oxazolidinecarboxylic acid tert-butyl ester are obtained.

B) To a suspension of sodium hydride (0.82 g) in 50 ml of dimethylformamide is added 4.6 g of 2-indolinone and the mixture is stirred for 90 minutes. 6.6 g of product a) in 60 ml of dimethylformamide are then added at 50 ° C overnight. The solvent is evaporated, the residue is dissolved in ethyl acetate and the solution is washed with water, dried and evaporated. The residue is purified on silica gel eluting with ethyl acetate / hexane (1: 4). 2.5 g of (R) -2,2-dimethyl-4- (2-oxo-1-indol-10-ylmethyl) -3-oxazolidinecarboxylic acid tert-butyl ester are obtained.

c) To a solution of the product of b) (2.5 g) in 30 ml of methanol is added 36 ml of 2M hydrochloric acid and the mixture is stirred overnight. The solvent is evaporated and the residue is azeotroped with toluene. 1.56 g of the resulting 1 - [(R) -2-amino-3-hydroxypropyl] -2-indolinone are dissolved in 2 equivalents of 1 M NaOH solution. To the solution is added 0.8 g of sodium hydrogencarbonate in 8.1 ml of water followed by a solution of 2-naphthylsulphochloride (1.46 g) in 28 ml of dioxane and the mixture is stirred overnight. The reaction mixture is poured into a mixture of 5% aqueous potassium hydrogen sulfate and 10% aqueous potassium sulfate solution (200 mL) and extracted with ethyl acetate. The organic phase is washed with water, dried and the solvent is distilled off. Residue Blow! The residue is purified on silica gel using methylene chloride 1: 98: 2 as the eluent. 1.9 g of N - [(R) -2-hydroxy-9S-1- (2-oxo-1-indolinylmethyl) ethyl] -2-naphthylsulphonamide are obtained.

d) To a solution of the product of c) (1.82 g) in 70 ml of acetone, add 30.4 g of 17.4 ml of Jones reagent in 0 "Cr and stir for 4 hours. The reaction mixture is poured onto ice and extracted with ethyl acetate. The organic phase is washed with water, 1'1 ', dried and evaporated and the product is purified on silica gel eluting with methylene chloride / methanol (19: 1) and 1% acetic acid.

• I I

1.5 g of N- (2-naphthylsulfonyl) -3- (2,3-dioxo-1-indolinyl-11) -D-alanine.

e) In analogy to Example 5, the product of d) is obtained from (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -5? - (2-naphthylsulfonamido-2,3-dioxo-1-indoline propionamine). diacetate (1: 1 epimers), FAB-MS: 671 (M + H) *.

Example 9 a) To a solution of (R) -phenylalanine (7.3 δ) in 1M NaOH (120 mL) is added 20 g of 2-naphthylsulfochloride in 10 150 mL of ether. After stirring for 15 hours, decant. The aqueous phase is separated, washed with ether, acidified to pH 3 with hydrochloric acid and extracted with ethyl acetate. The organic phase is dried and evaporated. The precipitated crystals are slurried in ether and filtered. 14.4 g of N- (2-naphthylsulfonyl) -3-phenyl-D-alanine are obtained, m.p. 146 ° C.

(b) The following N-sulfonated amino acids are prepared by an identical method:

N- (2-naphthylsulfonyl) -3-p-chlorophenyl-D-alanine, mp. 20 154 eC

N- (2-naphthylsulfonyl) -3-p-cyanophenyl-D-alanine, mp. 182 ° C

N- (2-naphthylsulfonyl) -3-p-nitrophenyl-D-alanine, m.p.

218 eC

• «*; , 25 N- (2-naphthylsulfonyl) -3-benzyl-D-alanine, m.p.

* · „138 eC

* ·! * N- (2-naphthylsulfonyl) -D-tryptophan, m.p. 167 eC

* '*: N- (4-biphenylsulfonyl) -D-tryptophan, m.p. 227-230 eC

: .i .: N- (2-Anthrylsulfonyl) -D-tryptophan, m.p. 210 ° C

: ί: 30 N- (4-nitrophenylsulfonyl) + D-tryptophan, MS: M * 389

N- (2-nitrophenylsulfonyl) -D-tryptophan, m.p. 70-80 ° C N- (3-nitrophenylsulfonyl) -D-tryptophan, m.p. 80-84 ° C

• · «. ···. N- (4-Benzyloxyphenylsulfonyl) -D-tryptophan, m.p.

193 ° C

• * · • · «« «· · • • • • • • • • • • • * 105474 27

N- (3,4-dimethoxyphenylsulfonyl) -D-tryptophan, m.p. 182-184 ° C

N- (2,3,6-trimethyl-4-methoxyphenylsulfonyl) -D-tryptophan, MS: M1 416 5 N- (2,4,6-triisopropylphenylsulfonyl) -D-tryptophan, MS: M + 470 N - (2-naphthylsulfonyl) -5-methyltryptophan, m.p. 192 ° C (R) -2- (2-naphthylsulfonyl) + 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, m / e 322, 191 , 176, 150, 127.

C) In analogy to Example 5, the product of (a) is obtained from (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) hydro-cinnamamide bisulfite (epi-1s), FAB-MS: 494 (M + H) +.

Example 10 15 a) 1.1 g of a 60% dispersion of sodium hydride are slurried in 50 ml of dimethylformamide. 5.23 8 4-Methyl-3- {-1,4-benzodiazepine-2,5 (1H, 4H) -dione is added thereto without raising the temperature to 35 ° C, and the mixture is stirred for 90 minutes at room temperature. A solution of 20 (S) -2,2-dimethyl-4- (p-tolylsulfonyloxymethyl) -3-oxazolidinecarboxylic acid tert-butyl ester (Example 6a) (5.3 g) in 50 ml of dimethylformamide is then added and the mixture is stirred overnight at 50 ° C. ° C. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, washed with 1 L of water and dried. The solvent is evaporated and the residue * .1 is purified on silica gel using an ethyl acetate / hexane / hexane (1: 1) mixture as eluent. 1.85 g of (R) - (2,3,4,5- * 'tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepin-1-ylmethyl) -2,2- dimethyl 3-oxazolidinecarboxylic acid * -?: 30 pert-butyl ester.

b) To a solution of the product of a) in 37 ml of methanol is added 23 ml of 2M hydrochloric acid. After stirring overnight, the reaction mixture is evaporated. 1.37 g of the resultant 1 - [(R) -2- (4-amino-3-hydroxypropyl) -3,4-dihydro-4-methyl-2H-1,4-d] benzodiazepine-2,5 ( 1H) -dione is dissolved in 15 ml of pyridine.

105474 28 Ridine and 2.08 g of 2-naphthylsulfochloride are added to the solution. After 3 hours, the reaction mixture is poured into 2N hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and the solvent is evaporated. The residue is purified on silica gel using methylene chloride / methanol (97: 3) for the elution. 0.5 g of N - [(R) -1-hydroxymethyl-2- (2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepine-1) are obtained. -ylmethyl) ethyl] -2-naphthyl-lisulfonamidia.

C) To a solution of the product of b) (0.4 g) in 12 ml of acetone at 0 ° C is added 3 ml of Jones reagent. After stirring at room temperature for 3 hours, the reaction mixture is poured onto ice and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to give 0.4 g of 15 N- (2-naphthylsulfonyl) -3- (2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1). 4-benzodiazepin-1-yl) -D-alanine.

d) In analogy to Example 5, the product of (c) is obtained from (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -1,2,3,4-tetrahydro-2-methyl-α- (2) naphthylsulfonamido) 1,4-20 dioxo-5H-2,5-benzodiazepine-5-propionamide (1: 1 epimers), FAB-MS: 606 (M + H) +.

Example 11 a) To a solution of D-tryptophan (0.9 g) in a mixture of 1 M NaOH (4.8 mL) and acetone (4.8 mL) is added dropwise 6- (1'25 acetoxynaphthyl-2-sulfonyl chloride (Monazh. 49, 1928, <· .1 ·: 96) (1.25 g) in acetone (4.4 ml) and the pH of the mixture is kept at 9 by the addition of 1M NaOH solution. The acetone * is then evaporated. , the resulting suspension is acidified with 1M hydrochloric acid and the product is extracted with ethyl acetate.

• M

Chromatograph on silica gel, eluting with ethyl acetate / acetone (1: 1). The main fraction is added at 0.5 m ···. NaOH-methanol (8.8 mL) and the solution is stirred for 17 hours. The solution is evaporated, water and 1M hydrochloric acid are added and it is extracted with ethyl acetate. Purification: by distillation on silica gel using ethyl acetate as eluent.

Acetone / Acetone (3: 2) mixture gives 0.54 g of N- (6-hydroxy). -2-naphthylsulfonyl) -D-tryptophan, MS: M1 410 m / e 207, 130.

b) By analogy to Example 5, the product of a) 5 is obtained from (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -? - (6-hydroxy-2-naphthylsulfonamido) indole-3-propionamide. hydrochloride (1: 1 epimers), FAB-MS: 549 (M + H) 1.

Example 12

In analogy to Examples 5 and 9, the following compounds are prepared: a) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -p-fluoro-α- (2-naphthylsulfonamido) hydro-cinnamamide-bisulfite ( epimers 1: 1), FAB-MS: 512 (M + H) 1.

b) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -15-chloro-α- (2-naphthylsulfonamido) hydro-cinnamamide bisulfite (1: 1 epimers), FAB-MS: 528 (M + H) @ +.

c) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -p-cyano-α- (2-naphthylsulfonamido) -hydro-cinnamamide-bisulfite (1: 1 epimers), FAB-MS: 519 (M + H) @ +.

D) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -? - (2-naphthylsulfonamido) -? - nitrohydro-cinnamamide-bisulfite (1: 1 epimers), FAB-MS: 539 (M + H) + 1.

e) (R) -? - amino-N - [(RS) -1-amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) -hydro-cinnamamide-bisul-; 25 phytes (1: 1 epimers), FAB-MS: 509 (M + H) 1.

* / f) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -1H, 3'- (p-hydroxyphenyl) -2- (2-naphthylsulfonamido) -propion- amide bisulfite (epimers 1: 1), FAB-MS: 510 (M + H) 1.

Example 13 ϊ 30 In analogy to Examples 5 and 9, the following compounds are prepared: a) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] - • · · · · · α- (2-naphthylsulfonamido) -o-nitrohydro-cinnamamide bisulfite (1: 1 epimers). FAB-MS: 539 (M + H) -.

• · · • 1 1

Mt · • • »• • • • • • • • • • · · · · 105474 30 b) (R) -N - [(RS) -1-Amidino-3 -piperidinylmethyl] -α- (2-naphthylsulfonamido) -cyclohexane-propionamide-bisulfite (1: 1 epimers), FAB-MS: 500 (M + H) + (c) (R) -N - [(RS) -1- amidino-3-piperidinylmethyl] -α- (5-naphthylsulfonamido) -4-phenylbutramide bisulfite (1: 1 epimers). FAB-MS: 508 (M + H) +.

d) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -a-2-naphthylsulfonamido) cyclohexane-butyramide-bisulfite (epimers 1: 1), FAB-MS: 514 (M + H) 10e) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) -1-naphthylpropionamide bisulfite (1: 1 epimers), FAB -MS: 586 (M + H) -1f) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) -2-naphthylpropionamide bisulfite 15 (Epimers 1: 1), FAB-MS: 544 (M + H) +.

g) (aR, 2S, 4aR and / or S, 8aR and / or S) -N - [(RS) -1-amidino-3-piperidinylmethyl] -decahydro-α- (2-naphthylsulfonamido) - 2-Naphthylpropionamide bisulfite (mixture of diastereomers), FAB-MS: 554 (M + H) +.

20 h) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) -4-imidazole-propionamide-bisulfite (1: 1 epimers), FAB-MS: 484 (M + H) + 1.

i) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl-α- (2-naphthylsulfonamido) -2-thienylpropionamide bisulfite] 25 (Epimers 1: 1), FAB-MS: 500 (M + H) +.

Example 14 In a manner analogous to Examples 5 and 11, the following compounds are prepared: p. ·. (a) (R) -N- [(RS) -1-amidino- 3-piperidinylmethyl] -α: T: 30 (3-methyl-8-quinoline sulfonamido) indole-3-propionamide bisulfite (1: 1 epimers). FAB-MS: 548 (M + H) -.

·· .1. b) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -o · · · · · ·. [(RS) -3-Methyl-1,2,3,4-tetrahydro-8-quinoline sulfonamido] indole-3-propionamide bisulfite (Epimers 1: 1). FAB-: ·: · j 35 MS: 552 (M + H) 1.

(R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] ] -a- (4-biphenylsulfonamido) indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS: 559 (M + H) 1.

d) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -5α- (2-anthrylsulfonamido) indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS: 583 (M + H) @ +.

(e) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (5- (1-methyl-5-trifluoromethylpyrazol-3-yl) -2-thienylsulfonamido) indole; 3-propionamide bisulfite (epi-10 mers 1: 1), FAB-MS: 637 (M + H) 1.

f) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (p-iodobenzenesulfonamido) indole-3-propionamide hydrochloride (Epimers 1: 1), FAB-MS: 609 (M + H) + 1.

g) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -15α- (o-iodobenzenesulfonamido) -indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS : 608 (M + H) +.

h) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -α- (p-nitrobenzenesulfonamido) indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS: 528 (M + H) + 1.

(I) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -? - (o-nitrobenzenesulfonamido) indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS: 528 (M + H) @ +.

j) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -,, α- (m-nitrobenzenesulfonamido) indole-3-propionamide hydrochloride (1: 1 epimers), FAB -MS: 528 (M + H) @ +.

(1) · (k) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] - *: · 1α- (p-Benzyloxybenzenesulfonamido) -indole-3-propionamide hydrochloride (epimers) 1: 1), FAB-MS: 589 (M + H) -.

J 1) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -30a- (3,4-dimethoxybenzenesulfonamido) -indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS: 543 (M + H) -.

. · 2. m) (R) -N-ITRST-1-imidino-3-piperidinylmethyl] - ···. , ···. α- (4-methoxy-2,3,6-trimethylbenzenesulfonamido) indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS: 555:: 35 (M + H) 1.

• i) >47 >47 I>> 2 2 2 2 2 105 105 105 105 105 10547 10547 105 1054747 10547 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 10547 105 105 105 105 105 105 105 105 105 10547 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 10547 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 10547 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 105 (2,4,6-triisopropylbenzenesulfonamido) indole-3-propionamide hydrochloride (1: 1 epimers), FAB-MS: 609 (M + H) *.

Example 15 In analogy to Example 5, the following compounds are prepared: a) (RS) -N - [(RS) -1-amidino-3-piperidinylmethyl] -5-methyl-α- (2-naphthylsulfonamido) indole-3- propionamide bisulfite, FAB-MS: 547 (M + H) *.

B) (RS) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -5-fluoro-α- (2-naphthylsulfonamido) indole-3-propionamide bisulfite, FAB-MS: 551 ( M + H) +.

c) 3 - [(R) -2 - [(RS) -1-Amidino-3-piperidinylmethylcarbamoyl] - (2-naphthylsulfonamido) ethyl] indole-1-acetic acid bisulfite, (Epimers 1: 1) ), FAB-MS: 591 (M + H) +.

Example 16

By analogy to Example 6 or 7, the following are obtained: a) (R) -N - [(R) -1-Amidino-3-piperidinylmethyl] -α- (2-naphthylsulfonamido) indole-3-propionamide bisulfite, FAB-MS: 533 (M + H) * or b) N- (2-naphthylsulfonyl-D-tryptophan (R) -1 - [(RS) -1-amidino-3-piperidinylmethyl ester-p-toluene sulfonate, respectively) (Epimers 1: 1), FAB-MS: 534 (M + H) +.

Example 17 In analogy to Examples 6 and 7, the following compounds are obtained: a) (R) -N - [(R) -1-amidino-3-piperidinylmethyl] -α- (p-iodobenzenesulfonamido) indole 3-propionamide-p-toluene: 1: 1 ene sulfonate, FAB-MS: 609 (M + H) *.

B) (R) -N - [(S) -1-Amidino-3-piperidinylmethyl] -α- (p-iodobenzenesulfonamido) -indole-3-propionamide-p-toluene ·· *. enen sulfonate (1: 1), FAB-MS: 609 (M + H) *.

«·. ···. c) N- (p-iodophenylsulfonyl) -D-tryptophan- (R) -1-amidino-3-piperidinylmethyl ester-p-toluenesulfo- • i. : 35 Nate (1: 1), FAB-MS: 609 (M + H) *.

D) N- (p-iodophenylsulfonyl) -D-tryptophan- (S) -? -? -? -? -? -? 1-amidino-3-piperidinylmethyl ester p-toluenesulfonate (1: 1), FAB-MS: 610 (M + H) +.

e) (R) -N - [(R) -1-Amidino-3-piperidinylmethyl] -α- (5-p-iodobenzenesulfonamido) -2-naphthylpropionamide-p-toluenesulfonate (1: 1), FAB-MS: 620 (M + H) @ +.

f) (R) -N - [(S) -1-Amidino-3-piperidinylmethyl] -α- (p-iodobenzenesulfonamido) -2-naphthylpropionamide-p-toluenesulfonate (1: 1), FAB-MS: 620 (M + H) + 1.

10 g) N- (p-iodophenylsulfonyl) -3- (2-naphthyl-D-alanine (R) -1-amidino-3-piperidinylmethyl ester p-toluenesulfonate (1: 1), FAB-MS : 621 (M + H) -1 h) N- (p-iodophenylsulfonyl) -3- (2-naphthyl-D-alanine (S) -1-amidino-3-piperidinylmethyl ester p-toluenesulfonate) 1: 1), FAB-MS: 621 (M + H) -1) (R) -N - [(R) -1-Amidino-3-piperidinylmethyl] -α- (pyridobenzenesulfonamido) -p-nitrohydro-cinnamide- bi-sulfite (1: 1), FAB-MS: 615 (M + H) 1.

j) (R) -N - ((S) -1-Amidino-3-piperidinylmethyl] -α- (p-iodobenzenesulfonamido) -p-nitro-hydro-cinnamamide-bisulfite (1: 1), FAB-MS: 615 ( M + H) k) N- (p-iodophenylsulfonyl) -3- (p-nitrophenyl) -D-alanine (R) -1-amidino-3-piperidinylmethyl ester p-toluenesulfonate (1: 1), FAB-MS: 616 (M + H) -.

25 1) N- (p-iodophenylsulfonyl) -3- (p-nitrophenyl-D- • alanine (S) -1-amidino-3-piperidinylmethyl ester-p-to-M · 1 luenesulfonate (1: 1), FAB -MS: 616 (M + H) -.

"2 Example 8J, j: In analogy to Example 5, the following compounds are prepared: a) (R) -Nt (RS) -1-amidino-3-piperidinylmethyl] -hexahydro-a-2-naphthylsulfamido - γ-oxo-1H-at sepine-1 · ···, butyramide-bisulfite (epimer 1: 1), FAB-MS: 543 (M + H) 1.

ti · • «• 1 1« f «

Mt · »♦ · • ·« ·

B) 1 - [(R) -N - [(RS) -1-Amidino-3-piperidinylmethyl-carbamoyl] -3- 2-naphthylsulfonamido) propionyl] -L-pro-methyl methyl ester (1: 1 epimers), FAB-MS: 573 (M + H) +.

c) 1 - [(R) -N - [(RS) -1-Amidino-3-piperidinylmethyl-5-lecarbamoyl] -3- (2-naphthylsulfonamido) propionyl] -L-proline (1: 1 epimers), FAB- MS: 559 (M + H) &lt; + &gt;.

d) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -3,4-dihydro-α- (2-naphthylsulfonamido) -γ-oxo-2 (1H) -isoquinoline butyramide (Epimers) 1: 1), FAB-MS: 577 (M + H) +.

E) (RS) -N - [(RS) -1-Amidino-3-piperidinylmethyl) -2- (2-naphthylsulfonamido) -3- (o-nitrobenzoyl) propionamide di-bisulfite, FAB-MS: 567 ( M + H) +.

f) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -3- (o-aminobenzoyl) -2- (naphthylsulfonamido) propionamide 15 (Epimers 1: 1), FAB-MS: 537 ( M + H +) 1.

g) (R) -N - [(RS) -1-Amidino-3-piperidinylmethyl] -3-anthraniloyl-2- (pyridobenzene sulfonamido) propionamide trifluoroacetate (Epimers 1: 1), FAB-MS: 613 (M + H) + 1.

h) (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -3-20 (o-formamidobenzoyl) -α- (2-naphthylsulfonamido) propionamide acetate (1: 1 epimers), FAB-MS: 565 (M + H) &lt; + &gt;. Example 19 a) To 70% NaOH solution (164 ml) add 199 ml of 2-aminoethylhydrogen sulphate, warm it to 25 ° C and add dropwise a solution of (RS) -benzyloxymethyl-1ir-oxirane in 280 ml methanol. After 1 hour at -50 ° C, an additional 280 ml of 70% NaOH solution are added and the '1' solution is stirred overnight. The reaction mixture is then poured onto ϊ51ϊ on ice and extracted with toluene. The organic phase is washed with water, dried and evaporated. Distillation of residue 9 gives 26.8 g of ras-2-benzyloxymethylmorpholine, MS: ···. M1 -91 = 116 (benzyl).

To a product of (a) (26.8 g) in 287 ml of dioxane add a solution of di-tert-butyl dicarbonate (31.0 g) I i «1 1 # · · IM« M) I « • · * »1» • · «« »·

• I I

105474 35 287 ml of dioxane and the reaction mixture is stirred overnight. The solvent is evaporated and the residue is chromatographed on silica gel using ethyl acetate / hexane as eluent to give 15 g of tert-butyl ras-2-benzyl-5-oxymethyl-4-morpholine carboxylate, MS: M1-56 = 251 (isobutylene).

c) A solution of b) (15 g) in 300 ml of ethanol is hydrogenated under normal conditions in the presence of Pd / C catalyst (1.5 g), the reaction mixture is filtered and the solvent is evaporated to give a quantitative yield of tert-butyl ras-2- hydroxymethyl 4-morpholine carboxylate, MS: M1 = 217.

d) To a solution of the product of c) (8.8 g) in 44 ml of pyridine is added 9.4 g of p-chlorobenzenesulfochloride. After stirring for 15 hours, the reaction mixture is evaporated, the residue is dissolved in ethyl acetate and the solution is washed with 10% copper sulfate solution. The organic phase is dried, the solvent is evaporated, and the residue is chromatographed on silica gel, eluting with ethyl acetate / 20 hexane, to give 14.7 g of tert-butyl ras-2- (p-chlorophenylsulfonyloxymethyl-4-morpholine carboxylate, MS: 392 ) 1.

e) To a solution of the product of d) (14.7 g) in 91 ml of dimethylformamide is added 7.3 g of sodium azide. After stirring for 24 hours at 50 ° C, the reaction mixture is poured onto ice and extracted with ether. The organic phase is washed with ·: ··· water, dried and evaporated. 8.1 g of tert- are obtained. butyl rac-2-azidomethyl-4-morpholinecarboxylate.

A solution of (e) (8.1 g) in 92 ml of ethanol hydro-. · - 30 ° C under normal conditions in the presence of platinum oxide catalyst ... (0.8 g) for 4 hours and isolating from the mixture 6.5 g of tert-butyl-ras-2-aminomethyl-4-morpholinecarboxylic acid. Cylate, MS: (M + H) 1-56 = 159 (isobutylene).

: g) to a solution of N- (2-naphthylsulfonyl) -D-tryptophan (Example 35) (3.0 g) in 35 ml of dimethylformamide. 1.2 ml 4-ethylmorpholine and 3.4 g benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate are added. To this mixture is added a solution of the product of f) (2.0 g) in 2 ml of dimethylformamide and the solution is stirred overnight. The solvent is then distilled off, the residue is dissolved in ethyl acetate. The solution is washed with water, dried and the solvent evaporated, and the residue is chromatographed on silica gel using ethyl acetate as the eluent to give 4.5 g of tert-butyl (RS) -2-N- (2-naphthylsulfonyl-10 1) -D-tryptophylaminomethyl-4 -morph oline carboxylate, MS: (M + H) 1 -56 = 537 (isobutylene).

h) To a solution of the product of g) (2 g) in 20 ml of ethyl acetate is added 20 ml of a 4M HCl-ethyl acetate solution. The solution is stirred and evaporated to dryness. The residue 15 is dissolved in 20 ml of dimethylformamide, 1.4 ml of triethylamine and 0.5 g of formamidine sulphonic acid are added and the mixture is centrifuged for 17 hours at room temperature. The solvent is then evaporated, 50 ml of ethyl acetate and 10 ml of methanol are added to the residue and the resulting solution is washed with water. The organic phase is dried, the solvent is evaporated and the residue is chromatographed on a RP column (alkylsilylated silica gel) eluting with water / acetonitrile to give 0.1 g of (R) -N - [(RS) -4-amide -2-morpholinylmethyl] -α- (2-naphthylsulfonamido) indole-3-propionamide bisulfite, MS: 535 (M + H) -.

. .1 · Example 20 • · · · · · ·: By analogy to Example 19 (g) and (h). . ·. tert-butyl-ras-2-hydroxymethyl-4-morpholinecarboxylic acid (Example 19c); and N- (2-naphthylsulfonyl) -D- · · · 30 tryptophan (RS) -4-amidino- 2-Morpholinylmethyl ester bisulfite, MS: 536 (M + H) + - Example 21 • · ·

Analogously to Example 19, the following are prepared: 1 · 1 · 1 · 1 · 1 · 1 · 1 · 1 · 105474 37 a) (R) -N - [(RS) -4-amidino-2-morpholinylmethyl] -α- (2-naphthylsulfonyl) -p-nitrohydro-cinnamamide bisulfite, MS: 541 (M + H) - b) (R) -N - [( RS) -4-Amidino-2-morpholinylmethyl] -α- (5-naphthylsulfonamido) -2-thienylpropionamide bisulfite, MS: 502 (M + H) 1.

c) (R) -N - [(RS) -4-Amidino-2-morpholinylmethyl] -3- (o-aminobenzoyl-2- (2-naphthylsulfonamido) propionamide bisulfite, MS: 539 (M + H) 1.

Example 22 a) To a solution of (D) -phenylalanine benzyl ester p-toluene sulfonate (10 g) in 150 ml of methylene chloride is added 8.2 ml of triethylamine and the mixture is cooled to 0 ° C. Then 5.8 g of 2-naphthylsulphochloride are added and stirred for 12 hours at room temperature. The reaction mixture is evaporated and 200 ml of ethyl acetate are added to the residue, the precipitated triethylammonium chloride salt is filtered off and the mother liquor is washed with water. The organic phase is evaporated and the residue is crystallized from hexane to give 9.7 g of 20 N- (2-naphthylsulfonyl) -3-phenyl-D-alanine benzyl ester, m.p. Mp 107 ° C.

b) To a solution of the product of a) (3 g) in 40 ml of tetrahydrofuran is added at -80 ° C 5 ml of a solution of 1,6 m butyl lithium in hexane followed by 1,2 ml of bromoacetic acid tert-butyl ester. . After stirring for 2 hours, the c. at room temperature, 200 ml of ethyl acetate are added to the reaction mixture, the mixture is washed with water and the organic phase is evaporated. The product is purified by chromatography on silica gel using hexane / ethyl acetate 30 (9: 1) for the elution. 1.35 g of N- (tert-butoxycarbonylmethyl) -N- (2-naphthylsulfonyl) -3-phenyl-D-alanine benzyl ester are obtained, NMR (CDCl3) 1.45 (s, 9H, tert. butyl).

··· c) A solution of the product of b) (1.35 g) in 50 ml of ethanol] is hydrogenated in the presence of Pd / C catalyst (0.3 g). reaction

Ml ». ···. The thiol mixture is evaporated and finally azeotroped with toluene to give 0.95 g of tert-butoxycarbonylmethyl) -N- (2-naphthylsulfonyl). -3-phenyl-D-alanine.

d) In analogy to Example 5, N - [(R) -5a - [[(S) -1-amidino-3-piperidinyl] methylcarbamoyl] phenethyl] -N- (2-naphthylsulfonyl) glycine is obtained, FAB-MS : 552 (M + H) +.

Example 23 a) To a solution of N-Boc-L-aspartic acid P-benzyl ester 10 (10.0 g) in 200 ml of dimethylformamide is added 13.7 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate and 16.9 g of of benzylamine and the reaction mixture is stirred overnight at room temperature. The solvent is then evaporated, the residue is dissolved in ethyl acetate and the solution is washed with water. The organic phase is dried, evaporated and chromatographed on silica gel, eluting with ethyl acetate / hexane (1: 4), to give 5.4 g of (S) -3- (1,1-dimethylethoxycarbonylamino) -4-oxo-butyric acid benzyl ester.

B) To a solution of the product of a) (2.0 g) in 10 ml of ethyl acetate is added 10 ml of 4M HCl-ethyl acetate solution. After stirring for 3 hours, the solvent is evaporated and the residue is suspended in 30 ml of dioxane. To the suspension «: add 5 ml of 1M sodium hydroxide solution, 0.8 g of sodium bicarbonate, 20 ml of water and then a solution of 2-naphthylsulphochloride (1.1 g) in 15 ml of dioxane and • · ·. ·. ·· cooked overnight at room temperature. The reaction mixture is poured. 5% potassium hydrogen sulphate solution and 10% • · ·. ···. potassium sulfate solution and extract with 30 ml of ethyl acetate. The organic phase is dried and evaporated and the residue is crystallized from ethyl acetate / hexane. 1 · 8 g of (S) -2-benzylcarbamoyl-N- (2-naphthylsulfonyl) -? -? -? - alanine benzyl ester are obtained.

: c) To a solution of the product of b) (1.0 g) in 20 ml of methanol, add 2 ml of 1 M NaOH solution and 35 ml of a mixed solvent. The solution is acidified, extracted with ethyl acetate, the solvent is evaporated and the residue is crystallized from methanol / methylene chloride / hexane to give 0.3 g of (S) -2-benzylcarbamoyl-N- (2-5 naphthylsulfonyl). -p-alanine.

d) In analogy to Example 5, (S) -N - [(RS) -1-amidino-3-piperidinylmethyl] -3-benzylcarbamoyl-3- (2-naphthylsulfonamido) propionamide-1'-fluoroacetate (epimers 1: 1), FAB-MS: 551 (M + H) +.

Example 24

In analogy to Example 23, (R) -N - [(RS) -1-amidino-3-piperidinylmethyl] -3-benzylcarbamoyl is obtained via (R) -2-benzylcarbamoyl-N- (2-naphthylsulfonyl) -β-alanine. -3- (2-naphthylsulfonamido) pro-15 pionamide hydrochloride, FAB-MS: 534 (M + H) +.

Example 25

By analogy to Example 23, using hexamethylenimine instead of benzylamine, (S) -N - [(RS) -1-amidino-3-piperidinylmethyl] hexahydro-β- (2-20 naphthylsulfonamido) -γ-oxo-1H-1-azepine butyramide -trifluoroacetate, FAB-MS: 543 (M + H) +.

Example 26

In analogy to Example 6, (R) -N - [(S) - * (f: 1-Amidino-3-piperidinylmethyl] -1,2,3,4-tetrahydro-2- (2-: 25-naphthylsulfonyl) -3 -isoquinolinecarboxamide hydrochloride, FAB-MS: 506 (M + H) *.

«·

Example 27 • «. . ·. In analogy to Examples 5 and 9, methyl • o - [(R) - α - ((RS) -1-amidino-3-piperidinylmethylcarbamoyl) benzoate is obtained, FAB-MS: 547 (M +). H) +.

EXAMPLE 28 By analogy to Examples 5 and 9, m * (RS) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -5-bromo is obtained. -naphthylsulfonamidoindole-3-propionamide sulfite, FAB-35 MS: 611 (M + H) +.

• · · # · · 40 105474

Example 29

In analogy to Examples 5 and 9, the following compounds are prepared: a) (R) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -5-pyridine-a-2-naphthylsulfonamido-hydro-cinnamamide-p-toluene - Nisulfonate, FAB-MS: 620 (M + H) - (b) (R) -N - [[(RS) -1-Amidino-3-piperidinyl] methyl] -α-2-naphthylsulfonamido-p-nitrohydro-cinnamide-p -toluene nisulfonate, FAB-MS: 539 (M + H) 1.

Example 30 a) To a solution of (R) -4-hydroxymethyl-2,2-dimethyl-3-oxazolidinecarboxylic acid tert-butyl ester (30.1 g) in 400 ml of methylene chloride is added 27, 2 ml triethylamine. 12.1 ml of methanesulfochloride are then added at 0 ° C and the reaction mixture is stirred for 1 hour. The salts are filtered off, the filtrate is evaporated and the product is crystallized from hexane. 32.7 g of (S) -2,2-dimethyl-4- (methanesulfonyloxymethyl) -3-oxazolidinecarboxylic acid tert-butyl ester are obtained, H1-20 NMR (CDCl3): 1.48, s, 9H, tert-butyl; 3.04: s: 3H: mesyl.

b) To a solution of product (a) (29.1 g) in 200 ml of dimethylformamide is added 24.5 g of sodium azide. The Suspen pellet is heated to 50 ° C and stirred for 24 hours.

The salts are filtered off and the filtrate is evaporated. Crude product. .1. Dissolve in ethyl acetate (400 mL) and wash with water. The organic phase is dried and evaporated. 20.2 g of (R) -2,2-dimethyl-4- (azidomethyl) -3-oxazolo-1 ", 1'-lidinecarboxylic acid tert-butyl ester, IR (CHCl3), are obtained. 2140 cm -1 (azide band).

c) To products of b) (20.2 g) in 400 ml of dioxane add 4 g of platinum oxide. The reaction mixture is hydrogenated under normal pressure at room temperature, filtered: and the filtrate is evaporated. 17.9 g of (R) -2,2-dimethyl-

<· I

105474 4- (Aminomethyl) -3-oxazolidinecarboxylic acid tert-butyl ester.

d) To a solution of the product of c) in 300 ml of methylene chloride at 0 ° C is added 19.9 ml of Hiinig's base (ethyldiisopropylamine) and 12.2 ml of benzyl chloroformate. After stirring, the reaction mixture is evaporated, the crude product is dissolved in 400 ml of ethyl acetate and the solution is washed with 100 ml of water. The organic phase is dried and evaporated and the crude product is purified on silica gel eluting with ethyl acetate / hexane (1: 9). 26.4 g of (R) -2,2-dimethyl-4- (carbobenzoxyaminomethyl) -3-oxazolidinecarboxylic acid tert-butyl ester are obtained.

e) To a solution of the product of d) in 300 ml of methanol is added 36.2 ml of 2M hydrochloric acid. After 24 hours, the solution is evaporated, the residue is dissolved in 400 ml of dioxane and 72.43 ml of 1M NaOH solution are added. 30.4 g of sodium hydrogencarbonate are then added and a solution of 2-naphthylsulfochloride (24.6 g) in 100 ml of dioxane is added to the resulting suspension. The suspension is stirred for 15 hours, the reaction mixture is filtered, evaporated, the residue is dissolved in ethyl acetate, the solution is washed and dried. The organic phase is evaporated and the crude product is purified on silica gel eluting with ethyl acetate / hexane (3: 7). 25.85 g of [(R) -3-] 'are obtained. · Hydroxy-2- (2-naphthylsulfonamido) propyl] urea. Benzyl ester, MS: 415 (M + H) 1, 371 (-CO 2), 347, 325, 281, 269, 225, 191, 135.

• ·. f) To a solution of the product of e) in 100 ml of ethanol is added 10% Pd / C catalyst (1 g) and the mixture is hydrogenated at room temperature under normal pressure 24 hours.

The catalyst is filtered off and washed with methanol.

· · ·

The filtrate is evaporated to give 2.8 g of N- (R) -2-amino-4,1-hydroxymethyl) ethyl] -2-naphthylsulfonamide, MS: 281: (M + H) + 251, 250, 221, 191 , 128, 127, 60.

To a solution of f) (1.3 g) in 50 ml of dimethylformamide is added 0.83. g of phenylglyoxalic acid and 0.9 ml of Hiinig base. Then, 2.0 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate-5-phate are added and the reaction mixture is stirred for 5 hours. The solvent is evaporated and the crude product is purified on silica gel using hexane / ethyl acetate (1: 1) as the eluent. 1.4 g of N - [(R) -3-hydroxy-2- (2-naphthylsulfonamido) -propyl] -2-phenylglyoxylic acid amide are obtained.

H) To a solution of the product of g) (0.42 g) in 30 ml of acetone at 0 ° C is added 3.5 ml of Jones reagent (2.67 mg of Cr 3 O in sulfuric acid). The mixture is stirred for 1 hour then poured into ice water and extracted with ethyl acetate The organic phase is dried and evaporated to give 0.44 g of (R) -2- (2-naphthylsulfonamido) -3- (2-phenylglyoxylamido) propionic acid, FAB-MS: 427 (M + H) *.

i) In analogy to Example 5, the product of (h) is obtained from (R) -N - [[(S) -1-amidino-3-piperidinyl] methyl] -2-naphthylsulfonamido-3- (2-phenylglyoxylamido) propion - 20 amide p-toluenesulfonate, FAB-MS: 565 (M + H) *.

Example 31

In analogy to Examples 5 and 9, a) N - [(6-benzyloxy-2-naphthyl) sulfonyl] -D-tryptophan is obtained, FAB-MS: 394 (M + H) *, 25 (R) -N-. [[(RS) -1-Amidino-3-piperidinyl] methyl] -α- (6-benzyloxy-2-naphthylsulfonamido-3-propionamide hydrochloride, FAB-MS: 639 (M + H) (B) N- (1-naphthylsulfonyl) -D-tryptophan mediated by FAB-MS: 394 (M + H) *, * · 30 (R) -N - [[( RS) -1-amidino-3-piperidinyl] methyl] -α- (1-naphthylsulfonamido) indole-3-propionamide hydrochloride, FAB · · · · MS: 533 (M + H) · · · · ac) N - (2-Naphthylsulfonyl) -3- (m-nitrophenyl) -DL-alanine, MS: 400 (M *),? [[(RS) -1-Amidino-3-piperidinyl] methyl] -α- [2-naphthylsulfonamido] -m-nitro-hydroquinnamide hydrochloride, FAB-MS: 539 (M + H) -.

Example 32 5 a) To a solution of D-tryptophan (0.71 g) in a mixture of water (4.8 mL) and 1M NaOH (2.13 mL) is added 0.36 sodium bicarbonate and methyl p- (chlorosulfonyl) - solution of benzoate (0.50 g) in 10 ml of ether. The resulting suspension is stirred for 22 hours. The N - [[p- (methoxy-10 carbonyl) phenyl] sulfonyl] -D-tryptophan sodium salt (0.52 g) is suction filtered and washed with water, MS: 400 (M-NA) '. The mother liquor is isolated by acidifying with 0.38 g of the product as the free acid with citric acid.

b) By analogy to Examples 5 and 11, the acid of 15 a) is obtained from methyl p - [[(R) -1 - [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- -indol-3-ylethyl] sulfamoyl] benzoate hydrochloride, FAB-MS: 541 (M + H) +. Example 33

In analogy to Example 31, (RS) -N-20 [[(S) -1-amidino-3-piperidinyl] methyl] -α-2-naphthylsulfonamido-m-nitro-hydro-cinnamamide hydrochloride, FAB-MS: 535 (M +) is obtained. + H) \

Example 34. (RS) -N - [[(RS) -1-Amidino-3-piperidinyl] methyl] -2-α-2-naphthylsulfonamido-m-nitro-hydro-cinnamamide hydro-. A solution of chloride (Example 33) (0.15 g) in 50 ml of ethanol is hydrogenated in the presence of 10% Pd / C catalyst at room temperature and pressure. Reaction solvents- • · · \ Y. the residue is dissolved in methanol.

To the solution is added ether, the separated (RS) -N - [[(S) -1-amidino-3-piperidinyl] methyl] -m-amino-α-2-naphthylsulfonamidohydro-cinnamamide hydrochloride is filtered off with suction and • · · washed with ether. Yield 0.12 g, FAB-MS: 509 (M + H) +: Example 35, ···. A) To a solution of 50 g of N- (2-naphthylsulfonyl) -3-p-nitrophenyl-D-alanine (Example 9b) in 100 ml of dimethylformamide is added 45 ml of Raney nickel and reaction solution • · · · · · · · · · · · · · m 105474 44 is hydrogenated at room temperature and normal pressure. The reaction solution is filtered, the filtrate is concentrated and then poured into water. The separated 3- (p-aminophenyl) -N- (2-naphthylsulfonyl) -D-alanine is suction filtered, washed with water and dried. Yield: 37.6 g, m.p. 211-212 ° C, MS: 370 (M) +.

b) To a suspension of product (a) (1.0 g) in 15 ml of methylene chloride is added 1.13 ml of triethylamine. The resulting solution is cooled in an ice bath and a solution of oxalic acid chloride monoethyl ester (0.3 mL) in 5 mL of triethylamine is added. The resulting solution is cooled in an ice bath and a solution of oxalic acid mono-ethyl ester (0.3 mL) in 5 mL of methylene chloride is added. After cooling for 30 minutes in an ice bath, the solution is stirred overnight at room temperature. The reaction mixture is evaporated, the residue is dissolved in water, the solution acidified with 10% citric acid and the separated product is suction filtered. The product is dissolved in ethyl acetate, washed with water, dried and evaporated. 0.92 g of oxalic acid ester amide is obtained, which in analogy to the procedure of Example 5, gives 0.87 g of ethyl 4 '- [(R) -2 - [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl]. -2 - [(2-naphthylsulfonamido) ethyl] oxanylate hydrochloride, FAB-MS: 609 (M + H) + -: Example 36 * *: 25 In analogy to Example 35, the following compounds are prepared: ··· a) methyl 4 '- [(R) -2 - [[[(RS) -1-amidino-3-piperidine]. . ·. ynyl] methyl] carbamoyl] -2 - [(2-naphthylsulfonamido) ethyl] · · · # ·· *. li] succinanilate hydrochloride, FAB-MS: 623 (M + H) *.

B) Methyl 3 '- [(RS) -2 - [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl · ··· ”] succinanilate hydrochloride, FAB-MS: 623 (M + H) *.

··· 'c) benzyl 4' - [(R) -2 - [[[(RS) -1-amidino-3-pipero- *]. dinyl] methyl] carbamoyl] -2 - [(2-naphthylsulfonamido) -35 ethyl] succinanilate hydrochloride, FAB-MS: 699 (M + H) *.

D) methyl 4 '- [(R) -2 - [[((RS) -1-amidino-3-piperidine)] -nyl] methyl] carbamoyl] -2- (p-iodobenzenesulfonamido) ethyl] succinanilate hydrochloride, FAB-MS: 699 (M + H) *.

e) ethyl 4 '- [(R) -2 - [[[(RS) -1-amidino-3-piperidin-5-yl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] carbanylate hydrochloride, FAB-MS: 581 (M + H) +.

Example 37

In analogy to Example 35, N- (2-naphthylsulfonyl) -3- [p- (2-phenylglyoxylamido) phenyl] -10 D-alanine is obtained, MS: 502 (M) *, analogously to Example 6e) -g). with (R) -N - [[(S) -1-amidino-3-piperidinyl] methyl] -α- (2-naphthylsulfonyl) -p- (2-phenylglyoxylamido) hydrocinnamamide hydrochloride, FAB- MS: 641 (M + H) @ + Example 38

In analogy to Examples 35 and 42, methyl p- [p - [(R) -2 - [[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] benzo [beta] is obtained. -amido] via benzoate hydrochloride, FAB-MS: 67120 (M + H) *, p- [p - [(R) -2- [r (RS) -1-amidino-3-piperidinyl] methyl] ] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] benzamido] benzoic acid hydrochloride, FAB-MS: 657 (M + H) *.

Example 39 (ir) Analogously to Example 35, there is obtained (R) -N- -: 25 [[(RS) -1-amidino-3-piperidinyl] methyl] -p- [2- (2-methoxy) ethoxy) acetamido] -α-2-naphthylsulfonamidohydro-cinnamamide- ··· ····· di-hydrochloride, FAB-MS: 625 (M + H) *.

. . ·. Example 40 • »· • · ·. ···. In analogy to Example 35, 4 '- [(R) -? - 2 - [[[((S) -1-amidino-3-piperidinyl] methyl] carbamoyl-2- (2-naphthylsulfonamido) ethyl] oxanilic acid hydrochloride is obtained. · FAB-MS: 581 (M + H) +.

Example 41: To a solution of 3- (p-aminophenyl) -N- (2-naphthylsulfonyl) -D-alanine (Example 35a) (0.7 g) in 5 mL of pyridine-M · III. Add 1 ml of acetic anhydride and allow to stand at room temperature for 20 hours. To the mixture is added water and concentrated hydrochloric acid (ice-cooled), the precipitated product is suction filtered, dissolved in ethyl acetate, washed with water, dried and evaporated. The product is dissolved in any 1M NaOH-methanol solution and allowed to stand. The solution is evaporated, the residue is dissolved in water, the aqueous solution is acidified with concentrated hydrochloric acid and the separated product is suction filtered, dissolved in ethyl acetate and the solution is washed with water, dried and evaporated. The residue is reacted in analogy to Example 5 to give 146 mg of (R) -p-acetamido-N - [[(RS) -1-amidino-3-piperidinyl] methyl] -α- (2-naphthylsulfonamido) hydro-cinnamamide. hyd-15 hydrochloride, FAB-MS: 551 (M + H) *.

Example 42

A suspension of ethyl 4 '- [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] oxanilate hydrochloride (Example 35) (150 mg). In 1 M NaOH-ethanol solution, stir at room temperature until a solution is obtained. The reaction solution is acidified by addition of 2.78 M ethanolic hydrochloric acid solution, the separated NaCl is filtered off with suction and ether is added to the filtrate.

/ '; The hydrochloride formed is separated by decantation and stirred in ether. The product is filtered off with suction. Yield 60 mg of 4'- [(R) -2 - [[[(RS) -1-amidino-3-piperidinyl] methylcarbamoyl] · · ] -2- (2-naphthylsulfonamido) ethyl] oxanilic acid hydrochloride, FAB-MS: 581 (M + H) - [*] * * * Example 43 Benzyl 4 '- [ (R) -2 - [[((RS) -1-Amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] · · · yl] succinanilate hydrochloride (Example 36c) ' A solution of 0.5 g in 20 ml of ethanol is hydrogenated in the presence of 10% Pd / C; 0.5 g of catalyst. The catalyst is filtered off. Concentrate and add ether to the residue. Decant by decantation, mix with ether and suction filtrate. Yield 0.35 g 4 '- [(R) -2 - [[[(RS) -1-Amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl li] succinanilidic acid 5-hydrochloride, FAB-MS: 609 (M + H) 1.

Example 44 To a solution of 3- (p-aminophenyl) -N- (2-naphthylsulfonyl) -D-alanine (Example 35a) (0.5 g) in 1 M NaOH (1.35 mL) and water (7 g) was added. ml) 6 ml of dioxane and 0.34 g of sodium hydrogen carbonate are added. 0.26 g of tosyl chloride are then added with stirring. After stirring for 24 hours at room temperature, the solution is concentrated, diluted with water and extracted with ether. To the ice-cooled aqueous phase is added 6 ml of 2M hydrochloric acid and the separated product is suction filtered. It is converted by purification as such in Example 5 into (R) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -α-2-naphthylsulfonamido-p- (p-toluenesulfonamido) hydroquinnamide hydrochloride, FAB -MS: 663 (M + H) ', yield 0.39 g.

Example 45

In analogy to Example 44, (R) -N - [[(S) -1-amidino-3-piperidinyl] methyl] -? - (p-iodobenzenesulfonamido) -α- (2-naphthylsulfonamido) hydroquinamide is prepared. hydrochloride, FAB-MS: 775 (M + H) -.

. '· 25 Example 46

'I I

,. ·. In analogy to Example 44, methyl-p - [[p - [(R) -2 - [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- - (2-Naphthylsulfonamido) ethyl] phenyl] sulfamoyl] benzoate hydrochloride, FAB-MS: 707 * 1 · 30 (M + H) 1, via p-C [p - [(R) -2 - [[[(RS) ) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] phenyl] sulfamoyl] benzoic acid hydrochloride, FAB · · · - · · - MS: 693 (M + H) + 1.

• · «... ---------- - • · · · • • • • • * <i 1« · · * I · · • ·

«I I

• t 105474 48

Example 47 To a suspension of 3- (p-aminophenyl) -N- (2-naphthylsulfonyl) -D-alanine (Example 35a) (0.37 g) in 20 mL of dioxane is added 0.45 mL of 50%: toluene solution of ethyl glyoxylate 5. 0.3 g of a 10% Pd / C catalyst are added to the resulting solution and the mixture is hydrogenated for 6 hours at room temperature under normal pressure. The catalyst is filtered off, the filtrate is evaporated and the residue is reacted as in Example 5. Yield 89 mg of N- [p-10 [(R) -2 - [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamate). yl] -2- (2-naphthylsulfonamido) ethyl] phenyl] glycine ethyl ester hydrochloride. FAB-MS: 595 (M + H) @ +.

Example 48

In analogy to Example 26, (R) -N-15 [[(RS) -1-amidino-3-piperidinyl] methyl] -1,2,3,4- (2-naphthylsulfonyl) -3-isoquinol is prepared. inicarboxamide hydrochloride (1: 1 epimers), [α] 58 D 5 = + 76.8 ° (MeOH, c = 0.5%), FAB-MS: 506 (M + H) +.

Example 49 In analogy to Example 5, (RS) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -3- (o-aminobenzoyl) -2- (2-naphthylsulfonamido) propionamide is prepared. hemi-sulfite, FAB-MS: 537 (M + H) 1.

. Example 50 In analogy to Example 23, the following compound is prepared. crude compounds: • 1 · a) (S) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] - • · β-2-naphthylsulfonamido-γ-oxo-4-morpholine butramide trifluoroacetate, FAB -MS: 531 (M + H) -.

B) (R) -N - [[(RS) -1-Amidino-3-piperidinyl] methyl] -hexahydro-β-2-naphthylsulfonamido-γ-oxo-1H-azepine-butyl ··· 1 tyramide trifluoroacetate, FAB-MS: 543 (M + H) 1.

M1 c) (S) -N - [[(RS) -1-Amidino-3-piperidinyl] methyl] -?: Hexahydro-β-2-naphthylsulfonamido-γ-oxo-1H-azokine-1?. 35 tyramide hydrochloride, FAB-MS: 557 (M + H) 1.

• «« * • · · «i i • · · · · · •» 49 105474

Example 51 a) 5 g of potassium salt of diphenylsulfone-3-sulfonic acid are refluxed in 50 ml of thionyl chloride overnight. The precipitated material is filtered off and dried, yielding 3.2 g of diphenylsulfone-3-sulfonic acid chloride.

b) To a solution of p-nitro-D-phenylalanine (1.52 g) in 37 ml of dioxane is added 6.7 ml of 1M NaOH solution and 2.82 g of sodium hydrogen carbonate. To this solution is added a solution of the product of (a) in 119 mL of dioxane and the mixture is stirred overnight at room temperature. The reaction mixture is then poured onto ice and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. This gives 1.75 g of 3- (p-nitrophenyl) -N - [[(m-phenylsulfonyl) phenyl] sulfonyl] -D-alanine.

C) The above acid is obtained in analogy to Example 6 steps e) -g) from (R) -N - [[(S) -1-amidino-3-piperidinyl] methyl] -p-nitro-α- [m- ( phenylsulfonyl) benzenesulfonamido] hydroquinnamide hemisulfite, FAB-MS: 629 (M + H) *.

Example 52 a) 2.3 g of p-nitro-D-phenylalanine are suspended in 25 ml of dioxane and 10 ml of 1M NaOH solution and 1.7 g of sodium hydrogen carbonate are added to the suspension. A solution of 2-chlorosulfonylbenzoic acid methyl ester 25 (2.6 g) in 22 mL of dioxane is then added dropwise and stirred for 9 hours i. at room temperature. The reaction mixture is poured into ice-cold 2M hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated.

• · ·

3.2 g of N - [[o- (methoxycarbonyl) phenyl] sulfonyl] -3- (p-nitrophenyl) -D-alanine are obtained.

b) Dissolve the material obtained in a) in 30 ml of dimethylformamide, add 5.3 ml of hexaethylene ethylene, and then stir for 5 hours at 80 ° C. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, and the solution is shaken once with 2M hydrochloric acid and twice with water. The organic phase is dried, evaporated and the residue is chromatographed on silica gel to give 0.9 g of N- [[o- (hexahydro-1H-azepin-1]]. -yl-1- (i) carbonyl] phenyl] sulfonyl] -3- (p-nitrophenyl) -D-alanine.

5 c) By analogy to Example 5, the material obtained in b) gives (R) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -α - o - [(hexahydro-1 H- azepin-1-yl) carbonyl] benzenesulfonamido] -p-nitro-hydro-cinnamamide hydrochloride FAB-MS: 614 (M + H) +.

Example 53

In analogy to Example 53, the following compounds are prepared: a) (R) -N - [[(RS) -1-Amidino-3-piperidinylmethyl] -α- (p-tert-butylbenzenesulfonamido) -p-nitrohydroxy-namamide; acetate, FAB-1S: 545 (M + H) +.

b) (R) -N - [((RS) -1-Amidino-3-piperidinyl] methyl] -p-nitro-α- (benzo [b] thiophenesulfonamido) hydroquinnamide hydrochloride, FAB-MS: 545 (M +) H) +.

Example 54 In analogy to Examples 19a) and 23, (SS, 2RS) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -2-benzyloxymethyl-β-2-naphthylsulfonamido-γ-oxo is obtained. 4-morpholinobutramide acetate, FAB-MS: 651 (M + H) +.

. Example 55 A solution of the product of Example 54 in ethanol / 1m HCl (hydrogenated in the presence of 10% Pd / C catalyst for 30 hours under normal conditions gives (SS, 2RS) -N-). · E ... [[(RS) -1-amidino-3-piperidinyl] methyl] -2-hydroxy

H1 Cymethyl-β-2-naphthylsulfonamido-γ-oxo-4-mor '-?' · 11,30 Folybutramide hydrochloride, FAB-MS: 561 (M + H) +.

Example 56 s1 · * ... · A) a) ras-2- (aminomethyl) -4-benzylmorpholine

• M

(23.3 g) to a solution of 250 ml of dioxane add 27.1 g of di-tert-butyl dicarbonate in 250 ml of dioxane and '··. The mixture is stirred for 17 hours at room temperature. The solvent is then evaporated and the residue is chromatographed on silica gel using methylene chloride / ethyl acetate (3: 1) for the elution. The product is recrystallized from methylene chloride / hexane to give 25.6 g of tert-5-butyl ras - [(4-benzyl-2-morpholinyl) methyl] carbamate.

A) To a solution of the product of a) a) in a mixture of ethyl acetate (500 ml) and acetic acid (50 ml) is added 2.6 g of Pd / C catalyst, then hydrogenated at room temperature for 10 hours at room temperature. The mixture is filtered, the filtrate is evaporated and the residue is dissolved in 230 ml of dimethylformamide. To the solution is added 46 ml of triethylamine and 10.8 g of forsamidine sulphonic acid and stirred for 20 hours at room temperature. The reaction mixture is then evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is dried and evaporated to give tert-butyl ras - [(4-amidino-2-morpholinyl) methyl] carbamate sulfite.

A) c) 6.5 g of the product obtained in b) are suspended in 50 ml of methylene chloride and 20 ml of TFA are added to the suspension at 0 ° C. After 7 hours at room temperature, the reaction mixture is evaporated and azeotroped with ethylene chloride and toluene. There is obtained ras-2- (amino-1-methyl) -4-morpholinecarboxamidine trifluoroacetate.

B) Analogously to a solution of (S) -P-2-naphthylsulfonamido-γ-oxo-4-morpholine butyric acid (0.8 g) in 16 ml of dimethylformamide obtained analogously to Example 23 a) -c): Add 0 , 76 ml of 4-ethylmorpholine, 0.89 g of benzotriat: * · *: sol-1-yloxitris (dimethylamino) phosphonium hexafluorophosphate and 1.16 g of the product obtained in Ac) and the mixture. After stirring at room temperature for 17 hours, 1 M hydrochloric acid is added to the reaction mixture and the mixture is evaporated to dryness. The residue is chromatographed on a RP-18 column using water / acetonitrile as eluent to give 0.5 g (S). ) -N - [[(RS) -4-Amidino-2-morpholinyl] -N- [(R) -N- [52,105,474 l] methyl] -β-2-naphthylsulfonamido-γ-oxo- morpholine butamamide hydrochloride, FAB-MS: 533 (M + H) +.

Example 57

Analogously to Example 56, 5a) (S) -N-4 - [[(RS) -4-amidino-2-morpholinylmethyl] -β-2-naphthylsulfonamidohexahydro-1 H -azepine-1-butyramide is obtained. hydrochloride, FAB-MS: 545 (M + H) +.

b) (S) -N-4 - [[(RS) -4-Amidino-2-morpholinyl] methyl] hexahydro-β-2-naphthylsulfonamido-γ-oxo-1 (2H) -azo-10-quinine-1 butyramide hydrochloride, FAB-MS: 559 (M + H) +.

Example 58

In analogy to Example 8, (R) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -α- (2-naphthylsulfonamido) -2-oxo-3-benzoxazoline propionamide tri-acetate is obtained. , FAB-MS: 551 (M + H)

Example 59

In analogy to Examples 8 and 56, the following compounds are prepared: a) (R) -N - [[RS] -4-Amidino-2-morpholinyl] methyl] -α-2-naphthylsulfonamido-2,3-dioxo-1 -indole inipropionamide hydrochloride, FAB-MS: 565 (M + H) +.

b) (R) -N - [[(RS) -4-Amidino-2-morpholinyl] methyl] -,, α-2-naphthylsulfoamido-2-oxo-3-benzoxazoline propionamide hydrochloride, FAB-MS: 553 :> 'ί 25 (M + H) +.

Example € 0 ': 1) A) (a) (S) - 3-Aminomethyl-1-piperidinecarboxyl-1'-acid tert-butyl ester (Example 6d) (10.0 g) in hexane (400 ml) and water (100 ml) add 30 g of tetrabutylammonium hydrogen sulphate and 100 ml of 1 m. ···. NaOH solution. To this mixture is added dropwise 9.3 ml of benzyl. chloroformate and the mixture is stirred for 3 hours at room temperature. The organic phase is then separated, washed with: 10% citric acid, water and saturated

Ml 35 with a solution of Strip Hydrogen Carbon, dried and evaporated.

«« · • ««

· I

«I I I •« · • 1 53 105474

Tert-Butyl (S) -3 - [(1- (benzyloxy) formamido] methyl] -1-piperidinecarboxylate is obtained.

A) b) Dissolve 11.3 g of the product obtained in a) in 120 ml of ethyl acetate, add 120 ml of 4M HCl-ethyl acetate solution at 4 ° C and stir for 5 hours at room temperature. The reaction mixture is then evaporated, the residue is dissolved in 265 ml of dimethylformamide, 18 ml of triethylamine and 4.3 g of formamidine sulphonic acid are added, and the mixture is stirred for 17 hours at room temperature. The solvent is evaporated, to the residue is added 1M hydrochloric acid, the mixture is again evaporated and the residue is chromatographed on a Rp-18 column using water / acetonitrile as eluent. 5.4 g of benzyl [[(S) -1-amidino-3-piperidinyl] methyl] carbamate hydro-15 chloride are obtained.

A) c) Dissolve 6.6 g of the product obtained in b) in a mixture of ethanol (165 ml) and 1M hydrochloric acid (165 ml), add 1 g of Pd / C catalyst and hydrogenate the mixture for 2 hours under normal conditions. The mixture is filtered, evaporated and azeotroped with ethanol to give 4.5 g of (S) -1-amidino-3- (aminomethyl) piperidine dihydrochloride, m.p. 252-254 ° C, FAB-MS: 156 (M) -1. ... [?] D = -16.9 (c = 1.0, water).

'B) To a solution of N- (2-naphthylsulfonyl) -3- (2,3-dioxo-1-yn-25-dolinyl) -D-alanine (1.9 g) in 30 ml of dimethylformamide is added 2, 3 ml of 4-ethylmorpholine, 2.0 g * J ': benzotriazol-1-yloxytris (dimethylamino) phosphonlumhexafluorophosphate and 1.0 g of the compound obtained in A) c) and the mixture is stirred for 20 hours at room temperature. The reaction mixture is evaporated, 1M hydrochloric acid is added, the mixture is evaporated to ice and the residue is chromatographed on silica gel using ethyl acetate / acetone / glacial acetic acid / water (16: 2) for the elution. : 1: 1), yielding 0.8 g of (R) -N - [(S) -1-amidino-3-piperidinylmethyl] -α- (2-butyl-2-butyl-2-yl) -5- · 1 · · · · 1 »· · · 54 54474 naphthylsulfonamido) -2,3-dioxo-1-indoline propionamide acetate FAB-MS: 563 (M + H).

Example 61

In analogy to Examples 8 and 60, the following compounds are obtained: a) (R) -N - [[(S) -1-amidino-3-piperidinyl] methyl] -α-2-naphthylsulfonamido-2-oxo-3-benzoxazolidinepro- pionamide hydrochloride, FAB-MS: 551 (M + H) *.

b) (R) -N - [[1S-Amidino-3-piperidinyl] methyl] -5-bromo-α-2-naphthylsulfonamido-2,3-dioxo-1-indoline propionamide tetraacetate, FAB -MS: 643 (M + H) - (c) (R) -N - [[(S) -1-Amidino-3-piperidinyl] methyl] -5-methyl-α-2-naphthylsulfonamido-2,3-dioxo -1-Indoline-propionamide acetate, FAB-MS: 577 (M + H) *.

D) (R) -N - [[1S-Amidino-3-piperidinyl] methyl] - [(p-iodophenyl) sulfonyl] -2,3-dioxo-1-indoline propionamide hydrochloride, FAB-MS : 639 (M + H) +.

e) (R) -N - [[(S) -1-Amidino-3-piperidinyl] methyl] -α- (o-nitrobenzenesulfonamido) -2,3-dioxo-1-indoline-20-propionamide hydrochloride, FAB- MS: 558 (M + H) &lt; + &gt;.

Example 62 a) To a solution of N-α-Z-L-2,3-diaminopropionic acid (15 g) in 189 ml of a 1M NaOH solution is added dropwise a solution of 2-naphthylsulphochloride (21.4 g) in 200 ml of ether-25 ethers. Stirring is continued for another 6 hours. The reaction mixture is then poured into ice-cold 2M hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried, and evaporated. Chromatography of the residue on silica gel, eluting with a methylene chloride / -30 methanol / acetic acid mixture (94: 5: 1), gives 17.9 g of N - [(benzyloxy) carbonyl] -3- (2-naphthylsulfonamido) - ···. ♦ ·. 1-alanine.

B) The product from step a) is prepared in a manner analogous to that of Example 5: Benzyl - [(S) ~ - · · 35 - CC [(RS) -1-Amidino-3-piperidinyl] methyl] carbamoyl «·« T * «1 1 1 1 • 105 105474 55 2- (2-Naphthylsulfonamido) ethylcarbamate, FAB-MS: 567 (M + H) \

Example 63 a) To a solution of the product of Example 62b) (1.1 g) in a mixture of 1 ml of hydrochloric acid (22 ml) and ethanol (11 ml) is added 0.2 g of Pd / C catalyst and the mixture is hydrogenated for 5 hours under normal conditions. The mixture is filtered and evaporated to give 0.96 g of (S) - [[(RS) -1-amidino-3-piperidinyl] methyl] -2-amino-3- (2-naphthylsulfonamido) -10-propionamide hydrochloride, FAB -MS: 433 (M + H) -.

b) To a solution of the product obtained in a) (0.95 g) in 20 ml of dimethylformamide is added 0.24 ml of 4-ethylmorpholine and 0.3 g of phthalic anhydride and the mixture is stirred at 50 ° C for 6 hours. The reaction mixture is evaporated and chromatographed on a Rp-18 column using a water / acetonitrile mixture for elution. 0.3 g of o - [[(S) -1 - [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] carbamoyl] -benzoic acid are obtained. -MS: 581 (M + H) -.

Example 64

To a solution of the product of Example 63a) (1.4 g) in 28 ml of dimethylformamide is added 1.05 ml of 4-ethylmorpholine, 1.23 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate and 0.95 g of o- ( benzyloxy) - 25 benzoic acid and the mixture is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is partitioned between ethyl acetate and water. The organic phases are dried, evaporated and the residue chromatographed on: T: silica gel, eluting with ethyl acetate / acetone / glacial acetic acid / water (16: 2: 1: 1). 0.2 g of (S) -2-N- [o- (benzyloxy) benzamide] -3- (2-naphthylsulfonamido) - ···. ··· are obtained. N - [[(RS) -1-Amidino-3-piperidinyl] methyl] propionamide acetate, FAB-MS: 643 (M + H) -. • · · a · · · 56 105474

Example 65 a) In analogy to the procedure of Example 64, using tert-butyl (R) -2-piperidinecarboxylic acid instead of o- (benzyloxy) benzoic acid, tert-butyl (R) -2 - [[(S) -1- [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] carbamoyl] -1-piperidinecarboxylate trifluoroacetate, FAB-MS: 644 (M + H) b) To a solution of the product of step a) (300 mg) in 10 ml of ethyl acetate is added 5 ml of 4m; HCl-ethyl acetate solution. After stirring at room temperature for 3 hours, the suspension is evaporated to dryness to give (R) -N- (S) ~ 1 - [[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) -2-piperidine-15 carboxamide dihydrochloride, FAB-MS: 544 (M + H) 1.

Example 66

A solution of the product of Example 64 (120 mg) in 12 ml of acetic acid is hydrogenated in the presence of Pd / C catalyst (50 mg) for 6 hours under normal conditions. The mixture is filtered and evaporated to give 80 mg of (S) -N - [[(RS) -1-amidino-3-piperidinyl] methyl] -2- (2-hydroxybenzamido) -3- (2-naphthylsulfonamido) propionamide acetate. FAB-MS: 553 (M + H)

Example 67 25 a) The compound obtained in Example 62a) is converted analogously to Example 6 a) -e) to tert-butyl (S) -3 - [[N - [(benzyloxy) carbonyl] -3- (2-naphthylsulfonamide) -do) -1-alanyl] amino] methyl] -1-piperidinecarboxylate, FAB-MS: 525 (M + H) - Boc.

(B) a solution of the product obtained in (a) (3,0 g), ··. In 80 ml of ethyl acetate / acetic acid (1: 1) hydro-. in the presence of Pd / C catalyst (0.8 g) for 48 hours under normal conditions. The mixture is filtered and evaporated, the residue is dissolved in 25 ml of dimethylformamide, 1.6 ml of 4-ethylmorpholine and 0.81 g of isazo are added to the solution. 57 105474 acid anhydride and the mixture is stirred for 16 hours at 80 ° C. The solvent is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water, dried and evaporated, and the residue is chromatographed on silica gel, eluting with a methylene chloride / ethyl acetate (3: 1) mixture. 1.3 g of tert-butyl (S) -3 - [[N-anthraniloyl-3- (2-naphthylsulfonyl) -L-alanyl] amino] methyl] -1-piperidinecarboxylate are obtained, FAB-MS: 610 (M +) H) +.

C) The product from c) is obtained analogously to Example 60 f) -g) to N - [(S) -1 - [[[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-Naphthylsulfonamido) ethyl] -o-aminobenzamide hemisulfite, FAB-MS: 552 (M + H) +.

15 Example 68

By analogy to Examples 23a) -c) and 60B), using ethyl ras-trans-4-methyl-2-piperidinecarboxylate in place of benzylamine gives ethyl (2RS, 4R) -1 - [(S) -3 - [[ (S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) propionyl] -4-methyl-2-piperidinecarboxylate acetate (1: 1 epimers). FAB-MS: 615 (M + H) +.

Example 69 i By treating the compound prepared in Example 68 with a solution of NaOH in methanol, (2RS, 4R) -1- [N4 - ([(S) -1-amidino-3-piperidinyl] methyl] -N2- (2- naphthylsulphonyl *: * ') -1-L-Asparaginyl] -4-methyl-2-piperidinecarboxylic acid (epimers 1: 1), FAB-MS: 587 (M + H) +.

• · ·

Example 70 30 a) To a solution of D-aspartic acid p-benzyl ester (5 g) and · ···, β-naphthylsulfonyl chloride (5.07 g) in 80 ml of dioxane is added dropwise 10 ° C. At C, 22.4 ml of 2M NaOH solution. The reaction mixture is then stirred for 2 hours at room temperature and 25 ml of 1M hydrochloric acid are then added. The dioxane is evaporated, the residue is dissolved in ethyl acetate and the solution is washed with water. The ethyl acetate phase is dried and evaporated to give 9.1 g of 4-benzyl-1-hydrogen (2-naphthylsulfonyl) -D-aspartate. R f = 0.53 (ethyl acetate / glacial acetic acid 0.97: 0.03).

b) To the product of a) in 100 ml of dimethylformamide are added, with stirring, 3.72 ml of Hunig's base, 9.67 g of benzotriazol-1-yloxytris (deacetylamino) phosphonium hexafluorophosphate and 4.68 g of (S) -3-aminomethyl -1-piperidinecarboxylic acid tert-butyl ester. The reaction mixture is stirred for 4 hours, then ether is added and the ether phases are washed with water. The ether phase is dried and evaporated and the residue is chromatographed on silica gel using ether / hexane (9: 1) as eluent. 9.1 g of benzyl (R) -3 - [[[(S) -1- (tert-butoxycarbonyl) -3-piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionate are obtained. R f = 0.35 (9: 1 ether / hexane).

c) A 3.0 g solution of the product of b) in 60 ml of methanol is hydrogenated in the presence of 10% Pd / C catalyst at room temperature and at normal pressure. After 8 hours, the catalyst is filtered off and the methanol solution is evaporated. 2.38 g of (R) -3 - [[[(S) -1- (tert-butoxycarbonyl) -3-piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionic acid are obtained, Rf = 0.8 (ethyl acetate).

D) A solution of the carboxylic acid obtained in (c) (1 g) in 18 ml of methylene chloride is cooled to -23 ° C and 0.25 ml of N-methylmorpholine and 0.3 ml of chloroformic acid isobutyl ester are added successively. Reaktioseos-

• M

it is stirred at -23 ° C and 0.36 µl of piperidine-3-30 carboxylic acid ethyl ester. 100 ml of ether are then added to the reaction mixture. The ethereal solution is washed with 1 M hydrochloric acid. with empty water and water. The ether phase is dried and evaporated and the residue is chromatographed on silica gel, eluting with ethyl acetate / hexane (4: 1). 917 mg of ethyl (R, S) -1- [(R) -3- [[[((S) -1- (tert-butoxybenzylcarbonyl) -3-piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3-piperidinecarboxylic acid Rf = 0.4 (ethyl acetate / hexane 4: 1).

e) To a solution of the product (400 mg) obtained in (d) in 9.5 ml of methylene chloride is added 1.2 ml of trifluoroacetic acid with stirring. The methylene chloride and trifluoroacetic acid are then evaporated at 50 ° C. The residue is dissolved in methanol, 0.42 ml of triethylamine and 150 mg of formamidine sulphonic acid are added to the methanol solution. The reaction mixture 10 is then stirred at room temperature for 8 hours. At intervals of 2 hours, 0.09 ml of triethylamine and 75 mg of formamidine sulphonic acid are added 3 times each time. The reaction mixture is evaporated, the residue is taken up in 20 ml of a Takeda solution / ethyl acetate (1: 1) (Takeda solution = ethyl 15 acetate / acetone / water / glacial acetic acid 6: 2: 1: 1) and the precipitate is filtered off. The filtrate is evaporated and the residue is chromatographed on silica gel using a Takeda solution / ethyl acetate (1: 1) as eluent. Chromatography affords 114 mL of ethyl (RS) -1 - [(R) - [[(S) -1-amidino-3-piperidinyl] methyl] -20 carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3- piperidine carboxylate acetate. R f = 0.34 MS (EI): 601 (M + H).

Example 71

(I T

V 'In analogy to Example 70, the following compounds are prepared: ·, ·, · a) [(R) -1 - [(S) -3 - [[(S) -1-amidino-3]]. -piperidinyl] - *: · 1: methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -1 · 1 · 3] piperidinyl] methyl acetate, Rf = 0.61 (Takeda solution), FAB -MS: 601 (M + 1).

b) [(S) -1 - [(S) -3 - [[(S) -1-amidino-3-piperidinyl] -. methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3-piperidinyl] methyl-p-tosylate (1: 1), R f = 0, Z 9 · · (Takeda solution), FAB-MS: 601 (M + 1).

ii · c) Methyl (RS) -1 - [(R) -3 - [[[(S) -1-Amidino-3-piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) - 9 9 9 9 9 9 $ 9 • 99 9 0 9 9 9 9 9 9 9 105474 60 propionyl] -4-oxo-3-piperidinecarboxylate acetate (1: 1), Rf = 0.27 (Takeda solution), FAB-MS: 601 (M + H) +.

d) [(S) -1 - ((R) -3 - [[(S) -1-Amidino-3-piperidinyl] methyl] carbamoyl] - (2-naphthylsulfonamido) acetyl] -3- piperidinylmethyl acetate acetate Rf = 0.29 (Takeda solution), FAB-MS: 601 (M + 1).

e) [(R) -1 - [(R) -3 - [[(S) -1-Amidino-3-piperidinyl] methyl] - (2-naphthylsulfonamido) acetyl] -3-piperidinyl] methyl acetate acetate, Rf = 0.35 (Takeda-1 solution), 10 FAB-MS: 601 (M + 1).

f) Diethyl (RS) -1 - [(R) -3 - [[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3 -piperidine carboxamide acetate, Rf = 0.3 (Takeda-1 solution), FAB-MS: 628 (M + 1).

15 g) [(S) -1 - [(S) -3 - [[[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3 piperidinyl] methyl isobutyrate acetate, Rf = 0.43 (Takeda solution), MS (EI): 629 (M + 1).

h) [(S) -1 - [(S) -3 - [[[(S) -1-amidino-3-piperidinyl] -20-methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3- piperidinyl] methyl butyrate acetate. R f = 0.47 (Takeda solution), FAB-MS: 629 (M + 1).

i) Ethyl (3R, 4R) -4-acetoxy-1 - [(R) -3 - [[[(S) -1-amine]. dino-3-piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3-piperidinecarboxylate

Se: ': acetate (1: 1), Rf = 0.21 (Takeda solution), FAB-MS: 659 ·; ··: (M + 1).

. j) Ethyl (3S, 4S) -4-acetoxy-1 - [(R) -3 - [[[(S) -1-amino-3 · piperidinyl] methyl] carbamoyl] -3- (2-naphthylsulfonamido) propionyl] -3-piperidinecarboxylate ... acetate (1: 1), Rf = 0.24 (Takeda solution), FAB-MS: 659 · · (m + d.

In the manufacture of products a), b), 8) and h), S-aspartic acid β-benzyl ester is used instead of D-aspartic acid p-benzyl ester (Example 70a).

«· · •

V

4 <I

I 4 ·

«· B

61 105474

The intermediates used in the preparation of a), b), d), e), i) and j) are synthesized by the following procedure: 2.0 g of (S) -3-hydroxymethyl-1-piperidinecarboxylic acid tert-butyl ester or (R), respectively. The 3-hydroxymethyl-1-piperidinecarboxylic acid tert-butyl ester is mixed with acetic anhydride (0.88 mL), dimethylaminopyridine (26.3 mg) and pyridine (3.0 mL). To the reaction mixture is then added ether 10, the ether phase is washed with 20% citric acid, saturated sodium bicarbonate and water. The ether phase is dried and evaporated, the product obtained (2.44 g, Rf = 0.85, ether) is dissolved in 50 ml of methylene chloride and 12 ml of trifluoroacetic acid are added. The reaction-thiol solution is stirred for 30 minutes, then evaporated to dryness. The (S) or (R) -3-acetoxymethyl-1-piperidine trifluoroacetic acid salt (Rf = 0.14, Takeda solution) is used in the preparation of d) with an equivalent amount of triethylamine.

The intermediates used in the synthesis of Examples g) and h) are prepared as follows: To 3.0 g of (S) -3-hydroxymethyl-1-piperidinecarboxylic acid tert-butyl ester are added 170 mg of dimethylaminopyridine and 3.4 ml of pyridine. 1.66 ml of isobutyric acid chloride are added dropwise to the mixture. The reaction mixture is evaporated, ether is added to the residue, and the ether phase * · · '···] is washed successively with 20% citric acid, water, sodium hydrogencarbonate solution and water. The ether phase is dried and evaporated to dryness to give 3.9 g of (S) -3-isobutyloxymethyl-1-piperidinecarboxylic acid tert-butyl ester, Rf = 0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and solution • · · · ** '; 20 ml of trifluoroacetic acid are added. 30 minutes • · ·. after stirring, the solution is evaporated. To the residue is added 30 ml of methylene chloride and then dropwise saturated sodium hydrogencarbonate solution (62 105474). The aqueous phase is extracted with methylene chloride, the methylene chloride extracts are dried and evaporated. 2.82 g of (S) -3-isobutyloxymethyl-1-piperidine trifluoroacetic acid salt, Rf = 0.4 (Takeda solution) are obtained.

The (S) -3-butyroxymethyl-1-piperidine trifluoroacetic acid salt is obtained by the same method, Rf = 0.4 (Takeda solution).

Example 72 10 a) To a mixture of glycine tert-butyl ester hydrochloride (6.91 g) and naphthalene-2-sulfochloride (12.1 g) in 70 ml of methylene chloride is added dropwise 14.4 ml of triethylamine. The reaction mixture is then diluted with 200 mL of ether. The organic phase is washed with 1M hydrochloric acid and water. The organic phase is dried and evaporated, the residue is taken up in ether and filtered. The crystals are dried to give 11.57 N (2-naphthylsulfonyl) glycine tert-butyl ester. R f = 0.49 (ether / hexane 2: 1).

b) 1 g of the product of a), 923 mg of dansyl chloride, 20 0.48 ml of triethylamine and 418 mg of dimethylaminopyridine are added to 10 ml of methylene chloride and the mixture is stirred. 100 ml of ether are added to the reaction mixture, and the organic phase is washed with 1M hydrochloric acid and water. The solution is dried and evaporated to give 1.67 g of N-, 25 - [[5- (dimethylamino) -1-naphthyl] sulfonyl] -N- (2-naphthyl- (1'-sulfonyl) glycine). Rf1 0.33 (methylene chloride / hexane: ···: # ni 9: 1).

* 1 c) A solution of the product of b) in 17 ml of methylene chloride is introduced at 0-5 ° C with HCl gas. Reaction solution • 1 V: 30 evaporate to give 1.7 g of carboxylic acid,

R f = 0.72 (ethyl acetate / glacial acetic acid 97: 3). To a solution of this product in 17 ml of methylene chloride is added 844 mg of dicyclohexylcarbodiimide (DCC) at room temperature.

• · ·. ·. Then, 877 mg of (S) -3-aminomethyl-1-piperidine 1 '* ··· 35 carboxylic acid tert-butyl ester dissolved in 3 ml are added. ♦ · «· · • 63 105474 methylene chloride. The reaction mixture is filtered, the filtrate is evaporated and the residue is chromatographed on silica gel using methylene chloride / ether (9: 1) as eluent. 0.82 g of tert-butyl (S) -3 - [[N - [[5- (dimethylamino-1-5 naphthyl) sulfonyl] -N- (2-naphthylsulfonyl) glycinyl] amino] methyl] -1 is obtained. Piperidine carboxylate Rf = 0.2 (9: 1 methylene chloride / ether) The resulting compound (0.82 g) is converted analogously to Example 70e) to N - [[(S) -1-amidino-3-piperidinyl] methyl ] -2 - [[[5- (dimethylamino) -1-naphthyl-10] sulfonyl] - (2-naphthylsulfonyl) amino] acetamide (316 mg). R f = 0.46 (Takeda solution), FAB-MS: 637 (M + 1).

Example 73

However, analogously to Example 30, however, using 2-thienylglyoxalic acid, benzoic acid or benzyl chloroformate instead of phenylglyoxalic acid (Example 30g) gives the following compounds: a) (R) -N - [[(S) -1-amidino-3-piperidinyl] methyl] -2- (2-naphthylsulfonamido) -3- (α-oxo-2-thiopheneacetamido) -20-propionamide-p-toluenesulfonate (1: 1), FAB-MS: 571 (M + H) - (b) N- [(R) -2 - [[[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] benzamide-p-toluenesulfonate (1: 1), FAB-MS: 537 (M + H) -.

, 25 c) Benzyl - [(R) -2 - [[[((S) -1-amidino-3-piperidinyl] -yl] methyl] carbamoyl] -2- (2-naphthylsulfonamido] methyl] - • · · * ··· [carbamate acetate (1: 1), FAB-MS: 567 (M + H) 1.

'1 Example 74

The product of Example 27 is obtained by treating '30 with aqueous NaOH solution - [[(R) -α - [[[(RS) -1-amidino-3-piperidinyl] methyl] carbamoyl] -p-nitrophenethyl] sulfamoyl · 1' : benzoic acid, FAB-MS: 533 (M + H) +.

• · «. ···. Example 75

Analogously to Examples 63 and 69, «« · • ·; : 35 (R) -4 - [(S) -3 - [[[(S) -1-Amidino-3-piperidinyl] methyl] -carboxylic acid. 1 · · · 105474 64 bamoyl] -2- (2-naphthylsulfonamido) propionyl] hexahydro-1,4-oxazepine-3-carboxylic acid, FAB-MS: 589 (M + H) 1. Example 76

In analogy to Example 52 (but using 2-naphthylsulfochloride) and Example 60, p - [(RS) -2 - [[[(S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2 - (2-naphthylsulfonamido) ethyl] benzoic acid, FAB-MS: 538 (M + H) -.

Example 77 In analogy to Example 43, 4 '- [(R) -2 - [[[((S) -1-amidino-3-piperidinyl] methyl] carbamoyl] -2- (2-naphthylsulfonamido) ethyl] succinic acid, FAB is obtained. -MS: 535 (M + H) -

Using a compound of formula I, a solvate thereof, or a salt thereof as an active ingredient, pharmaceutical preparations, e.g., tablets and capsules, may be prepared in the manner known per se, as follows: Example A

Per tablet (mg) Active substance 200

Microcrystalline cellulose 155

Maize starch

Talcum 25

Hydroxypropylmethylcellulose 20 25 425 mg

** ··] Example B

'' Per capsule (mg)

Active ingredient 100.0 V: 30 Maize starch 20.0

Milk Sugar 95.0

Talc 4.5 • · ·

Magnesium Stearate 220.0 mg • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 7

Claims (2)

65 105474 Claim Intermediate compounds of formula III 5. T-V N_M MU Y 111 NH 10 and salts thereof, wherein L is NH or O and T is CH 2 or O. 4 «« «R« * if · 4 · · f I · * f · «· • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • rt * if · 4 · · f I · * f ·« · • • • • 4 4 · • 4 4 66 105474 Föreningar med formeln III, som kan användas som mellanproduct 5 V_N NHZ III Y NH 10 och salter av dessa, I wilt formel L um NH eller 0, och T CH2 eller 0. Ill I · « II tt • • • • aa • • • • aa • • • • aaa • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • III III * I · a • «0 a« · aaa • I · a · · «« aa »0. a • a · • a