HRP930501A2 - Guanidins - Google Patents

Description

This invention relates to new guanidine formulas

[image]

where

R represents aryl, heteroaryl or heterocyclyl,

T CH2 or 0 i

-N(X)-M- and the group -N(SO2-R°)-CH2- or in a certain case an isoquinolylene group substituted in the phenyl ring, and

R° has the same meanings as R, or

X represents H, -CH2,COOH, -CH2COO-C1-4-alkyl, -CH2CO-(tetra-to heptamethyleneimino or in certain case N-mono- or N-di-C1-4-alkylated -CH2CONH2, group, and

M group R'-(CH2)1-2CH=, R1-COCH2CH=, R"-COCH2CH=, R'-(CO)1-2, NHCH2CH=, benzyl-OCONHCH2CH=, -CH2[R'-(CO )1-2 NH]CH-, -CH2 (benzyl-OCONH)CH- or -CH(CO-Q)CH2-,

R' aryl, heteroaryl, cycloalkyl or heterocyclyl,

R" tetra- to heptamethyleneimino in a certain case substituted with up to 2 substituents selected from the group consisting of oxo, -COO-C1-4-alkyl, -(CH2)0-1OH, -(CH2)OCO-C1-4- alkyl and in certain cases mono- or di-C1-4-alkylated carbamoyl, i

Q benzylamino or in a certain case with an O- or S-atom interrupted in a certain case with up to 2 substituents a substituted tetra- to heptamethyleneimino group, wherein the substituents are selected from the group consisting of C1-4-alkyl, COOH, -COOC1-4-alkyl , -CH2OH and -CH2O- benzyl,

as well as hydrates or solvates and physiologically acceptable salts of the compounds in question.

The invention further relates to procedures for obtaining the mentioned compounds, pharmaceutical preparations, which contain the mentioned compounds, as well as to the use of these compounds for obtaining pharmaceutical preparations.

Examples of physiologically acceptable guanidine salts of formula I are salts with physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid, sulfuric acid or phosphoric acid; or with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fimaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. Guanidines of formula I with a free carboxy group can also form salts with physiologically suitable bases. Examples of such salts are salts with alkali metals, alkaline earth metals, ammonia and alkylammonia salts, such as Na-, K-, Ca- or tetra-methylammonia salts. Guanidines of formula I can also have a dipolar (zwitter ionic) structure.

Guanidines of formula I can be solvated, especially hydrated. Hydration is carried out during the production process or gradually as a consequence of the hydroscopic properties at the beginning of the anhydrous compound of formula I.

The guanidines of formula I contain at least two asymmetric C-atoms and therefore exist as a diastereoisomeric mixture or as an optically pure compound.

C1-4-alkyl normal chain (C1-4-n-alkyl) or branched groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups are covered by this invention.

Aryl denotes groups, such as phenyl, naphthyl and anthryl, especially with 1 to 4 substituents, such as halogen, NO2, NH2, CN, OH, CH2, isopropyl, t-butyl, phenyl, phenylsulfonyl, OCH3, benzyloxy, formamido , COOH, COO-C1-4-n-alkyl or in certain cases a mono- or di-C1-4-alkylated amino group.

Further possible substituents for the phenyl group are -NHSO2-Ar or -NHCO-Ar (where Ar is phenyl substituted with up to 3 substituents such as halogen, NO2, CF3, COOH and C1-4-alkyl, e.g. CH3), -NHCOCH2CH2COO (H, C1-4-alkyl or benzyl), acetamido, -NH2COCH2OCH2CH3 OCH, -NHCOO(H or C1-4-alkyl), -NHCOCOO (H or C1-4-alkyl), -NHCH2 COO-ethyl, -NHCOCOC6 H5 and tetra- to hepta-methyleneiminocarbonyl.

Examples of cycloalkyl groups are cyclohexyl and decalyl. Heteroaryl groups consist of one or two rings and contain 3 to 9 carbon atoms and 1 or 2 heteroatoms. Examples of the same are imidazolyl, thienyl, benzothienyl, quinolyl and indolyl. They can be substituted, for example, with CH3, halogen, -CH2COOH or 1-methyl-5-trifluoromethylpyrazolyl group.

Heterocyclyl means 1 or 2 rings, with 4 to 7 C-atoms and 1 or 2 heteroatom groups, such as tetrahydroquinolyl, azepinyl, piperidinyl, pyrrolidinyl, benzodiazepinenyl, benzooxazolyl and benzopyrrolidinyl, in certain cases with 1 or 2 substituents such as methyl , halogen, oxo, COOH or COOCH3.

Examples of tetra- to heptamethyleneimino groups are piperidino, hexahydroazepine and heptahydroazocine. Examples of substituents of such an R" group are acetoxy, acetoxymethyl, carbomethoxy, carbethoxy, diethylcarbamoyl, butyryloxymethyl and isobutyryloxymethyl.

Examples of O- or S-atom terminated and in some cases substituted tetra- to heptamethyleneimino groups Q are carboxyhexahydrooxazepine and hexahydrothiazepine.

As a substituent for the phenyl ring in the isoquinolylene group -N(X)-M, for example Cl, NO2, NH2, and OH come into consideration.

Examples of compounds of formula I are those of the formula:

[image]

where

-N(X')-M- represents in a certain case an inoquinolylene group substituted in the phenyl ring, or

X' H, -CH2COOH, -CH2COO-C1-4-alkyl, -CH2CO- (tetra- to heptamethyleneimino) or in certain case N-mono- or N-di-C1-4-alkylated -CH2CONH, group, and

M' group R'-(CH2)1-2CH=, R'-COCH2CH= or -CH(CO-Q1)CH2-,

Q' is benzylamino, morpholino or tetra- to heptamethyleneimino, and R, R', L and T have the same meanings as defined above, as well as hydrates or solvates and physiologically acceptable salts of these compounds.

The best of the IA compounds are those in which X' is H and R, M', L and T have the meanings given above.

The best of compounds I are those of the formula

[image]

where

M" represents the group R"-COCH2CH=, R'-(CO)1-2 NHCH2CH=, benzyl-OCONHCH2CH=, -CH2[R'-(C)1-2NH]CH-, -CH2(benzyl-OCONH) CH- or -CH(CO-Q")CH2-,

Q" tetra- to heptamethyleneimino group in a certain case with an O- or S-atom interrupted and in a certain case substituted with up to 2 substituents selected from the group consisting of C1-4-alkyl, COOH, -COO-C1-4-alkyl, -CH2OH and -CH2O-benzyl, and R, R', R", L and T have the meanings defined above.

Examples of aryl groups R are naphthyl, hydroxynaphthyl, 4-biphenyl, 2-anthryl, iodophenyl, nitrophenyl,

benzyloxylenyl, dimethoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl, 2,4,6-triisopropylphenyl, carboxyphenyl, methoxycarbonylphenyl, benzyloxynaphthyl, phenylsulfonylphenyl, hexahydroazepinoylphenyl and t-butylphenyl.

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

One example of a heterocyclyl group R is 3-methyl-1,2,3,4-tetrahydro-8-quinolyl.

An example for the sulfonamide group -N(SO2-R°)-CH2- when it denotes -N(X)-M-is N-

dimethylaminonaphthylsulfonyl-aminomethylene.

The best compounds of formula I are those in which X is H or -CH2COOH.

Examples of the other M when M represents R'-(CH2)1-2CH= are 3-indolylethylidene, 2,3-dioxo-1-indolinylethylidene, phenethylidene, 1,4-dioxo-5H-2,5-benzodiazepine-5- ilethylidene, (fluorine, chlorine, iodine, cyano, nitro, amino, carboxy, C1-4-alkoxycarbonyl or hydroxy)-phenethylidene, cyclohexylpropylidene, decalylethylidene, imidazolylethylidene, thienylethylidene (methyl, bromo, fluorine or carboxymethyl)-3-indolethylidene, naphthylethylidene (ethoxycarbonylcarbonylamino, methoxycarbonylethylcarbonylamino, benzyloxy carbonylethylcarbonylamino, ethoxycarbonylamino, benzoylcarbonylamino, carboxybenzoylamino, methoxy ethoxyacetamido, acetamido, carboxycarbonylamino, tolylsulfonamido, iodophenylsulfonamido, carboxyphenyl sulfonamido or ethoxycarbonylmethylamino) phenethylidene, oxobenzoxazolinethylidene or 5-bromo- or 5-methyl-2,3-dioxo-1 -indolinylethylidene.

Examples of residues M when M represents (R' or R")-COCH2CH= are hexahydroazepinoylethylidene (methoxycarbonyl or carboxy)-pyrrolidinoylethylidene, 3,4-dihydro-2(1H)-isoquinolinoylethylidene (nitro, amino, iodo or formamido)benzoylethylidene, heptahydroazocinoylethylidene (ethoxycarbonyl, acetoxymethyl, dimethylcarbamoyl, isobutyryloxymethyl or butyryloxymethyl) piperidinoylethylidene, 3-methoxycarbonyl-4-oxopiperidinoylethylidene or 4-acetoxy-3-ethoxycarbonylpiperidinoylethylidene.

Examples of residues M when M represents R'-(CO)1-2-NHCH2CH= are benzoylcarboxamidoethylidene, thienoylcarboxy aminoethylidene, benzoylamidoethylidene or benzoyloxycarboxamidoethylidene.

Examples of residues M when M represents -CH2[R'-(CO)1-2-NH]CH- are 2-(carboxybenzoylamido)ethylene, 2-(benzyloxybenzoyl-amido)ethylene, 2-(2- piperidinecarboxamido)ethylene , 2-(hydroxybenzoylamido)ethylene and 2-(aminobenzoyl amido)ethylene.

Examples of other M when M represents -CH(CO-Q)CH2- are 1-(benzylaminocarbonyl)ethylene, 1-(hexahydroazepinoyl)-ethylene, 1-(morpholinoyl)ethylene, 1-(heptahydroazocinoyl)ethylene, 1-[2 -(benzoyloxymethyl-morpholinoyl)ethylene, 1-[2-(hydroxy methylmorpholinoyl)]ethylene, 1-(2-ethoxycarbonyl-4-methylpiperidinoyl)ethylene and 1-(2-carboxy-4-methylpiperidinoyl)ethylene and 1-(3 -carboxyhexahydro-1,4-oxazepinoyl)ethylene.

In the above formulas in the first row R is aryl, especially naphthyl or nitro- or iodophenyl, L is NH and the asymmetric C-atom in the piperidine- or morpholine- ring is in the first row in the (S)-configuration.

Further, the best compounds of formula I are those of formula

[image]

where A is aryl, aroyl or heterocyclyl, especially phenyl, nitrophenyl, indolyl, 2,3-dioxo-1-indoinyl or aminobenzoyl.

Examples of particularly suitable compounds are the following:

(R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthylsulfonamido)-2,3-dioxo-1-indolinepropionamide,

(R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthylsulfonamido)-o-nitrohydrocinnamamide,

(R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(o-nitrobenzenesulfonamido)indole-3-propionamide,

(R)-N-[(S)-1-amidino-3-piperidinylmethyl)-α-(p-iodobenzenesulfonamido)indole-3-propionamide,

(R)-N-[(S)-1-amidino-3-piperidinylmethyl]-α-(p-iodobenzenesulfonamido)-p-nitrohydrocinnamamide,

(R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-3-(o-aminobenzoyl)-(2-naphthylsulfonamido)propionamide,

N-[(R)-α-[[(S)-1-amidino-3-piperidinyl]methylcarbamoyl]-phenethyl]-N-(2-naphthylsulfonyl)glycine,

(R)-N-[(S)-1-amidino-3-piperidinylmethyl]-1,2,3,4-tetrahydro-2-(2-naphthylsulfonyl)-3-isoquinolinecarboxamide,

(S)-N-[(RS)-1-amidino-3-piperidinylmethyl]hexahydro-β-(2-naphthylsulfonamido)-γ-oxo-1H-1-azepinebutyramide,

(R)-N-[(S)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonalnido),2,3-dioxo-1-indolinepropionamide,

4'-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)ethyl]oxanilic acid,

(S)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]hexahydro-β-2-naphthylsulfonamido-γ-oxo-1(2H)-azocynbutyramide,

(2RS,4R)-1-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]N2-(2-naphthylsulfonyl)-L-asparaginyl]-4-methyl-2-piperidinecarboxylic acid,

4'-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)ethyl]succinanilidic acid.

The above-mentioned compounds are obtained by

a) acid formula

R-SO2N(X)-M-COOH II

in which the carboxy group present in the X, R or M group was previously protected, reacts with an amine or an alcohol of the formula

[image]

or with some salt of the same or

b) compound of the formula

[image]

reacts with an amidination reagent or

c) amine formula

[image]

reacts with an acid of the formula R'COOH or with its functional derivative, i

d) if desired, the reactively favorable group located in group M of the compound of formula I, i is functionally changed

e) if desired, the compound of formula I is converted into a physiologically acceptable salt or the salt of the compound of formula I is converted into a free acid or base.

Thus, advantageously, acid II in a solvent such as dimethylformamide (DMF) in the presence of a base such as 4-ethylmorpholine or ethyldiisopropylamine is reacted with a salt of a compound of formula III, for example such as trifluoroacetate, bisulfite, nitrate, hydrochloride or hydroiodide, and with benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate at room temp. When the group X, R or M is protected, for example as t-butyl ester, the carboxy group is free.

According to process variant b), compound IV in a solvent such as DMF, in the presence of a base such as triethylamine, is reacted with formamidinesulfonic acid or 3,5-dimethyl-1-pyrazolylformamidinium nitrate, preferably at a temperature of up to 50°C.

According to process variant c) amine V reacts with the acid R'COOH or with its functional product, e.g. acid anhydride, in a solvent such as DMF in the presence of a base, such as 4-ethylmorpholine, at an elevated temperature, e.g. up to 50 or 80°C.

The following can be mentioned as functional changes in variant d):

1. Reduction of the nitroaryl group in group M to an aminoaryl group, in a solvent such as ethanol, with Pd/C;

2. Saponification of an ester group such as ethoxycarbonyl, eg in ethanol or methanol, using a base such as aqueous sodium hydroxide;

3. Saponification of an ester group, such as benzyloxycarbonyl, eg in ethanol with Pd/C;

4. Cleavage of the benzyl ether, eg in ethanol with Pd/C in the presence of an acid such as hydrochloric acid or acetic acid.

N-sulfonated amino acids II are obtained by reacting a suitable reaction-favorable sulfonic acid product, such as the sulfochloride R-SO2Cl, 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, eg diethylether or dioxane, and water.

According to one variant, acid II can be obtained by oxidation of the corresponding alcohol

R-SO2-N(X)-M-CH2OH VI

eg in a solvent such as acetone, with an oxidizing agent such as Jones reagent. In doing so, the heterocyclyl radical R' of alcohol VI such as 2-oxo-1-indolinyl is oxidized to 2,3-dioxo-1-indolinyl in the M group.

Alcohol VI can be obtained by reacting the corresponding α-amino alcohol HN(X)-M-CH2OH in the presence of aqueous sodium hydroxide and sodium bicarbonate with sulfochloride R-SO2Cl in dioxane.

Aminoalcohol HN(X)-M-CH2OH, where M is, for example, the group =CH(CH2-R') can be obtained by cleavage of the corresponding N-atom protected, in the 4-position with -CH2-R' substituted oxazolidine, e.g. (R)-2,2-dimethyl-4-(CH2-R')-3-oxazolidine-carboxylic acid t-butyl ester, in methanol with hydrochloric acid.

The above oxazolidine can be obtained in a known manner, e.g. if R' is a heterocyclyl radical attached via the N-atom, such as 2-oxo-1-indolinyl, by reaction of the corresponding cyclic amine H-R' with (S)-2,2-dimethyl -4-(p-tolylsulfonyloxymethyl)-3-oxazolidinecarboxylic acid in the form of t-butyl ester in the presence of a suspension of sodium hydride in DMF.

To obtain the amino acid II, where R is a hydroxyaryl radical, the corresponding sulfochloride R-SO2Cl, where the OH- group is protected, e.g. as an acetoxy group in acetone reacts with the amino acid HN(X)-M-COOH in the presence of sodium hydroxide in water, after of which the protective group, eg acetyl, is removed with a solution of sodium hydroxide in water and methanol.

To obtain a guanidine of formula I, where X is -CH2COOH, the sulfochloride R-SO2Cl is reacted with a salt, eg, p-toluenesulfonate H2N-M-COO-benzyl ester in a solvent such as methylene chloride in the presence of a base such as triethylamine. The resulting sulfonamide R-SO2NH-M-COO-benzyl is then reacted in a solvent such as THF at about -80°C in the presence of butyllithium with bromoacetic acid t-butyl ester. Then the benzyl group is selectively removed, for example by catalytic hydrogenation with Pd/C in ethanol, and the resulting diester

R-SO2N(CH2COO-t-butyl)-M-COO-benzyl

removes. As described above, reaction of the resulting acid with a compound of formula III with a carboxyl group protected with t-butyl ester liberates the side chain.

The starting acids R-SO2NHCH(CO-Q)-CH2COOH are obtained

a) by the reaction of aspartic acid products, e.g.

t-butoxy-CONHCH(COOH)CH2COO-benzyl with the corresponding amine H-Q in a solvent such as DMF, in the presence of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,

b) reaction of the amide formed

t-butoxy-CONHCH(CO-Q)-CH2COO-benzyl in a solvent such as ethyl acetate, with an acid such as hydrochloric acid and then in dioxane with sodium hydroxide, sodium bicarbonate and sulfochloride R-SO2Cl and

c) by reaction of the benzyl group in the resulting sulfonamide R-SO2NHCH(CO-Q)-CH2COO-benzyl in a solvent such as methanol using sodium hydroxide.

Compounds III, IV and V are new and as such are the subject of this invention. Piperidine derivatives of formula III as described in examples 1, 2 and 3 can be obtained from 3-picolylamine, if L+ is NH or from 3-hydroxymethylpiperidine if L=O.

Aminomethylmorpholine products of formula III are obtained by the reaction of 2-aminomethyl-4-benzylmorpholine (J. Med. Chem. 33, 1990, 1406-1413) with di-t-butyldicarbonate in dioxane, by reduction of the product with a Boc-protected amine in ethanol in the presence of Pd/ C in 2-(t-butoxycarbonylaminomethyl)morpholine and amidinating the latter. Hydroxy methyl morpholine products of formula II can be obtained by amidination of 2-hydroxymethylmorpholine.

Compounds of formula IV can be obtained by reacting the corresponding acid II with a compound of formula

[image]

where W is a protecting group such as Boc or Z,

for example, as described above for the reaction of II with III, after which removal of the protecting group is carried out, for example using trifluoroacetic acid in methylene chloride, p-toluenesulfonic acid in acetonitrile or using a solution of hydrogen chloride in ethyl acetate.

Alcohols of formula III' can be obtained as described in example 3a) by introducing a protecting group with the N-atom of 3-hydromethylpiperidine, or as described in example 19a) to c) deriving from benzyloxymethyloxirane via 2-benzyloxymethylmorpholine, thus obtaining e.g. Boc-protected 2-benzyloxymethylmorpholine. As described in examples 6a) to d) and 19d) and e), the resulting alcohol can be converted to the corresponding amine III'.

Amines V can be converted into the corresponding compounds of the formula I by breaking the benzyloxycarbonyl group, into the corresponding compounds of the formula I, where, for example, the M group is:

-CH2(benzyl-OCONH)CH-

eg in ethanol in the presence of hydrochloric acid with Pd/C.

Guanidines of formula 1, their solvates and their salts thus inhibit thrombin-induced platelet aggregation as well as thrombin-induced coagulation of fibrinogen in blood plasma. The mentioned compounds also affect platelet-induced coagulation as well as plasmatic blood coagulation. In this way, they prevent the existence of coagulation thrombi, but also from thrombi rich in platelets and can be used to fight or prevent diseases such as thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis. Furthermore, these compounds have an effect on tumor cells and prevent the formation of metastases. Thus, they can be used as anti-tumor agents.

Specific inhibition of thrombin and other serine proteases with the mentioned compounds is desirable in order to obtain compounds with the greatest possible specificity, thus avoiding possible side effects. In addition to other tested serine proteases, the ratio between trypsin inhibition and thrombin inhibition was taken as a general measure for the specificity of the compounds (q in the following table), because trypsin, as the most non-specific serine protease, can be easily inhibited by a wide variety of inhibitors. In order to be able to directly compare the inhibition of thrombin and trypsin despite the use of a specific substrate as a measure of inhibition, the constant Ki was calculated independent of enzyme and substrate concentration.

In order to prove the inhibition of the catalytic activity of the above proteases, specific chromogenic peptide substrates can be used. Inhibition of the amidolytic activity of thrombin and trypsin with the above-mentioned guanidines was carried out in the manner described below.

Measurements were made on microtiter plates at room temperature. Therefore, 150 μl of buffer (50 mM Tris, 100 mM NaCl, 0.1% polyethylene glycol; pH 7.8) with 50 μl of DMSO dissolved and mixed with the inhibitory substance was mixed into each well of the plate, and 25 μl of human thrombin (0 .5 nM final concentration). After 10 minutes of incubation, the reaction was started with the chromogenic substrate S-2238 (H-D-Phe-Pip-Arg-Paranitroaniline from Kabivitrum; 10 or 50 μM final concentration), and the hydrolysis of the substrate was monitored spectrophotometrically on a kinetic Microtiter plate counter for 5 minute.

After graphical presentation of the inhibition curves, Ki-values were determined according to the described method (Biochem. J. 55, 1955, 170-171). Inhibition of trypsin was performed in an analogous way, but using the substrate S-2251 (H-D-Val-Leu-Lys-Paranitroaniline (in 200 and 750 μM final concentration.

The results are given in the following table:

[image]

Guanidines of formula I have low toxicity. Medicines containing guanidine of formula I, a solvate or a salt thereof, are also the subject of this invention, as well as processes for obtaining these medicines and are characterized by the fact that one or more of the mentioned compounds, and if desired, one or more other therapeutically active substances are formulated into some galenic form for administration. The drug can be administered enterally, eg in the form of tablets, lactablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, eg in the form of suppositories, or as a spray. Administration can also be parenteral, for example in the form of a solution for injections.

To obtain tablets, lactablets, dragees and hard gelatin capsules, the active substance is mixed with a pharmaceutical inert, inorganic or organic excipient. Such excipients for tablets, lactablets, dragees and hard gelatin capsules are lactose, corn starch or their derivatives, talc, stearic acid or its salts. For soft gelatin capsules, excipients are, for example, vegetable oils, waxes, fats, semi-liquid and liquid polyols; but according to the characteristics of the active substance, although it is not necessary to use excipients for such capsules. For obtaining solutions and syrups, excipients are, for example, water, polyol, sucrose, invert sugar and glucose, for solutions that are used by means of injections, excipients are water, alcohols, polyols, glycerol and vegetable oils, and for suppositories, they are natural or solid oils, waxes, fats, semi-liquid or liquid polyols. Pharmaceutical preparations may also contain a preservative, a solvent as a diluent, a stabilizing agent, a wetting agent, an emulsifying agent, a sweetening agent, a coloring agent, a deodorizing agent, salts for changing the osmotic pressure, a buffer, an agent for coating or antioxidant.

To combat or prevent the aforementioned diseases, the dosage of the active substance is within limits that are variable and depends on the chosen method of administration. Doses from about 0.1 to 20 mg/kg, especially from about 0.5 to 4 mg/kg per day for adults, are suitable, so that they can be exceeded above or below the given doses, if necessary.

Example 1

a) A solution of 66.6 g of di-t-butyldicarbonate in 200 ml of dioxane is added to a solution of 30 g of 3-picolylamine in 300 ml of dioxane, so that the temperature does not exceed 25°C. The reaction mixture was stirred for 3 hours at room temperature and evaporated. After filtering through silica gel and ethyl acetate, 55.5 g of 3-t-butyloxycarbonyl-picolylamine is obtained.

b) 45.5 g of 3-t-butyloxycarbonyl-picolylamine are dissolved in 220 ml of methanol and hydrogenated in the presence of a catalyst with 4.6 g of ruthenium on aluminum (5%) at 60°C under a hydrogen pressure of 100 bar. After filtering the catalyst and evaporating the solvent, 46 g of rac-3-t-butyloxycarbonyl-aminomethylpiperidine are obtained.

c) 38.8 g of the product from b) are dissolved in 900 ml of DMF and mixed with 74.5 ml of triethylamine. After adding 26.5 g of formamidinesulfonic acid, the reaction mixture is stirred for 15 hours and then filtered. The mother liquor is evaporated, the residue is dissolved in water and diluted with ethyl acetate. The aqueous phase is evaporated and the product is azeotroped with ethanol, toluene and dichloroethane. The residue is suspended in ether and filtered. Thus, 44.0 g of rac-3-t-butoxycarbonyl-aminomethyl-1-amidinopiperidinehemisulfite are obtained, MS (mass spectrum): 257 (M++1), 201, 157, 126, 96.

d) 27.8 g of the product from c) are dissolved in 70 ml of methylene chloride, mixed with 70 ml of trifluoroacetic acid at 0°C and stirred for 1 hour. The reaction mixture is evaporated and azeotropically evaporated with toluene and ethanol. Thus, 27.6 g of rac-3-aminomethyl-1-amidinopiperidine-sulfite, MS: 156 (M+), 126(M+-CH2NH2), 69, 45, are obtained.

Example 2

A solution of 5.3 g of rac-3-hydroxymethylpiperidine in 100 ml of DMF was mixed with 19 ml of triethylamine. After adding 6.8 g of formamidinesulfonic acid, the reaction mixture was stirred for 15 hours. The suspension is filtered, the precipitate is washed with ether and dried. Thus, 10.3 g of rac-3-hydroxymethyl-1-amidinopiperidine-hemisulfate, MS 158(M+1), 143, 116, 102 are obtained; d.p. 100°C.

Example 3

a) A solution of 211.2 g of di-t-butyldicarbonate in 500 ml of dioxane is added to a solution of 92.9 g of rac-3-hydroxymethylpiperidine in 1500 ml of dioxane so that the temperature does not exceed 25°C. The reaction mixture was stirred for 15 hours at room temperature and evaporated. The residue is suspended in 800 ml of hexane and filtered. Thus, 120.7 g of rac-N-t-butyloxycarbonyl-3-hydroxymethylpiperidine are obtained, m.p. 78°C.

b) A solution of 100 g of the product from a) in 4000 ml of methylene chloride is mixed with 56.2 ml of pyridine and cooled to 0°C. Then 58.3 ml of butyric acid chloride is added drop by drop, so that the temperature does not exceed 10°C. The reaction mixture is then stirred for 15 hours at room temperature. The suspension is filtered, the filtrate is evaporated and the residue is dissolved in ethyl acetate. The organic phase is washed with a 10% CuSO4 solution, dried and evaporated. The residue is filtered through silica gel and eluted with hexane/ethyl acetate (8/2). Thus, 119.7 g of rac-3-(butyroxymethyl)-1-piperidine-carboxylic acid is obtained in the form of butyl ester.

c) 116.6 g of the product from b) is emulsified in 2 dm3 of 0.1 M sodium chloride solution and 80 ml of 0.1 M sodium phosphate buffer, pH 7.0. The pH is maintained at 7.0 with 1.0 M sodium hydroxide and the reaction is started by adding 1.00 g of lipoprotein lipase obtained from Pseudomonas fluorescens (Lipase P30, Amano) in 10 ml of 0.1 M sodium chloride solution. The pH is maintained at 7.0 during mixing with the addition of a 2.0 M sodium hydroxide solution. After 14 hours, the reaction is stopped by adding 500 ml of methylene chloride, the reaction mixture with methylene chloride is extracted and the organic phase is dried and evaporated. Chromatography of the residue over silica gel with hexane/ethyl acetate gives 36.6 g of [S]-3-hydroxymethyl-1-piperidinecarboxylic acid in the form of t-butyl ester, m.p. 89-90°C, [α]25365 = +53.5° (c=?o; EtOH).

d) 65.7 g of ester fraction e from c) is emulsified in 1.15 dm3 of 0.1 M sodium chloride solution and 45 ml of 0.1 M sodium phosphate buffer (pH 7.0) and mixed with 0.50 g of Lipase P-30 in 5 ml of 0.1 M sodium chloride solution. The pH is maintained at 7.0 during mixing with the addition of 2.0 M sodium hydroxide. After 40 hours, the reaction is finished by adding 400 ml of methylene chloride. The reaction mixture is extracted with methylene chloride and the organic phase is dried and evaporated. Chromatography of the residue over silica gel with hexane/ethyl ester gives 49.5 g of [R]-3-(butyryloxymethyl)-1-piperidinecarboxylic acid t-butyl ester. The same is dissolved in 250 ml of ethanol, mixed with 88 ml of 2 M sodium hydroxide, stirred overnight and then evaporated. The residue is dissolved in 200 ml of methylene chloride and washed with water, the aqueous phase is extracted with methylene chloride and the organic phase is dried and concentrated. Chromatography of the residue over silica gel and with hexane/ethyl acetate gives 33.7 g of [R]-3-hydroxymethyl-1-piperidinecarboxylic acid t-butyl ester, [α]25365 =-60.7° (c=1.0; EtOH).

e) A solution of 5.0 g of the product from d) in 20 ml of methylene chloride is cooled to 0°C and mixed with 15 ml of trifluoroacetic acid. After 2 hours, the reaction mixture is evaporated and the residue is dissolved in water and adjusted to pH with sodium bicarbonate. This aqueous phase is evaporated and the crystalline mass is suspended in 100 ml of methylene chloride/ethanol (9/1). The salt is separated by filtration and the filtrate is evaporated. The residue was dissolved in 30 ml of DMF and mixed with 9.7 ml of triethylamine. After adding 3.5 g of formamidinesulfonic acid, the reaction mixture was stirred for 15 hours. The precipitate is separated by filtration and the solvent is evaporated. The residue is purified by reverse-phase chromatography over silylated silica gel RP-18 with water. 2.6 g of (R)-3-hydroxymethyl-1-amidinopiperidine-hemisulfate are thus obtained, FAB-MS (fast atom bombardment mass spectrometry): 158 (M+1).

Example 4

Similar to example 3e) (s)-3-hydroxymethyl-1-amidinopiperidine hemisulfate is obtained from t-butyl ester [S]-3-hydroxymethyl-1-piperidinecarboxylic acid, FAB-MS: 158 (M+1).

Example 5

A solution of 1.5 g of N-(2-naphthylsulfonyl)-D-tryptophan in 30 ml of DMF was mixed with 1.5 ml of ethylmorpholine. After adding 0.7 g of rac-3-aminomethyl-1-amidinopiperidine-sulfite (example 1) and 1.7 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate, the reaction mixture was stirred for 15 hours. The solvent is evaporated, the residue is dissolved in 50 ml of water and extracted with 100 ml of ethyl ester. The ethyl acetate phase is washed with water, dried and evaporated. The crude material was purified on an RP-18 column with water/acetonitrile (0.30%). 0.8 g of (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthylsulfonamido)indole-3-propion-amide-bisulfite, FAB-MS: 533 ( M+H)+.

Example 6

a) A solution of 5.0 g of (S)-3-hydroxymethyl-1-piperidinecarboxylic acid in the form of t-butyl ester (example 3c) in 100 ml of pyridine is mixed with 5.4 g of p-chlorosulfonyl chloride. The reaction mixture is stirred for 15 hours, evaporated, dissolved in 200 ml of ethyl acetate and washed with water and an aqueous 10% solution of CuSO4. The organic phase is dried and evaporated. The residue is filtered through silica gel and eluted with hexane/acetic acid and ethyl ester (8/2). 6.5 g of t-butyl ester (S)-3-(p-chlorophenylsulfonyloxy-methyl)-1-piperidinecarboxylic acid is thus obtained.

b) The solution of the product from a) in 500 ml of DMF is mixed with 3.25 g of sodium azide. The reaction mixture is stirred and evaporated for 15 hours at 50°C. The residue is dissolved in water and ether and washed with water. The ether phase is dried and evaporated. Thus, 4.0 g of t-butyl ester (S)-3-azidomethyl-1-piperidinecarboxylic acid is obtained.

c) A solution of the product from b) in 100 ml of ethanol in the presence of 0.6 g of platinum oxide and under a hydrogen pressure of 1 bar is hydrogenated. The reaction mixture is then filtered through silica gel and eluted with m ethanol. 3.4 g of t-butyl ester (R)-3-aminomethyl-1-piperidinecarboxylic acid are obtained, [α]25D = +23.0° (c=0.4; EtOH).

d) It is obtained in a similar way from (R)-3-hydroxymethyl-1-piperidinecarboxylic acid, t-butyl ester t-butyl ester (S)-3-aminomethyl-1-piperidinecarboxylic acid, [α]25D=17.7 ° (c=0.6; EtOH).

e) A solution of 1.5 g of N-(2-naphthylsulfonyl)-D-tryptophan in 50 ml of DMF is mixed with 0.8 ml of ethyldiisopropylamine. After adding 1.0 g of the product from d) and 1.7 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate, the reaction mixture is stirred for 15 hours. The solvent is evaporated, the residue is dissolved in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated. Chromatography over silica gel with ethyl acetate gives 2.3 g of (R)[(S)-1-(t-butoxycarbonyl)-3-piperidinylmethyl]-α-naphthylsulfonamidoindole-3-propionamide.

f) A solution of the product from e) in 10 ml of methylene chloride is mixed with 3 ml of trifluoroacetic acid at 0°C. The reaction mixture is stirred for 1 hour at 0°C, evaporated and azeotropically evaporated with ethylene chloride. The residue is dissolved in water and ethyl acetate, adjusted to pH with 10% sodium carbonate and stirred. The organic phase is dried and evaporated. 2.5 g of (R)-α-naphthylsulfonamido-N-[(S)-3-piperidinylmethyl]-indole-3-propionamide are obtained.

g) A solution of the product from f) in 50 ml of DMF is mixed with 1.7 ml of triethylamine. After adding 0.7 g of formamidinesulfonic acid, the reaction mixture was stirred for 15 hours. The solvent is evaporated, the residue is dissolved in ethyl acetate and methanol. The organic phase is washed with water, dried and evaporated. Purification of the product on an 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 , FAB-MS: 533 (M+H) + .

Example 7

a) A solution of 1.0 g of N-2-naphthylsulfonyl-(D)-tryptophan in 20 ml of DMF is mixed with 0.5 ml of ethyldiisopropylamine. After adding 0.6 g of (S)-3-hydroxymethyl-1-piperidinecarboxylic acid in the form of t-butyl ester (example 3c) and 1.1 g of benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium-hexafluorophosphate, the reaction mixture is mixed for 15 hours. The solvent is evaporated, the residue is dissolved in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated. Chromatography over silica gel with ethyl acetate gives 1.0 g of N-(2-naphthylsulfonyl)-D-tryptophan-(S)-1-tt-butoxycarbonyl-3-piperidinyl-methyl ester.

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

c) A solution of the product from b) in 20 ml of DMF is mixed with 0.4 ml of triethylamine. After adding 0.2 g of formamidinesulfonic acid, the reaction mixture is stirred for 15 hours. DMF is evaporated, the residue is dissolved in ethyl acetate and washed with water. The organic phase is dried and evaporated. Purification on an RP-column with water/acetonitrile gives 0.27 g of N-(2-naphthylsulfonyl)-D-tryptophan-(S)-1-amidino-3-piperidinylmethylester-bisulfite, FAB-MS: 534 (M+1) .

Example 8

a) A solution of 10.7 g of t-butyl ester (R)-4-hydroxymethyl-2,2-dimethyl-3-p-xazolidinecarboxylic acid (J. Org. Chem. 52, 1987, 2361-64) in 107 ml of pyridine is mixed with 9.7 g of p-toluenesulfonic acid in the form of chloride. The reaction mixture is stirred for 17 hours, then dissolved in ethyl acetate and washed with water. After drying and evaporation, the residue is purified over silica gel with hexane-ethyl acetate (3:1). Thus, 15.1 g of t-butyl ester (S)-2,2-dimethyl-4-(p-tolylsulfonyloxymethyl)-3-oxazolidinecarboxylic acid are obtained.

b) Add 4.6 g of 2-indolinone to a suspension of 0.82 g of sodium hydride in 50 ml of DMF and continue stirring for 90 minutes. Then 6.6 g of the product from a) is added to 60 ml of DMF and the reaction mixture is stirred at 50°C overnight. After evaporation of the solvent, the residue is dissolved in ethyl acetate and washed with water. After drying and evaporation of the solvent, the residue is purified over silica gel with ethyl acetate/hexane (1/4). Thus, 2.5 g of t-butyl ester (r)-2,2-dimethyl-4-(2-oxo-1-indolinylmethyl)-3-oxazolidine carboxylic acid is obtained.

c) A solution of 2.5 g of the product from b) in 30 ml of methanol is mixed with 36 ml of 2 M hydrochloric acid and stirred overnight. After evaporation of the solvent, the residue is azeotropically evaporated with toluene. 1.56 g of the resulting 1-[(R)-2-amino-3-hydroxypropyl]-2-indolinone are dissolved in 2 equivalents of 1 M sodium hydroxide. Add 0.8 g of sodium bicarbonate in 8.1 ml of water and then a solution of 1.46 g of 2-naphthylsulfonyl chloride in 28 ml of dioxane, and continue stirring overnight. The reaction mixture is placed on 200 ml of aqueous 5% potassium sulfate/10% potassium sulfate and extracted with ethyl acetate. After washing the organic phase with water and drying, the solvent is distilled. The residue is purified over silica gel with methylene chloride/methanol (98/2). 1.9 g of N-[(R)-2-hydroxy-1-(2-oxo-1-indolinylmethyl)ethyl]-2-naphthylsulfonamide are thus obtained.

d) A solution of 1.82 g of the product from c) in 70 ml of acetone is mixed with 17.4 ml of Jones reagent at 0°C and stirred for 4 hours. The reaction mixture is placed on ice and extracted with ethyl acetate. After washing the organic phase with water, drying and evaporation, the product is purified over silica gel with methylene chloride/methanol (19/1) and 1% acetic acid. 1.5 g of N-(2-naphthylsulfonyl)-3-(2,3-dioxo-1-indolinyl)-D-alanine are thus obtained.

e) Similar to example 5, the product from d) yields (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthylsulfonamido-2,3-dioxo- 1-Indolinepropionamide-acetate (epimers 1:1), FAB-MS: 671 (M+H)+.

Example 9

a) 20 g of 2-naphthylsulfonyl chloride in 150 ml of ether is added to a solution of 7.3 g of (R)-phenylalanine in 120 ml of 1 M sodium hydroxide. The reaction mixture is stirred for 15 hours and drained. The aqueous phase is separated, washed with ether, acidified with HCl to pH 3 and extracted with ethyl acetate. The organic phase is dried and evaporated. The resulting crystals are suspended in ether and filtered. Thus, 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 obtained in an identical way:

N-(2-naphthylsulfonyl)-3-p-chlorophenyl-D.alanine, m.p. 154°C

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

N-(2-naphthylsulfonyl)-3-p-nitrophenyl-D-alanine, m.p. 218°C

N-(2-naphthylsulfonyl)-3-benzyl-D-alanine, m.p. 138°C

N-(2-naphthylsulfonyl)-D-tryptophan, mp 167°C

N-(4-biphenylsulfonyl)-D-tryptophan, m.p. 227-230°C

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

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

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

N-(2,3,6-trimethyl-4-methoxyphenylsulfonyl)-D-tryptophan, MS: M+ 416

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-isoquinoline-carboxylic acid, m/e 322, 191, 176, 150, 127.

c) In a similar way as in example 5, (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthylsulfonamido)hydrocinnamide-bisulfite (epimers 1) is obtained from the product from a) :1), FAB-MS: 494 (M+H) + .

Example 10

a) 1.1 g of sodium hydride dispersion (60%) is suspended in 50 ml of DMF. The same 5.23 g of 4-methyl-3H-1,4-benzodiazepine-2,5(1H,4H)-dione is added, so that the temperature does not exceed 35°C, and it is stirred at room temperature for 90 minutes. Then a solution of 5.3 g of t-butyl ester (S)-2,2-dimethyl-4-(ptolylsulfonyloxymethyl)-3-oxazolidinecarboxylic acid (example 6a) in 50 ml of DMF is added and stirring is continued overnight at 50° C. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, washed with water and dried. After evaporation of the solvent, the residue is purified over silica gel with ethyl acetate/hexane (1/1). Thus, 1.85 g of t-butyl ester (R)-(2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepine-1-ylmethyl)-2 is obtained ,2-dimethyl-3-oxazolidine carboxylic acids.

b) A solution of the product from a) in 37 ml of methanol is mixed with 23 ml of 2 M hydrochloric acid. After stirring overnight, the reaction mixture was evaporated, 1.37 g of the resulting 1-[(R)-2-amino-3-hydroxypropyl]-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2 ,5(1H)-dione is dissolved in 15 ml of pyridine and mixed with 2.08 g of 2-naphthyl sulfochloride. After 3 hours, the reaction mixture is placed in 2 M hydrochloric acid and extracted with ethyl acetate. It is washed with water, dried and the solvent is evaporated. The residue is purified over silica gel with methylene chloride/methanol (97/3). Thus, 0.5 g of N-[(R)-1-hydroxymethyl-2-(2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H-1,4-benzodiazepine-1- ylmethyl)ethyl]-2-naphthylsulfonamide.

c) A solution of 0.4 g of the product from b) in 12 ml of acetone is mixed with 3 ml of Jones reagent at 0°C. After 3 hours at room temperature, the reaction mixture was placed on ice and extracted with ethyl acetate. After washing with water and drying, and after evaporation, 0.4 g of N-(2-naphthylsulfonyl)-3-(2,3,4,5-tetrahydro-4-methyl-2,5-dioxo-1H- 1,4-benzodiazepine-1-yl)-D-alanine.

d) Similar to example 5 from product c) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-1,2,3,4-tetrahydo-2-methyl-α-( 2-naphthylsulfonamido)-1,4-dioxo-5H-2,5-benzodiazepine-5-propionamide (epimers 1:1), FAB

e) -MS: 606 (M+H)+.

Example 11

a) A solution of 0.9 g of D-tryptophan in 4.8 ml of 1 M NaOH and 4.8 ml of acetone is added drop by drop to a solution of 1.25 g of 6-acetoxynaphthyl-2-sulfonyl chloride (Monatsh. 49,1928,96 ) in 4.4 ml of acetone and pH adjusted to 9 with the addition of 1 M NaOH. Then the acetone is evaporated, the obtained suspension is acidified with 1 M HCl and the product is extracted with ethyl acetate. The product is chromatographed on silica gel with ethyl acetate/acetone (1:1). The main fraction is mixed with 0.5 M NaOH solution in 8.8 ml of methanol solution and stirred for 17 hours. The solution is evaporated, mixed with water and 1 M HCl and extracted with ethyl acetate. Purification on silica gel with ethyl acetate-acetone (3:2) gives 0.54 g of N-(6-hydroxy-2-naphthylsulfonyl)-D-tryptophan. MS: M+ 410, m/e 207, 130.

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

Example 12

Similar to examples 5 and 9, the following compounds are obtained:

a) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-p-fluoro-α-(2-naphthylsulfonamido)hydrocyananamide bisulfite (epimers 1:1),

FAB-MS: 512 (M+H) + .

b) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-p-chloro-α-(2-naphthylsulfonamido)hydrocinnamamide-bisulfite (epimers

1:1), FAB-MS: 528 (M+H) + .

c) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-p-cyano-α-(2-naphthylsulfonamido)hydrocinanamide-bisulfite (epimers

1:1), FAB-MS: 519 (M+H) + .

d) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-p-nitrohydrocinnamamide-bisulfite (epimers

1:1), FAB-MS: 539 (M+H) + .

e) (R)-p-amino-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthylsulfonamido)hydrocinnamamide-bisulfite (epimers

1:1), FAB-MS: 509 (M+H) + .

f) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-3-(p-hydroxyphenyl)-2-(2-naphthylsulfonamido)propionamide-bisulfite (epimers 1:1), FAB-MS : 510 (M+H)+.

Example 13

Similar to examples 5 and 9, the following compounds are obtained:

a) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-o-nitrohydrocinnamamide-bisulfite (epimers

1:1), FAB-MS: 539 (M+H) + .

b) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-bisulfite (epimers 1:1), FAB-MS: 500 (M+H)+.

c) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-2-(2-naphthyl-sulfonamido)-4-phenylbutyramide bisulfite (epimers 1:1),

FAB-MS: 508 (M+H) + .

d) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)cyclohexanebutyramide bisulfite (epimers 1:1), FAB-MS: 514 (M+H)+ .

e) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-1-naphthylpropionamide bisulfite, FAB-MS: 586 (M+H) + .

f) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-2-naphthylpropionamide bisulfite (epimers 1:1), FAB-MS: 544 (M+ H)+,

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

h) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-4-imidazolepropionamide-bisulfite (epimers

1:1), FAB-MS: 484 (M+H) + .

i) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-2-thienylpropionamide bisulfite (epimers 1:1),

FAB-MS: (M+H)+.

Example 14

Similar to examples 5 and 11, the following compounds are obtained:

a) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(3-methyl-8-quinolinesulfonamido)indole-3-propionamide-bisulfite (epimers 1:1), FAB-MS : 548 (M+H)+.

b) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-[(RS)-3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonamido]]indol- 3-Propion-amide-bisulfite, FAB-MS: 552 (M+H) + .

c) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(4-biphenyl-sulfonamido)indole-3-propionamide hydrochloride (epimers

1:1), FAB-MS: 559 (M+H) + .

d) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2-anthryl-sulfonamido)indole-3-propionamide hydrochloride (epimers

1:1), 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 (epimers 1:1), FAB-MS: 637 (M+H) + .

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

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

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

i) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(o-nitro-benzenesulfonamido)indole-3-propionamide-hydrochloride (epimers 1:1), FAB-MS: 528 (M+H)+.

j) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(m-nitro-benzenesulfonamido)indole-3-propionamide hydrochloride

(epimers 1:1), FAB-MS: 528 (M+H) + .

k) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(p-benzyl-oxybenzenesulfonamido)indole-3-propionamide-hydrochloride (epimers 1:1), FAB-MS: 589 (M+H)+.

l) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(3,4-dimethoxybenzenesulfonamido)indole-3-propionamide-

hydrochloride (epimers 1:1), FAB-MS: 543 (M+H)+.

m) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(4-methoxy-2,3,6-trimethylbenzenesulfonamido)indole-3-

propionamide hydrochloride (epimers 1:1), FAB-MS: 555 (M+H)+.

n) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(2,4,6-triisopropylbenzenesulfonamido)indole-3-propionamide-hydrochloride (epimers 1:1), FAB-MS : 609 (M+H)+.

Example 15

Similar to example 5, the following compounds are obtained:

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-(2-naphthylsulfonamido)ethyl]indole-1-acetic acid-

bisulphite (epimers 1:1), FAB-MS: 591 (M+H) + .

Example 16

Similar to example 6 and 7, we get:

a) (R)-N-[(R)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)indole-3-propionamide bisulfite, FAB-MS: 553 (M+H)+ or

b) N-(2-naphthylsulfonyl)-D-tryptophan-(R)-1-amidino-3-piperidinylmethylester-p-toluenesulfonate (1:1), FAB-MS: 534 (M+H)+.

Example 17

Similar 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-toluenesulfonate (1:1), FAB-MS: 609 ( M+H)+.

b) (R)-N-[(S)-1-amidino-3-piperidinylmethyl]-α-(p-iodobenzenesulfonamido)indole-3-propionamide-p-toluenesulfonate (1:1), FAB-MS: 609 ( M+H)+.

c) N-(p-iodophenylsulfonyl)-D-tryptophan-(R)-1-amidino-3-piperidinylmethylester-p-toluenesulfonate (1:1), FAB-MS: 609 (M+H)+.

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

e) (R)-N-[(R)-1-amidino-3-piperidinylmethyl]-α-(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)+.

g) N-(p-iodophenylsulfonyl)-3-(2-naphthyl)-D-alanine-(R)-1-amidino-3-piperidinylmethylester-p-toluenesulfonate (1:1), FAB-MS: 621 (M +H)+.

h) N-(p-iodophenylsulfonyl)-3-(2-naphthyl)-D-alanine-(S)-1-amidino-3-piperidinylmethylester-p-toluenesulfonate (1:1), FAB-MS: 621 (M +H)+.

i) (R)-N-[(R)-1-amidino-3-piperidinylmethyl]-α-(p-iodobenzenesulfonamido)-p-nitrohydrocinnamamide bisulfate (2:1), FAB-MS: 615 (M+H )+.

j) (R)-N-[(S)-1-amidino-3-piperidinylmethyl]-α-(p-iodobenzenesulfonamido)-p-nitrohydrocinnamamide-p-toluenesulfonate (1:1), FAB-MS: 615 (M +H)+.

k) N-(p-iodophenylsulfonyl)-3-(p-nitrophenyl)-D-alanine-(R)-1-amidino-3-piperidinylmethylester-p-toluenesulfonate (1:1),

FAB-MS: 616 (M+H) + .

l) N-(p-iodophenylsulfonyl)-3-(p-nitrophenyl)-D-alanine-(S)-1-amidino-3-piperidinylmethylester-p-toluenesulfonate (1:1),

FAB-MS: 616 (M+H) + .

Example 18

Similar to example 5, the following compounds are obtained:

a) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]hexahydro-α-2-naphthylsulfonamido-γ-oxo-1H-azepine-1-butyramide-bisulfite (epimers 1:1), FAB -MS: 543 (M+H)+.

b) 1-[(R)-3-[(RS)-1-amidino-3-piperidinylmethylcarbamoyl]-3-(2-naphthylsulfonamido)propionyl]-L-proline methyl ester (epimers 1:1), FAB-MS : 573 (M+H)+.

c) 1-[(R)-3-[(RS)-1-amidino-3-piperidinylmethylcarbamoyl]-3-(2-naphthylsulfonamido)propionyl]-L-proline (epimers

1:1), FAB-MS: 559 (M+H) + .

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

e) (RS)-N-[(RS)-1-amidino-3-piperidinylmethyl]-2-(2-naphthyl-sulfonamido)-3-(onitrobenzoyl)propionamide-bisulfite, FAB-MS: 567 (M+H )+.

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

g) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-3-anthraniloyl-2-(p-iodobenzenesulfonamido)propionamide-trifluoroacetate (epimers 1:1), FAB-MS: 613 (M +H)+.

h) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-3-(o-formamidobenzoyl)-a-(2-naphthylsulfonamido)

propionamide acetate (epimers 1:1), FAB-MS: 565 (M+H)+.

Example 19

a) 199 g of 2-aminoethylhydrogensulfate is added to 164 ml of 70% sodium hydroxide, the solution is heated to 50°C and a solution of (RS)-benzyloxymethyloxirane in 280 ml of methanol is added drop by drop. After one hour at 50°C, another 280 ml of 70% sodium hydroxide is added and the solution is stirred overnight. The reaction mixture is then placed on ice and extracted with toluene. The organic phase is washed with water, dried and evaporated. Thus, after distillation, 26.8 g of rac-2-benzyloxymethylmorpholine are obtained, MS: M+ -91+116 (benzyl).

b) A solution of 31.0 g of di-t-butyldicarbonate in 286 ml of dioxane is added to 26.8 g of the product from a) in 287 ml of dioxane and the reaction mixture is stirred overnight. After evaporation of the solvent and chromatography of the residue on silica gel with ethyl acetate-hexane, 15 g of t-butylrac-2-benzyloxymethyl-4-morpholinecarboxylate is obtained, MS: M+-56=251 (isobutylene).

c) A solution of 15 g of the product from b) in 300 ml of ethanol is hydrogenated in the presence of 1.5 g of Pd/C under normal conditions, so after filtering and evaporating the solvent, tbutyl-rac-2-hydroxymethyl-4-morpholinecarboxylate is obtained quantitatively, MS : M+=217.

d) A solution of 8.8 g of the product from c) in 44 ml of pyridine is mixed with 9.4 g of p-chlorobenzene sulfochloride. After 5 hours of stirring, the reaction mixture is evaporated, the residue is dissolved in ethyl acetate and washed with a 10% solution of copper sulfate. After drying the organic phase, evaporation of the solvent and chromatography of the residue on silica gel with ethyl acetate-hexane, 14.7 g of t-butylrac-2-(p-chlorophenylsulfonyloxymethyl)-4-morpholinecarboxylate is obtained, MS: 392 (M+H)+.

e) To a solution of 14.7 g of the product from d) in 91 ml of DMF, 7.3 g of sodium triazide is added. After stirring for 24 hours at 50°C, the reaction mixture was placed on ice and extracted with ether. The organic phase is washed with water, dried and evaporated. Thus, 8.1 g of t-butyl-rac-2-amizomethyl-4-morpholinecarboxylate is obtained.

f) A solution of 8.1 g of the product from e) in 92 ml of ethanol is hydrogenated in the presence of 0.8 g of platinum oxide for 4 hours under normal conditions, resulting in 6.5 g of t-butyl-rac-2-amino -methyl-4-morpholinecarboxylate, MS: (M+H)+ -56=159 (isobutylene).

g) A solution of 3.0 g of N-(2-naphthylsulfonyl)-D-tryptophan (Example 9) in 35 ml of DMF was mixed with 3.4 g of benztriazol-1-yloxy-tris-(dimethylamino)phosphonium-hexafluorophosphate. A solution of 2.0 g of the product from f) in 2 ml of DMF is added and the solution is stirred overnight. Then the solvent is distilled off, the residue is dissolved in ethyl acetate and washed with water. After drying, evaporation of the solvent and chromatography, the residue on silica gel with ethyl acetate yields 4.5 g of t-butyl-(RS)-2-N-(2-naphthylsulfonyl)-D-tryptophyllaminomethyl-4-morpholinecarboxylate, MS: (M +H)+ -56=537 (isobutylene).

h) A solution of 2 g of the product from g) in 20 ml of ethyl acetate is mixed with 20 ml of a 4 M solution of HCl in ethyl acetate. After mixing, the solution is evaporated to dryness. The residue is dissolved in 20 ml of DMF, mixed with 1.4 ml of triethylamine and 0.5 g of formamidinisulfonic acid and stirred for 17 hours at room temperature. Then the solvent is evaporated, the residue is dissolved in 50 ml of ethyl acetate and 10 ml of methanol and this solution is washed with water. After drying the organic phase, evaporation of the solvent and chromatography of the residue on an RP-column (alkyl-silicified silica gel) with water-acetonitrile, 0.1 g of (R)-N-[(RS)-4-amidino-2-morpholinemethyl] is obtained. -α-(2-naphthylsulfonamido)-indole-3-propionamide-bisulfite, MS: 535 (M+H)+.

Example 20

Similar to example 19g) and h) it is obtained from t-butyl-rac-2-hydroxymethyl-4-morpholinecarboxylate (example 19c) and N-(2-naphthylsulfonyl)-D-tryptophan N-(2-naphthylsulfonyl)-D- tryptophan-(RS)-4-amidino-2-morpholinemethylester-bisulfite, MS: 536 (M+H)+.

Example 21

Similar to example 19, we get:

a) (R)-N-[(RS)-4-amidino-2-morpholinylmethyl]-α-(2-naphthyl-sulfonyl)-p-nitrohydrocinnamamide bisulfite, MS: 541

(M+H)+.

b) (R)-N-[(RS)-4-amidino-2-morpholinylmethyl]-α-(2-naphthyl-sulfonamido)-2-thienylpropionamide bisulfite, MS: 502

(M+H)+.

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

Example 22

a) A solution of 10 g of (D)-phenylalanine benzyl ester-p-toluenesulfonate in 150 ml of methylene chloride is mixed with 8.2 ml of triethylamine and cooled to 0°C. 5.8 g of 2-naphthyl sulfochloride is added and the mixture is stirred for 12 hours at room temperature. The reaction mixture is evaporated and dissolved in 200 ml of ethyl acetate, the resulting triethylammonium chloride salt is separated by filtration and the mother liquor is washed with water. After evaporation of the organic phase and crystallization from hexane, 9.7 g of N-(2-naphthylsulfonyl)-3-phenyl-D-alanine-benzyl ester are obtained, m.p. 107°C.

b) A solution of 3 g of the product from a) in 40 ml of THF is mixed at -80°C with 5 ml of 1.6 M butyllithium in hexane and then with 1.2 ml of bromoacetic acid t-butyl ester. After stirring for 2 hours at room temperature, the reaction mixture is dissolved in 200 ml of ethyl acetate, washed with water and the organic phase is evaporated. The product is purified over silica gel with hexane/ethyl acetate (9:1). Thus, 1.35 g of N-(t-butoxycarbonylmethyl)-N-(2-naphthylsulfonyl)-3-phenyl-D-alanine benzyl ester is obtained, NMR (nuclear magnetic resonance) (CDCl3) 1.45(s,9H,t -butyl).

c) A solution of 1.35 g of the product from b) in 50 ml of ethanol in the presence of 0.3 g of Pd/C is hydrogenated. After evaporation of the reaction mixture and azeotropic distillation with toluene, 0.95 g of N-(t-butoxycarbonylmethyl)-N-(2-naphthylsulfonyl)-3-phenyl-D-alanine is obtained.

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

Example 23

a) 13.7 g of benzotriazol-1-yloxy-tris-dimethylamino)phosphonium-hexafluorophosphate and 16.9 ml benzylamine and the mixture is stirred overnight at room temperature. Then the solvent is evaporated, the residue is dissolved in ethyl acetate and washed with water. After drying, evaporation and chromatography on silica gel with ethyl acetate-hexane (1:4), 5.4 g of (S)-3-(1,1-dimethylethoxycarbonylamino)-4-benzylamino-4-oxobutyric acid is obtained in the form of benzyl ester .

b) A solution of 2.0 g of the product from a) in 10 ml of ethyl acetate is mixed with 10 ml of a 4 M HCl solution. After 3 hours of stirring, it is evaporated and the residue is suspended in 30 ml of dioxane. Add 5 ml of 1 M sodium hydroxide, 0.8 g of sodium bicarbonate, 20 ml of water and then a solution of 1.1 g of 2-naphthylsulfochloride in 15 ml of dioxane and continue stirring overnight at room temperature. The reaction mixture is placed on a 5% potassium sulfate-10% potassium sulfate solution and extracted with ethyl acetate. After drying and evaporation of the organic phase, the residue is crystallized from ethyl acetate-hexane, and 1.8 g of (S)-2-benzylcarbamoyl)-N-(2-naphthylsulfonyl)-β-alanine benzyl ester is obtained.

c) A solution of 1.0 g of the product from b) in 20 ml of methanol is mixed with 2 ml of 1 M sodium hydroxide and the mixing is carried out overnight at room temperature. After acidification, extraction with ethyl acetate and crystallization after evaporation of the obtained residue from methanol-methylene chloride hexane, 0.3 g of (S)-2-benzylcarbamoyl-N-(2-naphthylsulfonyl)-β-alanine is obtained.

d) Similar to example 5, (S)-N-[(RS)-1-amidino-3-piperidinylmethyl]-3-benzylcarbamoyl-3-(2-naphthylsulfonamido)propionamide-trifluoroacetate (epimers 1:1) is obtained. FAB-MS: 551 (M+H) + .

Example 24

Similar to example 23 via (R)-2-benzylcarbamoyl-N-(2-naphthylsulfonyl)-(3-alanine) (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-3- benzylcarbamoyl-3-(2-naphthylsulfonamido)propionamide hydrochloride, FAB-MS: 551 (M+H)+.

Example 25

Similar to example 23, using hexamethyleneimine instead of benzylamine gives (S)-N-[(RS)-1-amidino-3-piperidinylmethyl]-hexahydro-β-(2-naphthylsulfonamido)-γ-oxo-1H-1-azepinebutyramide -trifluoroacetate, FAB-MS: 543 (M+H)+.

Example 26

Similar to example 6, (R)-N-[(S)-1-amidino-3-piperidinylmethyl]-1,2,3,4-tetrahydro-2-(2-naphthylsulfonyl)-3-isoquinolinecarboxamide hydrochloride is obtained , FAB-MS: 506 (M+H) + .

Example 27

Similar to examples 5 and 9, methyl-o-[(R)-α-[(RS)-1-amidino-3-piperidinylmethylcarbamoyl]-p-nitrophenethyl-sulfamoyl]benzoate is obtained, FAB-MS: 547 (M+ H)+.

Example 28

Similar to examples 5 and 9, (RS)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-5-bromo-α-2-naphthylsulfonamido-indole-3-propionamide-sulfite is obtained, FAB-MS: 611 (M+H) + .

Example 29

Similar to examples 6 and 9, we get:

a) (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-p-iodo-α-2-naphthylsulfonamidohydrocinnamide-p-toluenesulfonate, FAB-MS: 620 (M+H)+ .

b) (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-α-2-naphthyl-sulfonamido-p-nitrohydrocinnamide-p-toluenesulfonate, FAB-MS: 539 (M+H )+.

Example 30

a) A solution of 30.1 g of (R)-4-hydroxymethyl-2,2-dimethyl-3-oxazolidinecarboxylic acid t-butyl ester cooled to 0°C in 400 ml of methylene chloride is mixed with 27.2 ml of triethylamine. After adding 12.1 ml of methanesulfochloride at 0°C, the reaction mixture is stirred for 1 hour. The salt is separated by filtration, the filtrate is evaporated and the product is crystallized from hexane. Thus, 32.7 g of t-butyl ester (s)-2,2-dimethyl-4-(methanesulfonyloxymethyl)-3-oxazolidine carboxylic acid is obtained, H1-NMR (CDCl3): 1.48,s,9H,t- butyl; 3.04;s;3H;mesyl.

b) A solution of 29.1 g of the product from a) in 200 ml of DMF is mixed with 24.5 g of natriazide. The suspension is heated to 50°C and stirred for 24 hours. The salt is filtered off and the filtrate is evaporated. The crude product is dissolved in 400 ml of ethyl acetate and washed with water. The organic phase is dried and evaporated. Thus, 20.2 g of t-butyl ester (R)-2,2-dimethyl-4-(azidomethyl)-3-oxazolidine carboxylic acid are obtained, IR (CHCl3) 2140 cm-1 (azide band).

c) A solution of 20.2 g of the product from b) in 400 ml of dioxane is mixed with 4 g of platinum oxide. The reaction mixture is hydrogenated at room temperature under normal pressure. After filtering and evaporating the filtrate, 17.9 g of t-butyl ester (R)-2,2-dimethyl-4-(aminomethyl)-3-oxazolidinecarboxylic acid is obtained.

d) A solution of the product from c) in 300 ml of methylene chloride is mixed at 0°C with 19.9 ml of Hunig's base (ethyldiisopropylamine) and 12.2 ml of benzyl chloroformate. After mixing, the reaction mixture is evaporated, the crude product is dissolved in 400 ml of ethyl acetate and washed with 100 ml of water. The organic phase is dried and evaporated, and the crude material is purified over silica gel with ethyl acetate/hexane 1/9, and 26.4 g of t-butyl ester (R)-2,2-dimethyl-4-(carbobenzoxy-aminomethyl)- 3-oxazolidinecarboxylic acids.

e) The solution of the product from d) in 300 ml of methanol is mixed with 36.2 ml of 2 M HCl. After 24 hours, the solution is evaporated, dissolved in 400 ml of dioxane and mixed with 72.43 ml of 1 M NaOH. After adding 30.4 g of sodium bicarbonate, the suspension is mixed with 24.6 g of 2-naphthyl sulfochloride in 100 ml of dioxane. The suspension is stirred for 15 hours, the reaction mixture is filtered, evaporated, dissolved in ethyl acetate, washed with water and dried. The organic phase is evaporated and the crude product is purified over silica gel with ethyl acetate/hexane 3/7. 25.85 g of benzyl ester [(R)-3-hydroxy-2-(2-naphthylsulfonamido) propyl] carbamic acid, MS 415 (M+H)+, 371 (-CO2), 347, 325, 281 , 269, 225, 191, 135.

f) A solution of 5 g of the product from e) in 100 ml of ethanol is hydrogenated after the addition of 1 g of 10% Pd/C at room temperature, under normal pressure. The catalyst is separated by filtration and washed with methanol. After evaporation, 2.8 g of N-[(R)-2-amino-1-hydroxymethyl)ethyl]-2-naphthylsulfonamide are obtained, MS: 281 (M+H)+ 251, 250, 221, 191, 128, 127 , 60.

g) A solution of 1.3 g of the product from f) in 50 ml of DMF is mixed with 0.83 g of phenylglyoxal acid and 0.9 ml of Hunig's base. After adding 2.0 g of benzotriazol-1-yloxy-tris)dimethylamino)phosphonium hexafluorophosphate, the reaction mixture was stirred for 5 hours. The solvent is evaporated and the crude product is purified over silica gel with hexane/ethyl acetate 1/1. Thus, 1.4 g of N-[(R)-3-hydroxy-2-(2-naphthylsulfonamido)propyl]-2-phenylglyoxylic acid amide is obtained.

h) A solution of 0.42 g of the product from g) in 30 ml of acetone is mixed at 0° with 3.5 ml of Jones's reagent (2.67 mg of CrO3 in sulfuric acid). The mixture is stirred for 1 hour, placed on ice and extracted with ethyl acetate. The organic phase is dried and evaporated. Thus, 0.44 g of (R)-2-(2-naphthylsulfonamido)-3-(2-phenylglyoxyl-amido)propionic acid is obtained, FAB-MS: 427 (M+1)+.

i) Similar to example 5 from product h) is obtained (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-2-naphthylsulfonamido)-3-(2-phenylglyoxylamido)propionamide- p-toluenesulfonate. FAB-MS: 565 (M+H) + .

Example 31

Similar to example 5 and 9, we get:

a) via N-[(6-benzyloxy-2-naphthyl)sulfonyl]-D-tryptophan, FAM-MS: 394 (M+H)+, (R)-N-[[(RS)-1-amidino- 3-piperidinyl]methyl-α-(6-benzyloxy-2-naphthylsulfonamido)indole-3-propionamide hydrochloride, FAB-MS:

639 (M+),

b) via N-(1-naphthylsulfonyl)-D-tryptophan, FAB-MS: 394 (M+H)+, (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl] - α-(1-naphthylsulfonamido)indole-3-propionamide hydrochloride, FAB-MS: 533 (M+H)+,

c) via N-(2-naphthylsulfonyl)-3-(m-nitrophenyl)-DL-alanine, MS: 400 (M+), (RS)-N-[[(RS)-1-amidino-3-piperidinyl] methyl]-α-[2-naphthylsulfonamido]-m-nitrocinnamamide hydrochloride, FAB-MS: 539 (M+H) + .

Example 32

a) To a solution of 0.71 g of D-tryptophan in 4.8 ml of water and 2.13 ml of 1 M NaOH, add 0.36 g of sodium bicarbonate and a solution of 0.50 g of methyl-p-(chlorosulfonyl)bezoate in 10 ml ether. The resulting suspension is stirred for 22 hours. The sodium salt of N-[[p-(methoxycarbonyl)-phenyl]sulfonyl]-D-tryptophan is separated and washed with water (0.52 g), MS: 400 (M-Na)-. After acidification with citric acid, 0.38 g of product is isolated from the mother solution as free acid.

b) Similar to examples 5 and 11, methyl-p-[[(R)-1-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-indole is obtained from acid a) -3-ylethyl]sulfamoyl]benzoate hydrochloride, FAB-MS: 541 (M+H)+.

Example 33

Similar to example 31, (RS)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-α-2-naphthylsulfonamido-m-nitrohydrocinnamamide hydrochloride is obtained, FAB-MS: 539 (M+ H)+.

Example 34

A solution of 0.15 g of (RS)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-α-2-naphthylsulfonamido-m-nitrohydrocinnamamide hydrochloride (Example 33) in 50 ml of ethanol was treated with 0 .12 g of 10% Pd/C is mixed and reduced at room temperature under normal pressure. The reaction mixture is filtered, evaporated, the residue is dissolved in methanol and diluted with ether. The resulting (RS)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-m-amino-α-2-naphthylsulfonamido-hydrocinnamamide hydrochloride is separated and washed again with ether. Yield 0.12 g, FAB-MS: 509 (M+H) + .

Example 35

a) A solution of 50 g of N-(2-naphthylsulfonyl)-3-p-nitrophenyl-D-alanine (example 9b) in 100 ml of DMF is mixed with 45 ml of Raney nickel and reduced at room temperature and normal pressure. The reaction solution is filtered, then concentrated and placed in water. The resulting 3-(p-aminophenyl)-N-(2-naphthylsulfonyl)-D-alanine is separated and washed with water and dried. Yield 37.6 g, m.p. 211-212°C. MS: 370 (M+).

b) A suspension of 1.0 g of the product from a) in 15 ml of methylene chloride is mixed with 1.13 ml of triethylamine. The resulting solution is cooled in an ice bath and 0.3 ml of ethyl oxalyl chloride in 5 ml of methylene chloride is added. After a further 30 minutes in an ice bath, the solution is stirred overnight at room temperature. The reaction mixture is concentrated, the residue is dissolved in water, acidified with 10% citric acid and the resulting product is filtered. The same is dissolved in ethyl acetate, washed with water and dried. After evaporation, 0.92 g of oxamic acid ester is obtained, which analogously to example 5 gives 0.87 g of ethyl-4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl] carbamoyl]-2-[(2-naphthylsulfonamido)ethyl]oxanilate hydrochloride. FAB-MS: 609 (M+H) + .

Example 36

Similar to example 35, the following compounds are obtained:

a) Methyl-4'-[(R)-[[[(RS)-1-amino-3-piperidinyl]methyl]carbamoyl]-2-[(2-naphthylsulfonamido)ethyl]succinanilate hydrochloride. FAM-MS: 623 (M+H) + .

b) Methyl-3'-[(RS)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]-carbamoyl]-2-[(2-naphthylsulfonamido)ethyl] succinanilate hydrochloride.

c) Benzyl-4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]-carbamoyl]-2-[(2-naphthylsulfonamido)ethyl] succinanilate hydrochloride. FAM-MS: 699 (M+H) + .

d) Methyl-4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]]methyl]-carbamoyl]-2-[(p-iodobenzenesulfonamido)ethyl] succinanilate hydrochloride. FAB-MS: 699 (M+H) + .

e) Ethyl-4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]-carbamoyl]-2-(2-naphthylsulfonamido]ethyl]carbanilate hydrochloride. FAB- MS: 581 (M+H) + .

Example 37

Similar to example 35), N-(2-naphthylsulfonyl)-3-[p-(2-phenylglyoxylamido)phenyl]-D-alanine, MS: 502 (M+), is obtained, which analogously to example 6e)-g) reacts in (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-α-(2-naphthylsulfonyl)-p-(2-phenylglyoxylamido)-hydrocinnamamide hydrochloride. FABMS: 641 (M+H)+.

Example 38

Similar to examples 35 and 42, methyl-p-[p-[(R)-2-[[(RS)-1-amidino-3-piperidinyl]methyl] carbamoyl]-2-(2-naphthylsulfonamido) is obtained via ethyl]benzenamido]benzoate hydrochloride, FAB-MS: 671 (M+H)+, p-[p-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl] hydrochloride carbamoyl]-2-(2-naphthylsulfonamido)ethyl]benzenamido]benzoic acid, FAB-MS: 657 (M+H)+.

Example 39

Similar to example 35, (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-p-[2-(2-methoxyethoxy)acetamido]-α-2-naphthylsulfonamidohydrocinnamamide hydrochloride is obtained . FAB-MS: 625 (M+H) + .

Example 40

Similar to example 35, 4'-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)-ethyl]oxanilic acid is obtained in in the form of hydrochloride. FAB-MS: 581 (M+H) + .

Example 41

A solution of 0.7 g of 3-(p-aminophenyl)-N-(2-naphthylsulfonyl)-D-alanine (example 35a) in 5 ml of pyridine was mixed with 1 ml of acetic anhydride and kept at room temperature for 20 hours. After adding water and concentrated hydrochloric acid (cooling with ice), the resulting product is separated, dissolved in ethyl acetate, washed with water, dried and evaporated. The product is dissolved in 20 ml of methanolic 1 M NaOH and left to stand. The solution is evaporated, the residue is dissolved in water, acidified with concentrated hydrochloric acid, the resulting product is separated, dissolved in ethyl acetate and washed with water. After evaporation, the residue reacts analogously to the example, and 146 mg of (R)-p-acetamido-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-α-(2-naphthylsulfonamido)hydrocinnamamide hydrochloride is obtained. FAB-MS: 551 (M+H) + .

Example 42

Suspension 150 mg of ethyl-4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)ethyl] oxanilate hydrochloride (example 35 ) in 10 ml of ethanolic 0.1 M NaOH solution is dissolved at room temperature with stirring. The reaction solution is acidified with ethanolic 2.78 M HCl, the resulting NaCl is separated and the filtrate is mixed with ether. The resulting hydrochloride is drained and mixed with ether. The product separates. Yield 60 mg of 4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)ethyl]oxanilic acid in the form of hydrochloride. FAB-MS: 581 (M+H) + .

Example 43

acid 0.5 g of benzyl-4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamoyl-2-(2-naphthylsulfonamido)ethyl] succinanilate hydrochloride (example 36c) in 20 ml of ethanol is mixed with 0.5 g of 10% Pd/C and reduced. The catalyst is filtered off, the filtrate is concentrated and mixed with ether. The resulting product is drained, mixed with ether and then filtered. Yield: 0.35 g of 4'-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthyl-sulfonamido)ethyl]succionanilic acid in in the form of hydrochloride. FAB-MS: 609 (M+H) + .

Example 44

A solution of 0.5 g of 3-(p-aminophenyl)-N-(2-naphthylsulfonyl)-D-alanine (Example 35a) in 1.35 ml of 1 M NaOH and 7 ml of water was mixed with 6 ml of dioxane and 0.34 g of sodium hydrogen carbonate. During mixing, 0.26 g of tosyl chloride is added.

After 24 hours of stirring at room temperature, the solution is concentrated, diluted with water and extracted with ether. The aqueous phase is mixed with 6 ml of 2 M hydrochloric acid while cooling with ice and the resulting product is separated by filtration. The latter is converted without purification analogously to example 5 into 0.39 g of (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-α-2-naphthylsulfonamido-p-(p-toluenesulfonamido)hydrocinnamamide -hydrochloride. FAB-MS: 663 (M+H) + .

Example 45

Similar to example 44, (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-p-(p-iodobenzenesulfonamido)-α-(2-naphthylsulfonamido)hydrocinnamamide hydrochloride is obtained. FAB-MS: 775 (M+H) + .

Example 46

Similar to example 44 via methyl-p-[[p-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)-ethyl ]phenyl]sulfamoyl]benzoate hydrochloride, FAB-MS: 707 (M+H)+, p-[[p-[(RS)-1-amidino-3-piperidinylmethyl]carbamoyl]-2-(2- naphthylsulfonamido)ethyl]phenyl]sulfamoyl]benzoic acid in the form of hydrochloride. FAB-MS: 693 (M+H) + .

Example 47

0.45 ml of a 50% solution of ethylglyoxylate in toluene was added to a suspension of 0.37 g of 3-(p-aminophenyl)-N-(2-naphthylsulfonyl)-D-alanine (example 35a) in 20 ml of dioxane. The resulting solution is mixed with 0.3 g of 10% Pd/C and reduced for 6 hours at room temperature and 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-[(R)-2-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido) ethyl]phenyl]glycine ethyl ester in the form hydrochloride. FAB-MS: 595 (M+H) + .

Example 48

Similar to example 26, (R)-N-[[(RS)-amidino-3-piperidinyl]methyl]1,2,3,4-tetrahydro-2-(2-naphthylsulfonyl)-3-isoquinolinecarboxamide hydrochloride is obtained (epimers 1:1), [α]25589=+76.8° (MeOH, c=0.5%), FAB-MS: 506 (M+H)+.

Example 49

Similar to example 5, (RS)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-3-(o-aminobenzoyl)-2-(2-naphthylsulfonamido)propionamide-hemisulfite is obtained. FAB-MS: 537 (M+H) + .

Example 50

Similar to example 23, the following compounds are obtained:

a) (S)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-β-2-naphthyl-sulfonamido-γ-oxo-4-morpholinebutyramide-trifluoroacetate. FAB-MS: 531 (M+H) + .

b) (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]hexahydro-β-2-naphthylsulfonamido-γ-oxo-1H-azepinebutyramide-trifluoroacetate. FAB-MS: 543 (M+H) + .

c) (S)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]hexahydro-β-2-naphthylsulfonamido-γ-oxo-1(2H)-azocynbutyramide hydrochloride. FAB-MS: 557 (M+H) + .

Example 51

a) 5 g of the potassium salt of diphenylsulfone-3-sulfonic acid is refluxed overnight in 50 ml of thionyl chloride. The resulting material is separated by filtration and after drying, 3.2 g of diphenylsulfonic-3-sulfonic acid chloride is obtained.

b) 6.7 ml of 1 M sodium hydroxide and 2.82 g of sodium bicarbonate are added to a solution of 1.52 g of p-nitro-D-phenylalanine in 37 ml of dioxane. Then a solution of the product from a) in 119 ml of dioxane is added and stirring is continued overnight at room temperature. Then the reaction mixture is placed on ice and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated. Thus, 1.75 g of 3-(p-nitrophenyl)-N-[[(m-phenylsulfonyl)-phenyl]sulfonyl]-D-alanine are obtained.

c) The above acid is obtained similarly as in example 6e)-g) (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-p-nitro-α-[m-(phenyl -sulfonyl)benzenesulfonamido]hydrocinnamamide-hemisulfite, FAB-MS: 629 (M+H)+.

Example 52

a) 2.3 g of p-nitro-D-phenylalanine is suspended in 25 ml of dioxane and mixed with 10 ml of 1 M sodium hydroxide and 1.7 g of sodium bicarbonate. A solution of 2.6 g of methyl ester of 2-chlorosulfonylbenzoic acid in 22 ml of dioxane was added drop by drop and stirring was continued for 9 hours at room temperature. The reaction mixture is placed on ice-cooled 2 M hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and concentrated. Thus, 3.2 g of N-[[o-(methoxycarbonyl)phenylsulfonyl]-3-(p-nitrophenyl)-D-alanine are obtained.

b) The obtained material from a) is dissolved in 30 ml of DMF, mixed with 5.3 ml of hexamethyleneimine and stirred for 5 hours at 80°C. The reaction mixture is evaporated, the residue in ethyl acetate is dissolved once with 2 M hydrochloric acid and twice with distilled water. After drying the organic phase, evaporation and chromatography of the residue over silica gel, 0.9 g of N-[[o-[(hexahydro-1H-azepin-1-yl)carbonyl]phenyl]sulfonyl]-3-(p-nitrophenyl)- D-alanine.

c) Similar to example 5 from the obtained material b) is obtained (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-α-[o-[(hexahydro-1H-azepine- 1-yl)carbonyl]benzenesulfonamido]-p-nitrohydrocinnamamide hydrochloride. FAM-MS: 614 (M+H) + .

Example 53

Similar to example 52, the following compounds are obtained:

a) (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-α-(p-t-butyl-benzenesulfonamido)-p-nitrohydrocinnamamide-acetate. FAB-MS: 545 (M9H) + .

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

Example 54

Similar to example 19a) and 23, (βS,2RS)-N-[[(RS)-1-amidino-3-piperidinyl]methyl-2-benzyloxymethyl-β-2-naphthylsulfonamido-γ-oxo-4- morpholine butyramide-acetate. FAB-MS: 651 (M+H) + .

Example 55

A solution of the product from example 54 in ethanol/1 M hydrochloric acid is reduced in the presence of 10% Pd/C for 30 hours under normal conditions. Thus, (βS, 2RS)-N-[[(RS)-1-amidino-3-piperidinyl] methyl]-2-hydroxymethyl-β-2-naphthylsulfonamido-γ-oxo-4-morpholinebutyramide hydrochloride is obtained. FAB-MS: 561 (M+H) + .

Example 56

A)a) A solution of 23.3 g of rac-2-(aminomethyl)-4-benzylmorphoin in 250 ml of dioxane was mixed with 27.1 g of di-t-butyldicarbonate in 250 ml of dioxane and stirred at room temperature for 17 hours. Then the solvent is evaporated and the residue is chromatographed with methylene chloride-ethyl acetate 3:1 over silica gel. The product is crystallized from methylene chloride-hexane, and 25.6 g of t-butyl rac-[(4-benzyl-2-morphoin)methyl]carbamate is obtained.

A)b) The solution of the product from a) in 500 ml of ethyl acetate and 50 ml of acetic acid with 2.6 g of Pd/C is mixed and reduced for 5 hours at room temperature under normal conditions. After filtering and evaporation, the residue is dissolved in 230 ml of DMF, mixed with 46 ml of triethylamine and 10.8 g of formamidinesulfonic acid and stirred for 20 hours at room temperature. The reaction mixture is then evaporated and the residue partitioned between ethyl acetate and water. After drying the organic phase and evaporation, t-butyl-rac-[(4-amidino-2-morpholinyl)methyl] carbamate-hemisulfite is obtained.

A)c) 6.5 g of the obtained material from b) is suspended in 50 ml of methylene chloride and mixed with 20 ml of TFA at 0°. After 7 hours at 0°, the reaction mixture is evaporated and azeotropically evaporated with ethylene chloride and toluene. Thus, rac-2-(aminomethyl)-4-morpholine-carboxamidinetrifluoroacetate was isolated.

B) A solution of 0.8 g of (S)-β-2-naphthylsulfonamido-γ-oxo-4-morpholinebutyric acid obtained in a similar way as in example 23a)-c) in 16 ml of DMF is mixed with 0.76 ml of 4-ethylmorpholine . The reaction mixture is then mixed with 1 M hydrochloric acid and evaporated. After chromatography on an RP-18 column with water-acetonitrile, 0.5 g of (S)-N-[[(RS)-4-amidino-2-morpholinyl]methyl]-β-2-naphthylsulfonamido-γ-oxo- of morpholinbutyramide hydrochloride. FAB-MS: 533 (M+H) + .

Example 57

Similar to example 56, we get:

a) (S)-N-4-[[(RS)-4-amidino-2-morpholinyl]methyl-β-2-naphthyl-sulfonamidohexahydro-γ-oxo-1H-azepine-1-butyramide hydrochloride. FAM-MS: 545 (M+H) + .

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

Example 58

Similar to example 8, (R)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]-α-(2-naphthylsulfonamido)-2-oxo-3-oxo-benzoxazolinepropionamide-triacetate is obtained. FAB-MS: 551 (M+H) + .

Example 59

Similar to example 8 and 56, the following compounds are obtained:

a) (R)-N-[[(RS)-4-amidino-2-morpholinyl]methyl]-α-2-naphthyl-sulfonamido-2,3-dioxo-1-indolinpropionamide hydrochloride. FAB-MS: 565 (M+H) + .

b) (R)-N-[[(RS)-4-amidino-2-morpholinyl]methyl]-α-2-naphthyl-sulfonamido-2-oxo-3-benzoxazolinepropionamide hydrochloride. FAB-MS: 553 (M+H)+,

Example 60

A)a) To a solution of 10.0 g of t-butyl ester (S)-3-aminomethyl-1-piperidinecarboxylic acid (example 6d) in 400 ml of hexane and 100 ml of water, add 3.7 g of tetrabutylammonium hydrogen sulfate 1 100 ml of 1 M sodium hydroxide. 9.3 ml of benzyl chloroformate is added drop by drop to this mixture and it is stirred for 3 hours at room temperature. Then the organic phase is separated, washed with water, 10% citric acid, water and saturated sodium bicarbonate solution, dried and evaporated. Thus, t-butyl-(S)-3-[(1-(benzyloxy)formamido]methyl]-1-piperidinecarboxylate is obtained.

A)b) 11.3 g of the obtained material from a) are dissolved in 120 ml of ethyl acetate, mixed with 120 ml of a 4 M solution of hydrochloric acid in ethyl acetate at 4° and stirred for 5 hours at room temperature. Then the reaction solution is concentrated, the residue in 265 ml of DMF solution is mixed with 18 ml of triethylamine and 4.3 g of formamidinesulfonic acid and stirred for 17 hours at room temperature. The solvent is evaporated, the residue is mixed with 1 M hydrochloric acid, concentrated again and chromatographed with water-acetonitrile on an RP-18 column, thus 5.4 g of benzyl-[[(S)-1-amidino-3-piperidinyl]methyl]carbam is isolated. -hydrochloride-

A)c) 6.6 g of the obtained material from b) is mixed or dissolved in 165 ml of ethanol and 165 ml of 1 M hydrochloric acid, mixed with 1 g of Pd/C and reduced for 2 hours under normal conditions. After filtration, evaporation and azeotropic evaporation with ethanol, 4.5 g of (S)-1-amidino-3-(aminomethyl)-piperidine dihydrochloride are obtained, m.p. 252-254°C, FAB-MS: 156 (M+), [α]D -16.9° (c=1.0 water).

B) A solution of 1.9 g of N-(2-naphthylsulfonyl)-3-(2,3-dioxo-1-indolinyl)-D-alanine in 30 ml of DMF is mixed with 2.3 ml of 4-ethylmorpholine, 2.0 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate and 1.0 of the obtained material from A)c) and stirred at room temperature for 20 hours. The reaction mixture is concentrated, mixed with 1 M hydrochloric acid and evaporated once more, and the residue is chromatographed on silica gel with ethyl acetate-acetone-acetic acid-water 16:2:1:1. Thus, 0.8 g of (R)-N-1-amidino-3-piperidinylmethyl]-α-(2-naphthylsulfonamido)-2,3-dioxo-1-indolinepropionamide-acetate was isolated. FAB-MS: 563 (M+H) + .

Example 61

Similar to example 8 and 60, the following compounds are obtained:

a) (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-α-2-naphthyl-sulfonamido-2-oxo-3-benzoxazolidinepropionamide hydrochloride. FAM-MS: 551 (M+H)+,

b) (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-5-bromo-α-2-naphthylsulfonamido-2,3-dioxo-1-indolinepropionamide-tetraacetate. FAM-MS: 643 (M+H)+,

c) (R)-N-[[(S)-1-ammidino-3-piperidinyl]methyl]-5-methyl-α-2-naphthylsulfonamido-2,3-dioxo-1-indolinepropionamide-acetate. FAM-MS: 577 (M+H)+,

d) (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-α-(p-iodophenyl)sulfonyl]-2,3-dioxo-1-indolinepropionamide hydrochloride. FAM-MS: 639 (M+H)+,

e) (R)-N-[[(S)-1-amidino-3-piperidinyl]methyl]-α-(o-nitrobenzenesulfonamido)-2,3-dioxo-1-indolinepropionamide hydrochloride. FAB-MS: 558 (M+H) + .

Example 62

a) To a solution of 15 g of N-α-Z-L-2,3-diaminopropionic acid in 189 ml of 1 M sodium hydroxide, a solution of 21.4 g of 2-naphthyl sulfochloride in 200 ml of ether is added drop by drop while stirring. It is mixed for 6 hours. Then the reaction mixture is placed on ice-cooled 2 M hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated. After chromatography of the residue with methylene chloride-methanol-acetic acid 94:5:1 on silica gel, 17.9 g of N-[(benzyloxy)carbonyl]-3-(2-naphthylsulfonamido)-1-alanine was isolated.

b) From the obtained material a) similarly to example 5, benzyl-[(S)-1-[[[(RS)-1-amidino-3-piperidinyl]methyl]-carbamoyl-2-(2-naphthylsulfonamido) is obtained ethyl carbamate, FAM-MS: 567 (M+H) + .

Example 63

a) A solution of 1.1 g of the product from example 62b) in 22 ml of 1 M hydrochloric acid and 11 ml of ethanol is mixed with 0.2 g of Pd/C and reduced under normal conditions for 5 hours. After filtration and evaporation, 0.96 g of (S)-[[(RS)-1-amidino-3-piperidinyl]methyl-2-amino-3-(2-naphthylsulfonamido)propionamide is obtained

-dihydrochloride, FAB-MS: 433 (M+H)+.

b) A solution of 0.95 g of the obtained product from a) in 20 ml of DMF is mixed with 0.24 ml of 4-ethylmorpholine and 0.3 g of phthalic anhydride and stirred for 6 hours at 50°. The reaction mixture is concentrated and chromatographed with water-acetonitrile over an RP-18 column. Thus, 0.3 g of o-[[(S)-1-[[[(RS)-1-amidino-3-piperidinyl]methyl)carbamoyl]-2-(2-naphthylsulfonamido)ethyl]carbamoyl]benzoic acid is obtained , FAB-MS: 581 (M+H) + .

Example 64

A solution of 1.4 g of the product from example 63a) in 28 ml of DMF was added with 1.05 ml of 4-ethylmorpholine, 1.23 g of benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium-hexafluorophosphate and 0.95 g of o-( benzyloxy)benzoic acid is mixed and stirred overnight at room temperature. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The organic phase is dried, evaporated and the residue is chromatographed on silica gel with ethyl acetate-acetone-acetic acid-water 16:2:1:1. Thus, 0.2 g of (S)-2-N-[0-(benzyloxy)benzamido]-3-(2-naphthylsulfonamido)-N-[[(RS)-1-amidino-3-piperidinyl]methyl] was isolated of propionamide-acetate. FAB-MS: 643 (M+H) + .

Example 65

a) Similar to example 64, by using t-butyl-(R)-2-piperidine-carboxylic acid instead of o-(benzyloxy)benzoic acid, t-butyl-(R)-2-[[(S)-1- [[[(RS)-1-amidino-3-piperidyl]methyl]carbamoyl-2-(2-naphthylsulfonamido)ethyl]carbamoyl]-1-piperidinecarboxylate-trifluoroacetate, FAB-MS: 644 (M+H)+ .

b) A solution of 300 mg of the product from a) in 5 ml of ethyl acetate is mixed with 5 ml of a 4 M solution of hydrochloric acid in ethyl acetate. After stirring for 3 hours at room temperature, the suspension was evaporated to give (R)-N-(S)-1-[[(RS)-1-amidino-3-piperidin]methyl]carbamoyl-2-(2-naphthylsulfonamido) )-2-piperidinecarboxamide dihydrochloride, FAB-MS: 544 (M+H) + .

Example 66

A solution of 120 mg of the product from example 64 in 12 ml of acetic acid was mixed with 50 mg of Pd/C and reduced for 6 hours under normal conditions. After filtration and evaporation, 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

a) According to the procedure from example 6a)-e), the obtained material from example 62a) reacts in a similar way, so that t-butyl-(S)-3-[[[N-[(benzyloxy)carbonyl]-3-( 2-Naphthylsulfonamido)-1-alanyl]amino]methyl]-1-piperidinecarboxylate, FAB-MS: 525 (M+H)+Boc.

b) A solution of 3.0 g of the obtained material from a) in 80 ml of ethyl acetate-acetic acid (1:1) is mixed with 0.8 g of Pd/C and reduced under normal conditions for 48 hours. After filtering and evaporation, the residue is dissolved in 25 ml of DMF, 1.6 ml of 4-ethylmorpholine and 0.81 g of dihydro-2,4-dioxo-3,1-benzoxazine are added and stirred for 16 hours at 80°. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase is washed with water, dried and evaporated, and the residue is chromatographed on silica gel with methylene chloride-ethyl acetate 3:1. Thus, 1.3 g of t-butyl-(S)-3-[[N-anthraniloyl-3-(2-naphthylsulfonyl)-L-alanyl]amino]methyl]-1-piperidinecarboxylate were isolated, FAB-MS: 610 ( M+H)+.

c) From the isolated material b) is obtained similarly as in example 6f)-g N-[(S)-1-[[[(S)-1-amidino3-piperidinyl] methyl]carbamoyl]-2-(2-naphthylsulfonamido )ethyl-o-aminobenzamide-hemisulfite. FABMS: 552 (M+H)+.

Example 68

Similar to example 23a)-c) and example 60B), ethyl-rac-trans-4-methyl-2-piperidinecarboxylate is obtained with ethyl-(2RS,4R)-1-[(S)-3-[ [[(S)-1-amidino-3-piperidinyl]-methyl]carbamoyl]-2-(2-naphthylsulfonamido)propionyl]-4-methyl-2-piperidinecarboxylateacetate (epimers 1:1), FAB-MS: 615 ( M+H)+.

Example 69

Treatment of the product from example 68 with methanolic sodium hydroxide gives (2RS,4R)-1-[N4-[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2-naphthylsulfonyl)-L-asparaginyl ]-4-methyl-2-piperidinecarboxylic acid (epimers 1:1), FAB-MS: 587 (M+H)+.

Example 70

a) 22.4 ml of 2 M NaOH is added drop by drop to a solution of 5 g of β-benzyl ester of D-aspartic acid and 5.07 g of β-naphthylsulfonyl chloride in 80 ml of dioxane at 10°C cooled to 10°C. The reaction mixture was stirred for 2 hours at room temperature and then mixed with 25 ml of 1 M hydrochloric acid. After evaporation of dioxane, the resulting residue is dissolved in ethyl acetate and washed with water. After drying and evaporation of the ethyl acetate phase, 9.1 g of 4-benzyl-1-hydrogen-N-(2-naphthylsulfonyl)-D-aspartate is obtained. Rf=0.53 (ethyl acetate/acetic acid 0.97:0.03).

b) 3.72 ml of Hunig's base, 9.67 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate and 4.68 g of t-butyl ester are added to the product from a) in 100 ml of DMF while mixing. (s)3-Aminomethyl-1-piperidinecarboxylic acids. The reaction mixture is stirred for 4 hours, then it is diluted with ether and the ether phase is washed with water. After drying and evaporation of the ether phase, the residue is chromatographed over silica gel with ether-hexane 9:1. Thus, 9.1 g of benzoyl-(R)-3-[[[(s)-1-(t-butoxycarbonyl)-3-piperidinyl]methyl]carbamoyl]-3-(2-naphthylsulfonamido)propionate are obtained. Rf=0.35 (ether/hexane 9:1).

c) 3.0 g of the product from b) are dissolved in 60 ml of methanol and reduced by adding 105 Pd/C at room temperature and under normal pressure. After 8 hours, the catalyst is removed by filtration and the methanol solution is concentrated. Thus, 2.38 g of (R)-3-[[[(S)-1-(t-butoxycarbonyl)-3-piperidinyl]methyl]carbamoyl]-3-(2-naphthylsulfonamido)propionic acid is obtained, Rf= 0 .08 (ethyl acetate).

d) 1 g of carboxylic acid from c) in 18 ml of methylene chloride is cooled to -23°C and 0.25 ml of N-methylmorpholine and 0.3 ml of isobutyl ester of chloroformic acid are added in sequence. Then the reaction mixture is stirred at -23°C and mixed with 0.36 ml of ethyl ester of piperidine-3-carboxylic acid. The reaction mixture is then stirred with 100 ml of ether. The ether solution is washed with 1 M hydrochloric acid and water. After drying and evaporation of the ether phase, the residue is chromatographed over silica gel with ethyl acetate/hexane 4:1. 917 mg of ethyl-(R,S)-1-[(R)-3-[[[(S)-1-(t-butoxycarbonyl)-3-piperidinyl]methyl]carbamoyl]-3-(2 -naphthylsulfonamido)-propionyl]-3-piperidinecarboxylate. Rf=0.4 (ethyl acetate/hexane 4:1).

e) To a solution of 400 mg of the product from d) in 9.5 ml of methylene chloride, 1.2 ml of trifluoroacetic acid is added while stirring. Methylene chloride and trifluoroacetic acid are then evaporated at 50°C. The residue is dissolved in methanol, mixed with 0.42 ml of triethylamine and 150 mg of formamidinesulfonic acid. The reaction mixture is then stirred for 8 hours at room temperature. 0.09 ml of triethylamine and 75 mg of formamidinesulfonic acid were added three times at intervals of 2 hours. The reaction mixture is concentrated, the residue is suspended in 20 ml of Takeda solution/ethyl acetate 1:1 (Takeda solution=ethyl acetate/acetone/water/acetic acid 6:2:1:1) and filtered. The filtrate is concentrated and then chromatographed over silica gel with Takeda solution/ethyl acetate 1:1. Chromatography yields 114 mg of ethyl-(RS)-1-[(R)-[[(S)-1-amidino-3-piperidinyl]methyl]-carbamoyl]-3-(2-naphthylsulfonamido) propionyl]-3- of piperidinecarboxylate-acetate. Rf=0.34 MS (EI): 601 (M+H).

Example 71

Similar to example 70, the following compounds are obtained:

a) [(R)-1-[(S)-3-[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-3-(2-naphthylsulfonamido)propionyl]-3-piperidinyl]methyl -acetate, Rf=0.29 (Takeda solution), FAB-MS 601 (M+H),

b) [(S)-1-[(S)-3-[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-3-(2-naphthylsulfonamido)propionyl]-3-piperidinyl]methyl -p-tosylate (1:1), Rf=0.29 (Takeda solution), FABMS: 601 (M+1),

c) methyl-(RS)-1-[(R)-3-[[[(S)-1-amidino-3-piperidinyl]methyl]-carbamoyl]-3-(2-naphthylsulfonamido)propionyl]-4- oxo-3-piperidine]-carboxylate-acetate (1:1), Rf=0.27 (Takeda solution), FAB-MS: 601 (M+1),

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

f) [(R)-1-[(R)-3-[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-(2-naphthylsulfonamido)acetyl]-3-piperidinyl] methylacetate

g) -acetate, Rf=0.35 (Takeda solution), FAB-MS: 601 (M+1),

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

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

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

i) ethyl-(3R,4R)-4-acetoxy-1-[(R)-3-[[[(S)-1-amidino-3-piperidinyl]methylcarbamoyl]-3-(2-naphthylsulfonamido) propionyl] -3-piperidinecarboxylate-acetate (1:1), Rf=0.21 (Takeda solution), FABMS: 659 (M+1),

j) ethyl-(35,45)-4-acetoxy-1-[(R)-3-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-3-(2-naphthylsulfonamido) propionyl]-3-piperidinecarboxylate-acetate (1:1), Rf=0.24 (Takeda solution) FABMS: 659 (M+1).

To obtain products a), b) d) and h) instead of β-benzyl ester of D-aspartic acid (example 70a), β-benzyl ester of S-aspartic acid was used.

Intermediate products for obtaining products a), b), d), e), i) and j) were synthesized according to the following method:

2.0 g of t-butyl ester (S)-3-hydroxymethyl-1-piperidinecarboxylic acid, i.e. t-butyl ester (R)-3-hydroxymethyl-1-piperidine carboxylic acid together with 0.88 ml of acetic acid anhydride, 26, 3 mg of dimethylaminopyridine and 3.0 ml of pyridine are mixed for 30 minutes. The reaction mixture is then collected in ether, the ether phase is washed with 20% citric acid, saturated sodium bicarbonate solution and water. After drying and evaporation of the ether phase, 2.44 g of product Rf=0.85 (ether) are dissolved in 50 ml of methylene chloride and mixed with 12 ml of trifluoroacetic acid. The solution is stirred for 30 minutes and then concentrated to dryness. (S)- or (R)-3-acetoxymethyl-1-piperidine-trifluoroacetic acid salt Rf=0.14 (Takeda solution) is mixed with an equivalent amount of triethylamine in d).

Intermediate products for the synthesis of products from examples d) and h) are obtained in the following way:

170 mg of dimethylaminopyridine and 3.4 ml of pyridine are added to 3.0 g of t-butyl ester (S)-3-hydroxymethyl-1-piperidinecarboxylic acid. 1.66 ml of isobutyric acid chloride is added drop by drop. The reaction mixture is then concentrated. The residue is collected in ether and the ether phase is washed in order with 20% citric acid, water, sodium bicarbonate solution and once again with water. After drying and administration of the ether phase, 3.9 g of t-butyl ester (S)-3-isobutyroxymethyl-1-piperidinecarboxylic acid is obtained. Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and mixed with 20 ml of trifluoroacetic acid. After 30 minutes of mixing, the solution is concentrated. 30 ml of methylene chloride is added to the residue and a saturated solution of sodium bicarbonate is added dropwise. The aqueous phase is extracted with methylene chloride, the methylene chloride extract is dried and concentrated. Thus, 2.82 g of (S)-3-isobutyroxymethyl-1-piperidine-trifluoroacetic acid salt are obtained. Rf=0.4 (Takeda solution).

According to the above method, (S)-3-butyroxymethyl)-1-piperidine-trifluoroacetic acid salt is obtained. Rf=0.4 (Takeda solution).

Example 72

a) 14.4 ml of triethylamine is added dropwise to 6.91 g of glycine-t-butyl ester hydrochloride and 12.0 g of naphthalene-2-sulfochloride in 670 ml of methylene chloride. The reaction mixture is then diluted with 200 ml of ether. The organic phase is washed with 1 M hydrochloric acid and water. After drying and evaporation, the residue is suspended in ether and filtered. After drying the crystals, 11.57 g of N-(2-naphthylsulfonyl)-glycine-t-butyl ester are obtained. Rf=0.49 (ether/hexane 2:1).

b) 1 g of the product from a), 923 mg of 5-dimethylamino-naphthalene-1-sulfochloride, 0.48 ml of triethylamine and 418 mg of dimethylaminopyridine are mixed together in 10 ml of methylene chloride. The reaction mixture is collected in 100 ml of ether, washed with 1 M hydrochloric acid and with water. After drying and evaporation, 1.67 g of N-[[5-(dimethylamino)-1-naphthyl]sulfonyl]-N-(2-naphthylsulfonyl)glycine are obtained. Rf=0.33 (methylene chloride/n-hexane 9:1).

c) Hydrogen chloride is introduced into a solution of the product from b) in 17 ml of methylene chloride at 0 to 5°C. After concentration, 1.7 g of carbonic acid is obtained. Rf=0.72 (ethyl acetate/acetic acid 97:3). 844 mg of dicyclohexylcarbodiimide (DCC) is added to a solution of this product in 17 ml of methylene chloride at room temperature. Then 877 mg of t-butyl ester (S)-3-amidinomethyl-1-piperidinecarboxylic acid, dissolved in 3 ml of methylene chloride, was added. The reaction mixture is filtered, the filtrate is evaporated and the residue is chromatographed over silica gel with methylene chloride/ether 9:1. 0.82 g of t-butyl-(S)-3-[[N-[[(5-(dimethylamino-1-naphthyl]sulfonyl]-N-(2-naphthylsulfonyl)glycinyl]amino]methyl]- 1-piperidinecarboxylate. Rf=0.2 (methylene chloride/ether 9:1). This 0.82 g is converted similarly to example 70e) into 316 mg of N-[[(S)-1-amidino-3-piperidinyl] methyl]-2-[[[5-(dimethylamino)-1-naphthyl]sulfonyl]-(2-naphthylsulfonyl)amino]acetamide-acetate. Rf=0.46 (Takeda solution). FAB-MS: 637 (M +1).

Example 73

Similar to example 30, but using 2-thienyl-glyoxal acid, benzoic acid, or benzyl chloroformate instead of phenylglyoxal acid (example 30g), the following is obtained:

a) (R)-N-[[(S)-1-amidino-3-piperidinylmethyl]-2-(2-naphthyl-sulfonamido)-3-(α-oxo-2-thiophenacetamido) propionamide-p

b) -toluenesulfonate (1:1), FAB-MS: 571 (M+H)+,

b) N-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)ethylbenzamide-p-toluenesulfonate (1:1), FAB -MS: 537 (M+H)+, resp

c) benzyl-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido]ethyl]carbamate-acetate (1:1), FAB - MS: 567 (M+H) + .

Example 74

After treatment with aqueous sodium hydroxide, o-[[(R)-α-[[[(RS)-1-amidino-3-piperidinyl]methyl]carbamol]-p-nitrophenethyl]sulfamoyl]benzoeva is obtained from the product from example 27 acid, FAB-MS: 533 (M+H) + .

Example 75

Similar to examples 68 and 69, (R)-4-[(S)-3-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthyl-sulfonamido) is obtained )propionyl]hexahydro-1,4-oxazepine-3-carboxylic acid, FAB-MS: 589 (M+H)+.

Example 76

Similar to example 52 (but with 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

Similarly to example 43, 4'-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)-ethyl]succinanilidic acid is obtained. FAB-MS: 609 (M+H) + .

The compound of formula I, its solvate or its salt can be used in a known manner to obtain pharmaceutical preparations, wherein said compound is an active ingredient in these preparations. The preparations are formed in the form of tablets and capsules with the following composition:

Example A

per tablet

Active ingredient 200 mg

Microcrystalline cellulose 115 mg

Corn starch 25 mg

Talc 25 mg

Hydroxypropylmethylcellulose 20 mg

425 mg

Example B

per capsule

Active ingredient 100.0 mg

Corn starch 20.0 mg

Milk sugar 95.0 mg

Talc 4.5 mg

Magnesium stearate 0.5 mg

220.0 mg

Claims (23)

1. Guanidine formulas [image] indicated by what R represents aryl, heteroaryl or heterocyclyl, T CH2 or O, L NH or O and -N(X)-M namely the group -N(SO2-R°)-CH2 or in a certain case an isoquinolylene group substituted in the phenyl ring, and R° has the above meaning as for R, or X represents H, -CH2COOH, -CH2COO-C1-4-alkyl, -CH2CO-(tetra- to heptamethyleneimino) or in certain case an N-mono- or N-di-C1-4-alkylated -CH2CONH2 group, and M R'-(CH2)1-2CH=, R'-(COCH2CH=, R"-(COCH2 CH=, R'-(CO)1-2NHCH2CH=, benzyl OCONH CH2CH=, -CH2 [R'-( CO)1-2NH]CH-, -CH2(benzyl-OCONH)CH- or -CH(CO-Q)CH2- group, Rʹ aryl, heteroaryl, cycloalkyl or heterocyclyl, R" tetra- to heptamethyleneimino in certain cases substituted with up to 2 substituents selected from the group consisting of oxo, -COO-C1-4-alkyl, -(CH2)0-1OH, -(CH2)0-1OCO-C1-4- alkyl and in certain cases mono- or di-C1-4-alkylated carbamoyl, a Q benzylamino or in a certain case with an O- or S-atom interrupted and in a certain case with up to 2 substituents substituted tetra- to heptamethyleneimino group, wherein the substituents are selected from the group consisting of C1-4-alkyl, COOH, -COO-C1- 4-alkyl, -CH2OH and -CH2O-benzyl; as well as hydrates or solvates and physiologically acceptable salts of those guanidines of formula I. 2. Guanidines according to claim I and formula [image] indicated by what -N(X')-M- represents in a certain case an isoquinolylene group substituted in the phenyl ring, or X' H, -CH2COOH, -CH2 COO-C1-4 -alkyl, CH2CO- (tetra- to heptamethyleneimino) or in certain case N-mono - or N-di-C1-4-alkylated -CH2CONH2 group, and M' R'-(CH2)1-2CH=, R'-COCH2CH= or -CH(CO-Q')CH2- group, Q' is benzylamino, morpholino or tetra- to heptamethyleneimino, and R, R', L and T have the above meanings given in Claim 1, as well as hydrates or solvates and physiologically acceptable salts of these compounds. 3. Compounds according to Claim 2, characterized in that X' is H, and R, M', L and T have the meanings given above in Claim 2. 4. Guanidines according to Claim 1 and formulas [image] indicated by what M" represents R"-COVH2CH=, R'-(CO)1-2NHCH2CH=, benzyl-OCONHCH2CH=, -CH2[R'-(CO)1-2NH]CH-, -CH2(benzyl-OCONH)CH- or -CH(CO-Q")CH2- group, Q" in a certain case a tetra- to heptamethyleneimino group substituted with an O or S atom of up to 2 substituents selected from the group consisting of C1-4-alkyl, COOH, -CO-C1-4-alkyl, -CH2OH and -CH2O-benzyl , i R, R', R", L and T have the meanings given above in Claim 1. 5. Guanidines according to Claim 1, characterized in that R, L, T, M or -N(X)-M- and X have the meanings given above in Claim 1, and X is not H. 6. Guanidines according to Claim 1, characterized in that R is aryl, especially naphthyl, hydroxynaphthyl, 4-biphenyl, 2-anthryl, iodophenyl, nitrophenyl, benzyloxyphenyl, dilnetoxyphenyl, 4-methoxy-2,3,6-trimethylphenyl, 2, 4,6-triisopropylphenyl, carboxyphenyl, methoxycarbonylphenyl, benzyloxynaphthyl, phenylsulfonylphenyl, hexahydroazepinoylphenyl or t-butylphenyl. 7. Guanidines according to claim 1, characterized in that R is heteroaryl, especially 3-methyl-8-quinolyl, 5-(1-methyl-5-trifluoromethylpyrazol-3-yl)-2-thienyl or benzothienyl. 8. Guanidines according to claim 1 or 2, characterized in that R is heterocyclyl, especially 3-methyl-1,2,3,4-tetrahydro-8-quinolyl. 9. Guanidines according to Claim 1, characterized in that -N(X)-M- is isoquinolylene or N-dimethylaminonaphthylsulfonyl-aminomethylene. 10. Guanidines according to Claim 1 or 2, characterized in that X is H or -CH2COOH. 11. Guanidines according to Claim 1, characterized in that M is R'-(CH2)1-2CH=, especially 3-indolylethylidene, 2,3-dioxo-1-indolylethylidene, phenethylidene, 1,4-dioxo-5H-2 ,5-benzodiazepine-5-ylethylidene, (fluorine, chlorine, iodo, cyano nitro, amino, carboxy, C1-4-alkoxycarbonyl or hydroxy)phenethylidene, cyclohexylpropylidene, decalylethylidene, irnidazolylethylidene, thienylethylidene, (methyl, bromo, fluorine or carboxymethyl) -3-indolylethylidene, naphthylethylidene, (ethoxycarbonylcarbonylamino, methoxycarbonylethylcarbonylamino, benzyloxycarbonylethylcarbonylamino, ethoxycarbonylamino, benzoylcarbonyl amino, carboxybenzoylamino, methoxyethoxyacetamido, acetamido, carboxycarbonylamino, carboxypropionyl amino, tolylsulfonamido, iodophenylsulfonamido, carboxyphenylsulfonamido or ethoxycarbonylmethylamino)phenethylidene, oxobenzoxazolinethylidene or 5-methylbromo- or -2,3-dioxo-1-indolinylethylidene group. 12. Guanidines according to Claim 1, characterized in that M is (R' or R") COCH2CH= group, especially hexahydroazepinoylethylidene, (methoxycarbonyl or carboxy)pyrrolidinoylethylidene, 3,4-dihydro-2(1H)-isoquinolinoyl ethylidene, (nitro . 13. Guanidines according to Claim 1, characterized in that M is R'-(CO)1-2NHCH2CH= group, especially benzoylcarboxamidoethylidene, thienoylcarboxamidoethylidene, benzoylamidoethylidene or benzyloxycarboxamidoethylidene group. 14. Guanidines according to Claim 1, characterized in that M is -CH2[R'-(CO)1-2NH]CH- group, especially 2-(carboxybenzoyl-amido)ethylene, 2-(benzyloxybenzoylamido)ethylene, 2-( 2-piperidine-carboxyamido)ethylene, 2-(hydroxy benzoylamido)ethylene or 2-(aminobenzoylamido)ethylene group. 15. Guanidines according to Claim 1, characterized in that M is a -CH(CO-Q)CH2- group, especially 1-(benzylaminocarbonyl)-ethylene, 1-(hexahydroazepinoyl)ethylene, 1-(morpholinoyl)ethylene, 1-( heptahydroazocinoyl)ethylene, 1-[2-(benzyloxy methyl morpholinoyl]ethylene, 1-[2-(hydroxymethylmoriolinoyl)] ethylene, 1-(2-ethoxycarbonyl-4-methylpiperidinoyl)ethylene, 1-(2-carboxy-4-methylpiperidinoyl) )ethylene or 1-(3-carboxyhydro-1,4-oxazepinoyl)ethylene group. 16. Guanidines according to Claim 1, 2 or 6, characterized in that R is aryl, especially naphthyl- or nitro- or iodo-phenyl, L is NH and in that the asymmetric C-atom in the piperidine- or in the morpholine-ring has S - configuration. 17. Guanidines according to Claim 1, 11 or 12, and formulas [image] indicated by what A Represents aryl, aroyl or heterocyclyl, especially phenyl, nitrophenyl, indolyl, 2,3-dioxo-1-indolinyl or aminobenzoyl. 18. Guanidines according to Claim 1 or 2, characterized in that they are selected from the group consisting of: (R)-N-[(R,S)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-2,3-dioxo-1-indolinepropionamide, (R)-N-[(RS)-1-amidino-3-piperidinylmethyl)-α-(2-naphthyl-sulfonamido)-o-nitrohydrocinnamamide, (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-α-(o-nitro-benzenesulfonamido)indole-3-propionamide, (R)-N-[(S)-1-amidino-3-piperidinylmethyl)-α-(p-iodobenzenesulfonamido)indole-3-propionamide, (R)-N-[(S)-1-amidino-3-piperidinylmethyl)-α-(p-iodobenzenesulfonamido)-p-nitrohydrocinnamamide, (R)-N-[(RS)-1-amidino-3-piperidinylmethyl]-3-(o-aminobenzoyl)-(2-naphthylsulfonamido)propionamide, N-[(R)-α-[[(S)-1-amidino-3-piperidinyl]methylcarbamoyl]-phenethyl]-N-(2-naphthylsulfonyl)glycine, (R)-N-[(S)-1-amidino-3-piperidinylmethyl]-1,2,3,4-tetrahydro-2-(2-naphthylsulfonyl)-3-isoquinolinecarboxamide (S)-N-[(RS)-1-amidino-3-piperidinylmethyl]hexahydro-β-(2-naphthylsulfonamido)-γ-oxo-1H1-azepinebutyramide, (R)-N-[(S)-1-amidino-3-piperidinylmethyl]-α-(2-naphthyl-sulfonamido)-2,3-dioxo-1-ondolinpropionamide, 4'-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)ethyl]oxanilic acid, (S)-N-[[(RS)-1-amidino-3-piperidinyl]methyl]hexahydro-(-2-naphthylsulfonamido-γ-oxo-1(2H)-azocynbutyramide, (2RS,4R)-1-[N4[[(S)-1-amidino-3-piperidinyl]methyl]-N2-(2-naphthylsulfonyl)-L-asparaginyl]-4-methyl-2-piperidinecarboxylic acid, 4'-[(R)-2-[[[(S)-1-amidino-3-piperidinyl]methyl]carbamoyl]-2-(2-naphthylsulfonamido)ethyl]succinanilidic acid. 19. Compounds according to one of Claims 1-18, characterized in that they are used as medicine, in particular as an inhibitor of thrombin-induced aggregation of blood platelets and coagulation of fibrinogen in blood plasma. 20. Process for obtaining compounds according to one of Claims 1-18, characterized in that a) acid formula R-SO2N(X)-M-COOH II in which the carboxy group present in the group X, R or M has been previously protected reacts with an amine or an alcohol of the formula [image] or with some salt of the same or b) what compound formula [image] reacts with an amidination reagent or c) what amine formula [image] reacts with an acid of the formula R'COOH or with its functional derivative, i d) if desired, the functionally reactive group found in group M of the compound of formula I, i e) if desired, the compound of formula I is converted into a physiologically acceptable salt or the salt of the compound of formula I is converted into a free acid or base. 21. Pharmaceutical preparation, characterized in that it contains a compound according to one of Claims 1-18, which is an active ingredient. 22. Application of compounds according to one of claims 1-18, characterized in that said compound is used to obtain a drug for treatment or prophylaxis of diseases caused by thrombin-induced aggregation of blood platelets or coagulation of fibrinogen in blood plasma. 23. Compounds of formulas III, IV and V, indicated by the fact that they are defined in accordance with claim 20.