MXPA00003094A - Benzamidine derivatives as factor xa inhibitors - Google Patents

Abstract

The invention relates to novel compounds of formula (I), wherein X, Y, R1, R2 and R3 have the meanings given in Claim 1, are inhibitors of coagulation factor Xa, and can be used for preventing or treating thromboembolic disorders.

Description

BENZAMIDINE DERIVATIVES AS INHIBITORS OF THE XA FACTOR Field of the Invention The invention relates to the compounds of formula I wherein R1 represents -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] "-Ar, -COOA, -OH or with a conventional amino protecting group, REF .: 32784 R2 represents H, A, 0R6, N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr, NHS02A, NHS02Ar, COOR6, CON (R6) 2, CONHAr, COR6, COAr, S (0) nA or S (0) nAr, R "represents A, cycloalkyl, - [C (R6) 2] nAr, - [C (R6) 2] n-0-Ar, - [C (R6) 2] nHet or -C (R6) 2 = C (R6) 2-Ar, R6 represents H, A or benzyl, X is absent or represents -CO-, -C (R6) 2-, -C (R6) 2-C (R6) 2-, -C (R6) 2 -CO-, -C (R6) 2-C (R6) 2 -CO-, -C (R6) = C (R6) -CO-, NR6CO-, -N. { [C (R6) 2] n-COOR6} -CO- or -C (COOR6) R6-C (R6) 2-CO-, Y represents, -C (R6) 2-, -S02-, -CO-, -COO- 'or CONR6-, A represents alkyl from 1 to 20 carbon atoms in which one or two CH2 groups may be replaced by O or S atoms or by groups of -CR6 = CR6 and / or 1 to 7 H atoms can be replaced by F, Ar represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A, Ar ', OR6, N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr ', NHS02A, NHS02Ar', COOR6, CON (R6) 2, CONHAr ', COR6, COAr', S (0) nA or S (0) nAr, Ar 'represent phenyl or naphthyl or substituted or mono , di or trisubstituted with A, OR6, N (R6) 2, N02, CN, Hal, NHCOA, COOR6, CON (R6) 2, COR6 or S (0) nA, Het represents a heterocyclic mono or bicyclic, saturated or unsaturated, which contains one, two, three or four identical or different heteroatoms such as nitrogen, oxygen and sulfur and which is unsubstituted or mono- or polysubstituted with Hal, A, Ar ', COOR6, CN N (R6) 2, N02, Ar-C0NH-CH2 and / or carbonyloxy, Hal represents F, Cl, Br or I, n is 1, 1 or 2, and the salts of these compounds. The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates of these compounds. Background of the Invention The objective of the invention was to develop new compounds with valuable properties, in particular compounds that can be used in the manufacture of medicines. It was found that the compounds of formula I and their salts exhibit valuable pharmacological properties and are well tolerated. In particular, they have inhibitory properties of factor Xa and, therefore, can be used to combat and prevent thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication. Aromatic derivatives of amidine having an antithrombotic action are disclosed, for example, in European Patent No. 0 540 051. Cyclic guanidines which are intended for the treatment of thromboembolic diseases are described, for example, in the patent world No. 97/08165. Aromatic heterocycles that inhibit factor Xa are disclosed, for example, in the world patent no. 96/10022. The antithrombotic and anticoagulant effect of the compounds of the invention is due to the inhibitory action exerted by the latter on the activated coagulation protease, known as factor Xa. Factor Xa is one of the proteases that participate in the complex process of blood coagulation. Factor Xa catalyzes the transformation of prothrombin into thrombin which in turn contributes to the formation of thrombi. An activation of thrombin can cause the onset of thromboembolic diseases. Therefore, the inhibition of factor Xa can prevent the formation of thrombin. The compounds of the invention of formula I and their salts are involved in the blood coagulation process by inhibiting factor Xa and, consequently, inhibiting the formation of thrombi. The inhibition of factor Xa produced by the compounds of the invention and the measurement of the anticoagulant and antithrombotic activity can be determined in vivo or in vitro by means of usual methods. A suitable method is the one that describe, for example, J. Haupt ann et al. in Thrombosis and Haemostasis 63, p. 220 to 223 (1990). The inhibition of factor Xa can be determined, for example, according to the method of T. Hará et al. which is described in Thromb. Haemostas. 71, pgs. 314 to 319 (1994). The compounds of formula I can be used in medicine and veterinary medicine as active substances of drugs, in particular, to combat and prevent thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, apoplexy , angina pectoris, restenosis after angioplasty and intermittent claudication.

Description of the invention The object of the invention is constituted by the compounds of the formula I and their salts and also by a process for preparing the compounds of formula I, according to claim 1 and their salts, characterized in that a) they are liberated from one of its functional derivatives by treatment with a sovolysis or hydrogenolysis agent, and i) hydrogenolysis by releasing an amidino group of its oxadiazole derivative, ii) replacing a conventional amino-protecting group with hydrogen by treating it with an solvolysis or hydrogenolysis or releasing an amino group that is protected with a conventional protective group, b) because to prepare compounds of formula I wherein R1 represents X represents -CO- or -C (R6) 2-C0-, and R2, R3 and Y have the meanings indicated in claim 1, a compound of formula II is reacted wherein R3, R4, Rs, W and Y have the meanings indicated in claim 1, with a compound of formula III R ' where R is X represents -CO- or -C (R6) 2-C0-, R2 has the meaning indicated in claim 1 and L represents Cl, Br, I or a free OH group or functionally transformed into a reactive group, or c) because for preparing compounds of formula I wherein R1 is Y represents -S02-, -CO-, -COO- or -C (R6) 2-, and R2 and X have the meanings indicated in claim 1, a compound of formula V is reacted LY-R3 (IV) wherein Y represents -S02 -, - CO-, -COO- or -C (R6) 2-, R ° has the meaning indicated in claim 1 and L represents Cl, Br, I or a free OH group or functionally transformed a reactive group, with a compound of formula V R2 where R1 is and R2 and X have the meanings indicated in claim 1, d) because to prepare compounds of formula I wherein R1 is Y represents -CONH- and R2 and X have the meanings indicated in claim 1, a compound of formula VI is reacted R3-N = C = 0 (VI) wherein R has the meaning indicated in claim 1, with a compound of formula V where R is and R2 and X have the meanings indicated in claim 1, e) because to prepare compounds of formula I, wherein R 1 represents -C (= NH) -NH 2, a cyano group is transformed into an amidino group, f) and / or because it is a compound of formula I is transformed (n) ) one or more residues R1, R2 and / or R3 in one or more different radicals R1, R2 and / or R3, for example, i) hydrolyzing an ester group to a carboxyl group, ii) reducing a nitro group, iii) acylating an amino group, and / or transforming a base or an acid of formula I in one of its salts.

The meanings of all the remains that appear repeatedly in the present text, such as R6, are independent of each other. The residues or parameters L, X, Y, R1, R2 and R3 that are indicated in this text have the meanings indicated for the formulas I to VI, unless otherwise indicated. In the formula indicated above, • A represents alkyl of 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Preferred meanings of A are methyl, then ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tertbutyl, and then also pentyl, l-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-, or 4-methylpentyl, 1,1-, 1,2- 1,3- 2,2- 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1, 2, 2-trimethylpropyl, heptyl, octyl, nonyl or decyl. Alkyl also preferably represents, for example, trifluoromethyl, pentafluoroethyl, allyl or crotyl. Cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. In particular, it represents the remainder of a bicyclic terpene such as, for example, 3-menthyl and, more preferably, the canfo-10-yl moiety. COR6 is acyl and preferably represents formyl, acetyl, propionyl, then also butyryl, pentanoyl or hexanoyl. Hal preferably represents F, Cl or Br, but also I. R 2 preferably represents H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro amino, methylamino, dimethylamino, ethylamino, diethylamino, acetamido, sulfonamido, methylsulfonamido, phenylsulfonamido, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulphonyl, phenylsulphinyl, phenylsulphonyl, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, then also acyl or benzoyl.

R3 preferably represents, for example, A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2CH2Ar, CH2Het, CH2CH2Het or CH = CH-Ar. R6 represents H, A or benzyl, but mainly H. X is preferably absent or represents, for example -CO-, -CH2-, -CH2-CH2-, -CH2-CO-, -CH2-CH2-CO-, - CH = CH-CO-, NR6CO-, -. { [CH2] n-COOR6} -C0-o -CH (COOR6) -C2-CO-. And preferably represents, for example, -S02- or -CO-, then also -C00-, -CONH- or -CH2-. Ar preferably represents phenyl or unsubstituted naphthyl, then preferably mono, di or trisubstituted phenyl or naphthyl, for example with A, fluorine, chlorine, bromine, iodine, hydrophilic, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulphonyl, phenylsulfinyl, phenylsulphonyl, nitroamino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, phenylsulfonamido, (4- methylphenyl) -sulfonamido, carboxymethoxy, carboxyethoxy, methoxycarbonymethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, acyl or benzoyl, and then also biphenyl. Therefore, Ar preferably represents, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl , o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- ( N-methylamino) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, • m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o- , m- or p-methoxycarbonylphenyl, o-, - or p- (N, N-dimethylamino) -phenyl, o-, m- 'or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl , o-, m- or p-chlorophenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p- (phenylsulfonamido) -phenyl, o-, m- or p- (methylsulfonamido) -phenyl, or -, m- or p-methylthiophenyl, then preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4 -, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dibro Mophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino- or 3-nitro-4-N, N-dimet ilaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,4,5-trichlorophenyl, 2,4,6- trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4- bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or , 5-dimethyl-4-chlorophenyl. Particularly preferred meanings of Ar are that of unsubstituted phenyl or naphthyl, then preferably that of mono, di or trisubstituted phenyl or naphthyl, for example, with A, chloro, methoxy, amino, dimethylamino, and then also that of biphenyl. Ar 'preferably represents, for example, phenyl or naphthyl, then preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, or- , m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, or- , m- or p- (N-methylamino) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, - or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N-ethylamino) -phenyl, or-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, or-, m- or p-bromophenyl, o-, m- or p-chlorophenyl or o-, m- or p-methylsulfonylphenyl. Het preferably represents, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4 -, 5- or 6-pyrimidinyl, then preferably 1, 2, 3-triazol-l-, -4- or -5-yl, 1, 2, 4-triazol-l-, -3- or -5-yl , 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazole-2- or -5-yl, 1,2,4-thiadiazol-3-yl-5-yl, 1, 2, 3-thiadiazol-4-yl-5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benzo-2, 1, 3-oxadiazolyl, 2-, 3-, 4- , 5-, 6-, 7- or 8-quinoline, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinoline, 3-, 4-, 5-, 6-, 7- u 8-cinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo [1, 4 ] oxazinyl, then preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl, 2, 1, 3-benzoxadiazole-5 -yl or dibenzofuranyl. The heterocyclic moieties may also be partially or totally hydrogenated. Therefore, Het can also represent, for example, 2, 3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l-, -2-, - 3-, -4- or -5-pyrrolyl, 2,5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro- 1-, -2- or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4- pyrazolyl, 1,4-dihydro-l-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, - 5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl , 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl , 1-, 2- or -3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- u- 8-quinoline, 1, 2, 3, 4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinoline, 2-, 3 -, 5-, 6-, 7- or 8-3, 4-dihydro-2H-b enzo [1,4] oxazinyl, then preferably 2, 3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5 - or 6-yl, 2,3- (2-oxo-methylenedioxy) -phenyl or also 3,4-dihydro-2H-1, 5-benzodioxepin-6- or -7-yl, then preferably 2,3- dihydrobenzofuranyl or 2,3-dihydro-2-oxo-furanyl. Het may be unsubstituted or mono or polysubstituted with Hal, A, Ar ', COOR6, CN N (R6) 2, N02, Ar-CONH-CH2. By "polysubstituted" is meant di, tri, tetra or penta-substituted. The compounds of formula I can have one or more chiral centers and, therefore, have different stereoisomeric forms. The formula embraces all these forms. Accordingly, it is first and foremost object of the present invention those compounds of formula I in which at least one of the aforementioned residues have one of the preferred meanings indicated above. Some preferred groups of compounds may be represented by the partial formulas a If indicated below, which correspond to formula I and in which the moieties which are not explicitly detailed have the meaning indicated for formula I, - namely : in R1 represents -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] n-Ar, -COOA, -OH or with a conventional amino protecting group, R2 represents H, A, OR6, N (R6), N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr, NHS02A, NHS02Ar, COOR6, CON (R6) 2, CONHAr, COR6, COAr, S (0 ) nA or S (0) nAr, R3 represents A, cycloalkyl, Ar, CH2Ar, CH2OAr, CH2CH2Ar, CH2Het, CH2CH2Het or CH = CH-Ar, R6 represents H or A, X is absent or represents -CO-, -CH2 -CO, -CH2CH2-CO-, -CH2-, -CH2-CH2-, -CH = CH-CO-, -NHCO-, -N (CH2COOR6) -CO or -CH (COOR6) -CHz-CO-, Y represents -S02-, -CO-, -COO- or -CO-NH- or CH2-, A represents alkyl of 1 to 20 carbon atoms in which one or two groups of CH2 can be replaced by O or S atoms or by groups of -CR6 = CR6 and / or 1 to 7 atoms of H can be replaced by F, Ar represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A, Ar ', OR6, N (R6) 2, N02, CN Hal, NHCOA, NHCOAr', NHS02A, NHS02Ar ', COOR6, CON (R6) 2, CONHAr ', COR6, COAr', S (0) nA or S (0) "Ar, Ar 'represents phenyl or unsubstituted naphthyl or mono, di trisubstituted with A, OR6, N (R6) 2, N02, CN, Hal, NHCOA, COOR6, CON (R6) 2, COR6 or S (0) nA, Het represents a monocyclic or bicyclic, saturated or unsaturated heterocyclic system, containing one, two, three or four identical or different heteroatoms such as nitrogen, oxygen and sulfur and which is unsubstituted or mono- or polysubstituted with Hal, A, Ar ', COOR6, CN, N (R6) 2, N02, Ar-C0NH-CH2 and / or carbonyloxy, Hal represents F, Cl, Br olyn is O, 1 6 2; in Ib R1 represents -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] n-Ar, -COOA, -OH or with a conventional amino protecting group, R represents H, R3 represents A, cycloalkyl, Ar, -CH2Ar, -CH2OAr, -CH2CH2Ar, -CH2Het, -CH2CH2Het or -CH = CH-Ar, R6 represents H or A, X is absent or represents -CO-, -CH2-CO-, -CH2-CH2-CO-, -CH2 -, -CH2-CH2-, -CH = CH-CO-, -NHCO-, -N (CH2COOR6) -CO or -CH (COOR6) -CH2-CO-, Y represents -S02-, -CO-, - COO- or -CO-NH- or CH2-, A represents alkyl of 1 to 20 carbon atoms in which one or two groups of CH2 may be replaced by O or S atoms or by groups of -CR6 = CR6 and / or 1 to 7 H atoms can be replaced by F, Ar represents phenyl or naphthyl unsubstituted or mono, di or trisubstituted with A, Ar ', OR6, NH2, N02, CN, Hal, NHCOA, NHCOAr', NHS02A, NHS02Ar ', COOR6, CON (R6) 2, CONHAr', COR6, COAr ', S (O) nA or S (0) nAr, Ar' represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A, OR6, N (R6) 2, N02, CN, Hal, NHCOA, COOR6, CON (R6) 2, COR6 OS (0) nA, Het represents a monocyclic or bicyclic, saturated or unsaturated heterocyclic system, containing one, two, three or four identical or different heteroatoms such as Nitrogen, oxygen and sulfur and which is unsubstituted or mono or polysubstituted with Hal, A, Ar ', COOR6, CN N (R6) 2, N02, Ar-CONH-CH2 and / or carbonyloxy, Hal represents F, Cl, Br or I and n is 0, 1 0 2; where R1 represents -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] n-Ar, -COOA, -OH or with a conventional amino protecting group, R represents H, R3 represents A, cycloalkyl, Ar, • CH2Ar, -CH20Ar, -CH2CH2Ar, -CH2Het, -CH2CH2Het or -CH = CH-Ar, R6 represents H or A, X is absent or represents -CO-, -CH2-C0-, -CH2-CH2-C0-, -CH2 -, -CH2-CH2-, -CH = CH-CO-, -NHCO-, -N. { CH2COOR6} -CO or -CH (COOR6) -CH2-CO-, Y represents -S02-, -CO-, -COO- or -CO-NH- or -CH2-, A represents alkyl of 1 to 20 carbon atoms in the which one or two CH2 groups can be replaced by 0 or S atoms or by groups of -CR6 = CR6 and / or 1 to 7 H atoms can be replaced by F, Ar represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A, Ar ', OR6, N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr', NHS02A, NHS02Ar ', COOR6, CON (R6) 2, CONHAr', COR6, COAr ', S ( 0) nA or S (0) nAr, Ar 'represents phenyl naphthyl unsubstituted or mono, di or trisubstituted with A, OR, N (R6) 2, N02, CN, Hal, NHCOA, COOR6, CON (R6) 2, COR6 OS (0) nA, Het represents a heterocyclic mono or bicyclic system which is unsubstituted or mono or poly substituted with Hal, A, Ar ', COOR6, CN, N (R6) 2, N02, Ar-CONH-CH2 and / or carbonyloxy, and which is selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazpl, pyridine, benzodioxole or benzothiophene, Hal represents F, Cl, Br or I and n is 0, 1 or 2; in Id R1 represents -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] n-Ar, -COOA, -OH or with a conventional amino protecting group, R represents H, R3 represents A, cycloalkyl, Ar, -CH2Ar, -CH2OAr, -CH2CH2Ar, -CH2Het, -CH2CH2Het or -CH = CH-Ar, R6 represents H or A, X is absent or represents -CO-, - CH2-CO-, -CH2-CH2-CO-, -CH2-, -CH2-CH2-, -CH = CH-CO-, -NHCO-, -N. { CH2COOR6} -CO or -CH (COOR6) -CH2-CO-, Y represents -S02-, -CO-, -CO-NH- or -CH2-, A represents alkyl of 1 to 20 carbon atoms in which one or two groups of CH2 may be replaced by O or S atoms or by groups of -CR6 = CR6 and / or 1 to 7 H atoms may be replaced by F, Ar represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A, Ar ', OR6, N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr', NHS02A, NHS02Ar ', COOR6, CON (R6) 2, CONHAr', COR6, COAr ', S (0) nA or S (0) nAr, Ar 'represents phenyl, Het represents a monocyclic or bicyclic heterocyclic system which is unsubstituted or mono-polysubstituted with Hal, A, Ar', COOR6, CN, N (R6) 2, N02, Ar- CONH-CH2 and / or carbonyloxy and which is selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, benzothiophene or dibenzofuran, Hal represents F, Cl, Brolyn is 0.16 2; where R1 represents -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] n-Ar, -COOA, -OH or with conventional amino protecting group, R represents H, R3 represents A, cycloalkyl, Ar, -CH2Ar, -CH2OAr, -CH2CH2Ar, -CH2Het, -CH2CH2Het or -CH = CH-Ar, R6 represents H or A, X is absent or represents -CO-, - CH2-CO-, -CH2-CH2-C0-, -CH2-, -CH2-CH2-, -NHCO-, -N. { CH2COOR6) -CO or -CH (COOR6) -CH2-C0-, Y represents -S02-, -CO-, or -CH2-, A represents alkyl of 1 to 20 carbon atoms in which one or two groups of CH2 may be replaced by O or S atoms or by groups of -CR6 = CR6 and / or 1 to 7 H atoms may be replaced by F, Ar represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A, Ar ' , OR6, N (Rd) 2, N02, CN, Hal, NHCOA, NHCOAr ', NHS02A, NHS02Ar', COOR6, CON (R6) 2, CONHAr ', COR6, COAr', S (0) nA OS (0) nAr, Ar 'represents phenyl, Het represents a monocyclic or bicyclic heterocyclic system which is unsubstituted or mono- or polysubstituted with Hal, A, Ar', COOR6, CN N (R6) 2, N02, Ar-CONH-CH2 and / or carbonyloxy, which is selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole, enzothiophene or dibenzofuran, Hal represents F, Cl, Br or I and n is 0, 1 or 2; in If R1 represents -C (= NH) -NH2 which may also be monosubstituted with COOA, R represents H, R3 represents A, cycloalkyl, Ar, -CH2Ar, -CH20Ar, -CH2CH2Ar, -CH2Het, -CH2CH2Het or -CH = CH-Ar, R6 represents H or A, X is absent or represents -CO-, -CH2-CO-, -CH2-CH2-C0-, -CH2 -, -CH2-CH2-, -NHCO-, -N. { CH2COOR6} -CO or -CH (COOR6) -CH2-C0-, Y represents -S02-, -CO-, or -CH2-, A represents alkyl of 1 to 20 carbon atoms in which one or two groups of CH2 may be replaced by O or S atoms or by groups of -CR6 = CR6 and / or 1 to 7 H atoms can be replaced by F, Ar represents phenyl or unsubstituted naphthyl or mono, di or trisubstituted with A, Ar ', OR6 , N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr ', NHS02A, NHS02Ar', COOR6, CON (R6) 2, CONHAr ', COR6, COAr', S (0) nA or S (0) nAr , Ar 'represents phenyl, Het represents a monocyclic or bicyclic heterocyclic system which is unsubstituted or mono- or polysubstituted with Hal, A, Ar', COOR6, CN, N (R6) 2, N02, Ar-C0NH-CH2 and / or carbonyloxy, and which is selected from the group consisting of thiophene, tetrahydroquinoline, chroman, pyrazole, isoxazole, pyridine, benzodioxole or benzothiophene or dibenzofuran, Hal represents F, Cl, Br or I and n is 0, 1 or 2; In general, the compounds of formula I and the starting materials for their preparation are prepared according to known methods, as described in the literature (for example, in certain standard works such as those of Houben-Weyl, " Methoden der organischem Chemie "(Methods of Organic Chemistry), George-Thieme-Verlag, Stuttgart) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use of known variants of these methods and that are not detailed in this text.

If desired, the starting materials can be prepared in situ, but in such a way that instead of isolating them from the reaction mixture they are immediately reacted subsequently to form the compounds of formula I. The compounds of formula I can be preferably releasing one of its functional derivatives by treatment with a solvolysis or hydrogenolysis agent. As starting substances for solvolysis or hydrogenolysis, those substances which respond to formula I are preferred, but which instead of one or more free amino groups and / or free hydroxyl groups contain amino groups and / or hydroxyl correspondingly protected, preferably those which instead of an H atom attached to an N atom carry an amino protecting group, in particular those which instead of a group of NH carry a group of R '-N, where R' an amino protecting group, and / or those which instead of the H atom of the hydroxyl group bear a hydroxyl protecting group, for example, those that respond to formula I, but instead of a -COOH group carry a group of -COOR ", where R" is a hydroxyl protecting group. Among the starting materials, the oxydiazole derivatives which can be transfo into the corresponding amidino compounds are also preferred. The introduction of the oxadiazole group can be carried out, for example, by reaction of the cyano compounds with hydroxylamine and by reaction of phosgene, dialkyl carbonate, chloroformic acid ester, N, N'-carbonyldiimidazole or anhydroacetic acid. There can also be several groups, the same or different, of protected amino and / or hydroxyl in the starting material molecule. If the protective groups present are different from each other, then they can be excised in many cases selectively. The term "amino protecting group" is known and refers to the groups that are adapted to protect (block) an amino group from chemical reactions, but which can easily be cleaved after the desired chemical reaction has been carried out in another place in the molecule. Typical examples of these groups are, in particular, the unsubstituted or substituted groups of acyl, aryl, aralkoxymethyl or aralkyl. Since the amino protecting groups are cleaved after the desired reaction (or the sequence of reactions) has elapsed, the type and size thereof is not a critical point; however, those groups from 1 to 20, in particular from 1 to 8, C atoms are preferred. In the context of the process of the present invention, the expression "acyl group" has a very broad interpretation. It encompasses acyl groups deriving from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids such as, in particular, the alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl group of this type are alkanoyl groups such as acetyl, propionyl and butyryl; those of aralkanoyl such as phenylacetyl; those of aroyl such as benzoyl or toluyl; those of aryloxyalkanoyl such as POA (phenoxyacetyl); those of alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, terbutyloxycarbonyl (BOC), 2-iodoethoxycarbonyl; those of aralkyloxycarbonyl such as carbobenzoxy (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC); those of arisulphonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, then CBZ, Fmoc, benzyl and acetyl. The term "hydroxyl protecting group" is also known and refers to the groups that are suitable to protect a hydroxyl group from chemical reactions, but which are easily cleaved once the desired chemical reaction that has been carried out is completed. in a different place on the molecule. Typical examples of these groups are the substituted or unsubstituted groups of aryl, aralkyl or acyl mentioned above, and also the alkyl groups. The nature and size of the hydroxyl protecting groups are not a critical point because they re-excise once the chemical reaction (or the sequence of chemical reactions) desired; however, preference is given to groups of 1 to 20, in particular of 1 to 10 carbon atoms. Examples of hydroxyl protecting groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tertbutyl and acetyl; benzyl and tertiary butyl groups are particularly preferred. The release of the compounds of formula I from their functional derivatives is carried out - depending on the protecting group used - for example, with strong acids, conveniently with trifluoroacetic acid (TFA) or perchloric acid, but also with other strong inorganic acids such such as hydrochloric or sulfuric acid, with strong organic carboxylic acids such as trichloroacetic acid, or with sulfonic acids such as benzenesulfonic or p-toluenesulfonic acid. It is possible to carry out the reaction in an additional inert solvent, but the presence thereof is not indispensable in all cases. As inert solvents, organic solvents such as, for example, carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as such as dichloromethane, also alcohols such as methanol, ethanol or isopropanol and water. Mixtures of these solvents can also be used. The trifluoroacetic acid is preferably used in excess and without the additional addition of another solvent; the perchloric acid is used in the form of a mixture composed of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are conveniently between about 0 and 50 ° C, preferably between 15 and 30 ° C (room temperature). The BOC, Obut and Mtr groups can be cleaved preferably with, for example, TFA in dichloromethane or with about 3N HCl to 5N in dioxane, at a temperature comprised between 15 and 30 ° C; The FMOC group can be cleaved using an approximately 5-50% solution of dimethylamine, diethylamine or piperidine in DMF, at a temperature between 15 and 30 ° C. Protecting groups which are removed by hydrogenolysis (for example CBZ, benzyl or the release of the amidino group from their oxadiazole derivative) can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (for example, a noble metal catalyst such as palladium, conveniently on a support such as carbon). Suitable solvents are the same as mentioned above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. Generally, hydrogenolysis is carried out at temperatures between about 0 and 100 ° C and pressures between about 1 and 200 bar, preferably at temperatures between 20 and 30 ° C and pressures between 1 and 10 bar. Hydrogenolysis of the CBZ group proceeds favorably, for example, with 5-10% of Pd-C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF and at temperatures between 20 and 30 ° C. The compounds of formula I, in which R 1 represents X represents -CO- or -C (R6) 2-CO-, and R2, R3 and Y have the meanings indicated in claim 1, can preferably be prepared by reaction of compounds of formula II with compounds of formula III. In the compounds of formula III, L preferably represents Cl, Br, I or an OH group functionally transformed into a reactive form such as, for example, an activated ester, an imidazolide or an alkylsulfonyloxy group of 1 to 6 carbon atoms ( preferably methylsulfonyloxy) or arylsulfonyloxy of 6 to 10 C atoms (preferably phenylsulfonyloxy or p-tolylsulfonyloxy). In general, the reaction is carried out in an inert solvent and in the presence of an acid capturing agent, preferably an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or some other alkaline or alkaline earth metal salt of a weak acid, preferably a salt of potassium, sodium, calcium or cesium. It may also be convenient to add an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the amine component of formula II or the alkylation derivative of formula III. The reaction times are comprised, depending on the conditions employed, between a few minutes and 14 days, the reaction temperatures are between approximately 0 ° and 150 ° C, generally between 20 ° and 130 ° C. Suitable inert solvents include, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether (methyl glycol) or ethylene glycol monoethyl ether (ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone, amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide (DMSO); carbon sulphide, carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene, esters such as ethyl acetate or mixtures of the solvents mentioned. In general, the starting compounds of formula II and III are known. If not, they can be obtained according to methods known per se. The compounds of formula I, in which R 1 represents Y represents S02, CO or C00 and R2 and X have the meanings indicated in claim 1, they can preferably be prepared by reacting compounds of formula IV with compounds of formula V. In the compounds of formula IV, L preferably represents Cl, Br, I or an OH group optionally transformed into a reactive form such as, for example, an activated ester, an imidazolide or a group of alkylsulfonyloxy of 1 to 6 carbon atoms (preferably methylsulfonyloxy) or of arylsulfonyloxy of 6 to 10 carbon atoms. (preferably phenylsulfonyloxy or P-tolylsulfonyloxy). The reaction of the compounds of formula IV with those of formula V is preferably carried out in an inert solvent, in the presence of a base and at temperatures similar to those described above. In general, the starting compounds of formulas IV and V are known. If not, they can be obtained according to methods known per se. The compounds of formula I, in which R 1 represents Y represents CONH and R2 and X have the meanings indicated in claim 1, they can be prepared preferably by reaction of compounds of formula VI with compounds of formula V. The reaction of the compounds of formula VI with those of formula V is preferably carried out in an inert solvent at temperatures similar to those described above. As usual, the starting compounds of formula VI are known. If not, they can be obtained according to methods known per se. The compounds of formula I in which R 1 represents -C (= NH) -NH 2 can be prepared from the corresponding cyano compounds. The conversion of a cyano group into an amidino group is carried out, for example, with hydroxylamine and by subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example Pd / C. To prepare an amidine of formula I (R 1 = -C (= N) -NH 2), ammonia can also be added to a nitrile of formula I (R 1 = CN). The addition is preferably carried out in several stages by means of a process in which, in a manner known per se a), the nitrile is converted with H2S to a thioamide which in turn is reacted with an alkylating agent, for example with CH3I, to form the corresponding S-alkyl-imidothioester, which is finally reacted with NH3 to form the amidine, b) the nitrile is transformed with an alcohol, for example ethanol, and in the presence of HCL in the corresponding imidoester which is then treat with ammonia, or c) the nitrile is reacted with lithium bis- (trimethylsilyl) -amide and then the product obtained is hydrolyzed. It is also possible to convert a compound of formula I into another compound of formula I by transforming one or several residues R1, R2, R3, R4 and / or R5 into one or more different radicals R1, R2, R3, R4 and / or R5, example, reducing nitro groups to amino groups (for example, by hydrogenation with Raney nickel or Pd on carbon in an inert solvent such as methanol or ethanol). The esters can be saponified, for example, with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane, at temperatures between 0 and 100 °.

The free amino groups can also be acylated in the usual way with an acid anhydride chloride, or can be alkylated with a substituted or unsubstituted alkyl halide. These reactions are conveniently carried out in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine, at temperatures between -60 and + 30 °. A base of formula I can be converted into its salt by the addition of an acid, for example, by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol, and by subsequent evaporation. For this reaction, in particular, acids which form acceptable salts from the physiological point of view are suitable. Therefore, inorganic acids can be used, such as, for example, sulfuric acid, nitric acid, hydroacids such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids. , in particular the aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulphonic or sulfuric acids such as, for example, formic, acetic, propionic, pyralic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic, naphthalenedisulfonic and lauryl sulfuric. Salts of physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I. On the contrary, the compounds of formula I can be transformed with bases (e.g. , sodium carbonate or potassium hydroxide) in their respective metal salts, in particular in their alkali metal or alkaline earth metal salts, or in their respective ammonium salts. By virtue of their molecular structure, the compounds of formula I of the invention can be chiral and, therefore, have several enantiomeric forms. Thus, these compounds can be presented in racemic or optically active form.

Since the racemates and / or stereoisomers of the compounds of the invention may differ in their pharmaceutical activity, it is sometimes preferred to use the enantiomers. In these cases the final product or even the intermediate products can be separated into their enantiomers, using physical or chemical methods known to those skilled in the art, or they can be used directly as such to carry out the synthesis. In the case of racemic amines, the diastereomers are formed from the mixture by reaction with an optically active separation agent. As the separation agent, for example, optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, of amino acids suitably protected in nitrogen are suitable (for example, N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. It is also convenient to separate the enantiomers by chromatography using an optically active separation agent (for example, dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatives of methacrylate polymers which are fixed on silica gel). As the mobile phase, aqueous or alcoholic mixtures of solvents such as, for example, those of hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3, are used in this case. The invention also relates to the use of the compounds of formula I and / or their pharmaceutically acceptable salts in the preparation of pharmaceutical preparations, in particular by a non-chemical route. For this end, the compounds can be brought into a suitable dosage form together with at least one excipient or solid, liquid and / or semi-liquid auxiliary product and, optionally, in combination with one or more additional active substances. Another object of the present invention are pharmaceutical preparations containing at least one compound of formula I and / or one of its physiologically acceptable salts. These preparations can be used in medicine and in veterinary medicine as a medicine. Among the excipients there may be mentioned organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and which do not react with the new compounds. Examples of these excipients are water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. For oral administration, in particular, tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for the rectal application of suppositories, for parenteral administration to solutions, preferably solutions oily or aqueous, and also suspensions, emulsions or implants, and for topical application ointments, creams or powders. The new compounds can also be lyophilised and the resulting lyophilized products can be used, for example, for the preparation of injectable preparations. The aforementioned preparations can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing osmotic pressure, pH regulating substances, dyes, taste-correcting substances and / or various additional active substances, for example, one or several vitamins. The compounds of formula I and their physiologically acceptable salts can be used to combat and prevent thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication. In general, the substances of the invention are preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dose is preferably between about 0.02 and 10 mg / kg of body weight. However, the particular dose for each patient depends on a wide variety of factors, for example, the activity of the specific compound used, age, body weight, general health, sex, diet , of the moment and of the form of administration, of the rate of excretion, of the combination of medications and of the severity of the particular disease to which the therapy is applied. Oral administration is preferred. All temperatures indicated in this text are given in ° C. In the examples that follow, the expression "one works (or treats) in a usual manner" means the following: if necessary, water is added, if necessary, according to the constitution of the final product, it is adjusted to pH values • between 2 and 10, it is extracted with ethyl acetate or dichloromethane, the phases are separated and the organic phase is dried over sodium sulfate, concentrated by evaporation and purified by chromatography on silica gel and / or by recrystallization. The Rf values are given on silica gel and / or by recrystallization. The Rf values are given on silica gel; mobile phase: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): The (electron impact ionization) M + FAB (Fast Atom Bombardment (fast atom bombardment) (M + H) + Example 1 To a solution of 10.0 g of 4- (5-methyl-1,2,4-oxadiazol-3-yl) -benzoic acid in 150 ml of toluene is added 46 ml of thionyl chloride and 1 ml of DMF. The solution is refluxed for 5 hours. After removing the solvent, 4- (5-methyl-1,2,4-oxadiazol-3-yl) -benzoyl chloride, 222. is obtained. Subsequent reaction with 9.3 g of 1-terbutoxycarbonylpiperazine in 150 ml. of dichloromethane and 48 ml of triethylamine and after working the product in a usual manner, 4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoyl] -peperazin-1- is obtained. Terbutyl carboxylate, FAB 373. Cleavage of the BOC group is carried out with 4N HCl in dioxane. A 100 mg solution of the obtained [4- (5-methyl [1,2,4] oxadiazol-3-yl) -phenyl] -piperazin-1-yl-methanone ("A") and 120 mg of sodium chloride 6-chloronaphthalene-2-sulfonyl in 5 ml of dichloromethane mixed with 400 mg of 4-dimethylaminopyridine on polystyrene and the mixture is stirred for 18 hours at room temperature. After filtering and removing the solvent, [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl is obtained. ) -phenyl] -methanone, FAB 497. Analogously, [4- (4-biphenylylsulfonyl) -piperazin-1-yl] - is obtained by reaction of "A" with 4-biphenylyl-2-sulfonyl chloride. [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 2-naphthylsulfonyl chloride, [4- (2-naphthylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 4-propylphenylsulfonyl chloride, [4- (4-propylphenylsulfonyl) '- piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] - methanone; with 2-phenylvinylsulfonyl chloride, [4- (2-phenylvinylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 3-nitro-4-chlorophenylsulfonyl chloride, [4- (3-nitro-4-chlorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole-3] -yl) -phenyl] -methanone; with 2-nitro-4-methoxyphenylsulfonyl chloride, [4- (2-nitro-4-methoxyphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole-3 -yl) -phenyl] -methanone; with p-tolylsulfonyl chloride, [4- (4-tolylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -phenyl] -methanone; with decylsulfonyl chloride, [4- (decylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with benzylsulfonyl chloride, [4- (benzylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 3-nitro-6-methylbenzylsulfonyl chloride, [4- (3-nitro-6-methylbenzylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole] 3-yl) -phenyl] -methanone; with 2,3-dichlorophenylsulfonyl chloride, [4- (2, 3-dichlorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) - phenyl] -methanone; with 3-4-dichlorophenylsulfonyl chloride, [4- (3,4-dichlorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) - phenyl] -methanone; with phenylsulfonyl chloride, [4- (phenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 3-bromophenylsulfonyl chloride, [4- (3-bromophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methane to; with 3-4-dimethoxyphenylsulfonyl chloride, [4- (3, 4-dimethoxyphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) - phenyl] -methanone; with 4-acetamido-3-chlorophenylsulfonyl chloride, [4- (4-acetamido-3-chlorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole-3 -yl) -phenyl] -methanone; with 4-chloro-2,5-dimethylphenylsulfonyl chloride, [4- (4-chloro-2,5-di-netylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2] , 4] oxadiazol-3-yl) -phenyl] -methanone; with m-tolylsulfonyl chloride, [4- (3-tolylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 2-methoxy-5-methylphenylsulfonyl chloride, [4- (2-methoxy-5-methyl-phenylenesulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole- 3-yl) -phenyl] -methanone; with 3-chlorophenylsulfonyl chloride, [4- (3-chlorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 4-methoxyphenylsulfonyl chloride, [4- (4-methoxyphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 2-thienylsulfonyl chloride, [4- (2-thienylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 4-chlorophenylsulfonyl chloride, [4- (4-chlorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with isopropylsulfonyl chloride, [4- (isopropylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl]] -methanone; with 8-quinolysulfonyl chloride, [4- (8-quinolenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 4-nitrophenylsulfonyl chloride, [4- (4-nitrophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 3-chloro-6-methoxyphenylsulfonyl chloride, [4- (3-chloro-6-methoxyphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole-3] -yl) -phenyl] -methanone; with 4-acetamidophenylsulfonyl chloride, [4- (4-acetamidophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 2, 2, 5, 5, 7, 8-pentamethylchroman-6-ylsulfonyl chloride, [4- (2,2,5,7,8-p-ntamethyl-1-chroman-6-ylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with canfo-10-ylsulfonyl chloride, [4- (canfo-10-ylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl] ) -phenyl] -metanone; with 5- (l-methyl-5-trifluoromethyl-3-pyrazolyl) -2-thienyl sulphonyl chloride, la. { 4- [5- (1-methyl-5-trifluoromethyl-3-pyrazolyl) -2-thienylsulfonyl) -piperazin-1-yl} - [4- (5-methy1- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 2-5-dichlorophenylsulfonyl chloride, [4- (2, 5-dichlorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) - phenyl] -methanone; with 2,4,6-trimethylphenylsulfonyl chloride, [4- (2,4,6-trimethylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole-3] -yl) -phenyl] -methanone; with 2-methylsulfonylphenylsulfonyl chloride, [4- (2-methylsulfonylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 5-benzamidomethyl-2-t-ethylsulfonyl chloride, [4- (5-benzamidomethyl-2-thienylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazole -3-yl) -phenyl] -methanone; with methylsulfonyl chloride, [4- (methylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 1,3-dimethyl-5-chloro-4-pyrazolyl-sulfonyl chloride, [4- (1,3-dimethyl-1-5-chloro-4-pyrazolyl-sulfonyl) -piperazin-1-yl] - [ 4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 3,5-dimethyl-4-isoxazolylsulfonyl chloride, [4- (3,5-dimethyl-4-isoxazolyl-sulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1] 2,4] oxadiazol-3-yl) -phenyl] -methanone; with 4-bromo-2-ethylphenylsulfonyl chloride, [4- (4-bromo-2-ethylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole-3] -yl) -phenyl] -methanone; with 1-naphthylsulfonyl chloride, [4- (1-naphthylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -phenyl] -methanone; with 5-dimethylamino-l-naphthylsulfonyl chloride, [4- (5-dimethylamino-l-naphthylsulfonyl) • piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazole-3 -yl) -phenyl] -methanone; with 3-4-difluorophenylsulfonyl chloride, [4- (3, 4-difluorophenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) - phenyl] -methanone; with 4-tert-butylphenylsulfonyl chloride, [4- (4-tert-butylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -phenyl] -methanone; with 4-ethylphenylsulfonyl chloride, [4- (4-ethylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 4- (1,1-dimethylpropyl) -phenylsulfonyl chloride, [4- (4- (1,1-dimethylpropyl) -phenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [I]] , 2,4] oxadiazol-3-yl) ~ phenyl] -methanone; with 4-isopropylphenylsulfonyl chloride, [4- (4-isopropylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 4-trifluoromethylphenylsulfonyl chloride, [4- (4-trifluoromethylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 3-nitro-4-methylphenylsulfonyl chloride, [4- (3-nitro-4-methylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazole-3 -yl) -phenyl] -methanone; with 4-pentylphenylsulfonyl chloride, [4- (4-pentylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone; with 4-butylphenylsulfonyl chloride, [4- (4-butylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone; with 3-chloro-4-methylphenylsulfonyl chloride, [4- (3-chloro-4-methylphenylsulfonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazole-3] -yl) -phenyl] -methanone.

Example 2 A solution of 100 mg of [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1-yl] - [4- (5-methyl-1,2,4] oxadiazol-3-yl is mixed) phenyl] -methanone in 5 ml of methanol with 100 mg of Raney-nickel and with a drop of acetic acid and then hydrogenated at room temperature and atmospheric pressure until the reaction is complete. After removing the catalyst and the solvent, 4- [4- (6-chloro-naphthalene-2-sulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 457 is obtained. The compounds indicated below are obtained by analogous reaction of the methanone derivatives described in Example 1. 4- [4- (4-biphenylylsulfonyl) -piperazin-1-car onyl] -benzamidine, acetate, FAB 449; 4- [4- (2-naphthylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, 405 (M + -NH 2); 4- [4- (4-propylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 415; 4- [4- (2-phenylvinylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 399; 4- [4- (3-amino-4-chlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 422; 4- [4- (2-amino-4-methoxyphenylsulfonyl) -piperazin -carbonyl] -benzamidine, acetate, FAB 418; 4- [4- (4-tolylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 387; 4- [4- (decylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 437; 4- [4- (benzylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 387; 4- [4- (3-amino-6-methyl-benzylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 402; 4- [4- (2, 3-dichlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 441; 4- [4- (3,4-dichlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 441; 4- [4- (phenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 373; 4- [4- (3-bromophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 451.453; 4- [4- (3, 4-dimethoxyphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 433; 4- [4- (4-acetamido-3-chlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 464; 4- [4- (4-chloro-2,5-dimethylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 435; 4- [4- (3-tolylsulfonyl) -piperazin-1-car onyl] -benzamidine, acetate, FAB 387; 4- [4- (2-methoxy-5-methylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 417; 4- [4- (3-chlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 407; 4- [4- (4-methoxyphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 402; 4- [4- (2-thienylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 379; 4- [4- (4-chlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 407; 4- [4- (isopropylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 339; 4- [4- (1, 2, 3, 4-tetrahydroquinoline-8-ylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 428; 4- [4- (4-Aminophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 388; 4- [4- (3-chloro-6-methoxyphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 437; 4- [4- (4-acetamidophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 437; 4- [4- (2,2,5,7,8-pentamethylchroman-6-ylsulfonyl) -piperazine-1-carbonyl] -benzamidine acetate, FAB 499; 4- [4- (canfo-10-ylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 447; 4- . { 4- [5- (1-methyl-5-trifluoromethyl-1-3-pyrazol-1) -2-thienyl-sulfonyl] -piperazine-1-carbonyl} -benzamidine, acetate, FAB 527; 4- [4- (2, 5-dichlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 441; 4- [4- (2,4-, 6-trimethylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 415; 4- [4- (2-methylsulfonylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 451; 4- [4- (5-benzamidomethyl-2-thienylsulfonyl) -piperazine-1-carbonyl] -benzamidine, 'acetate, FAB 512; 4- [4- (methylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, El 292 (M + -NH 2); 4- [4- (1, 3-dimethyl-1-5-chloro-4-pyrazolyl-sulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate; 4- [4- (3, 5-dimethyl-4-isoxazolylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate; 4- [4- (4-bromo-2-ethylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, 461.463 (M + -NH2); 4- [4- (1-naphthylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, 405 (M + -NH 2); 4- [4- (5-dimethylamino-l-naphthylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, The 448 (M + -NH 2); 4- [4- (3,4-difluorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate; 4- [4- (4-tert-butylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 429; 4- [4- (4-ethylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 401; 4- [4- (4- (1, 1-dimethylpropyl) -phenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 442; 4- [4- (4-isopropylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 415; 4- [4- (4-trifluoromethylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 441; 4- [4- (3-amino-4-methylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 402; 4- [4- (4-pentylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 443; 4- [4- (4-Butylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 429; 4- [4- (3-chloro-4-methylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 421; Example 3 By reaction with equimolar amounts of methyl chloroformate in pyridine and catalytic amounts of dimethylaminopyridine and from 4- [4- (6-chloronaphthalene-2-sulfonyl) -piperazine-1-carbonyl] -benzamide is obtained. { imino- [4- (4- (6-chloronaphthalene-2-sulfonyl) -piperazine-1-carbonyl) -phenyl] -methyl} methyl carbamate after working the mixture in the usual manner.

Example 4 By analogous reaction to that of example 1 of 3- [4- (5-methyl- [1,2,4] -oxadiazol-3-yl) -phenyl} ] -l-piperazin-1-yl-propan-l-one '[obtainable by treatment of 3- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -1 - (4-tert-butyloxycarbonyl) -piperazin-1-yl-propan-1-one with TFA / CH2C12] and 6-chloronaphthalene-2-sulfonyl chloride gives the l- [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1-yl] -3- [4- (5-methyl- [1, 2, 4] -oxadiazol-3-yl) -phenyl] -propan-1-one and, after hydrogenate, the 4- . { 3-oxo-3- [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1-yl] -propyl} -benzamidine.

Example 5 By analogous reaction to Example 1 of [3- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -piperazin-1-yl-methanone with 5-chloronaphthalene- chloride 2-sulfonyl and by subsequent hydrogenation in a manner analogous to that of Example 2, 3- [4- (6-chloronaphthalene-2-sulfonyl) -piperazine-1-carbonylj-benzamidine, acetate, FAB 457 is obtained. By analogous reaction of [3- (5-Rethyl- [1, 2,4] oxadiazol-3-yl) -phenyl] -piperazin-1-yl-methanone with 4-propylphenylsulfonyl chloride and subsequent hydrogenation gives 3- [4 - (4-propylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 415.

Example 6 By analogous reaction to Example 1 of 2- [4- (5-methyl- [1,2,4] -oxadiazol-3-yl) -phenyl] -1-piperazin-1-yl-ethan-1 -one ("B") with 4-propylfhenylsulfonyl chloride gives l- [4- (4-propylphenylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1, 2, 4] ] oxadiazol-3-yl) -phenyl] -ethan-1-one and, after hydrogenating, the 4-. { 2-oxo-2- [4- (4-propylphenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, FAB 429. By analogous reaction of "B" with decylsulfonyl chloride, 1- [4- (decylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1, 2] is obtained. , 4] oxadiazol-3-yl) -phenyl] -ethan-1-one; with phenylsulfonyl chloride, 1- [4- (phenylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] - is obtained. etan-l-ona; With 3-4-dichlorophenylsulfonyl chloride, 1- [4- (3,4-dichlorophenylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole- is obtained. 3-yl) -phenyl] -ethan-1-one; with benzylsulfonyl chloride, 1- [4- (benzylsulfonyl) -pipe'razin-1-yl] -2- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl is obtained ] -etan-1-one; with 3-4-dimethoxyphenylsulfonyl chloride, 1- [4- (3,4-dimethoxyphenyl-l-phonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole is obtained. -3-yl) -phenyl] -ethan-1-one; with isopropylsulfonyl chloride, 1- [4- (isopropylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] - is obtained. etan-l-ona; With 1-40-campho-10-ylsulfonyl chloride, 1- [4- (canfo-10-ylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole- is obtained. 3-yl) -phenyl] -ethan-l-one; With 3-methoxy-4-methoxycarbonyl-1-thienylsulfonyl chloride there is obtained 1- [4- (3-methoxy-4-methoxycarbonyl-2-thienylsulfonyl) -piperazin-1-yl] -2- [4- (5 -methyl 1- [1, 2, 4] oxadiazol-3-yl) -phenyl] -ethan-1-one; with 2,4,6-trimethylphenylsulfonyl chloride, 1- [4- (2,4-, 6-trimethylphenylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,2] is obtained. 4] oxadiazol-3-yl) -phenyl] -ethan-1-one; with 2-phenylvinylsulfonyl chloride, 1- [4- (2-phenyvinylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl is obtained) '-phenyl] -ethan-1-one; with methylsulfonyl chloride, 1- [4- (methylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] - is obtained. ethan-1-one; with [2, 1, 3] -benzothiadiazol-4-ylsulfonyl chloride, l- [4- ([2, 1, 3-benzothiadiazol-4-ylsulfonyl) -piperazin-1-yl] -2- [4 is obtained - (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -ethan-1-one; With 2,4-dichlorophenylsulfonyl chloride, 1- [4- (2,4-dichlorophenylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole- is obtained. 3-yl) -phenyl] -ethan-1-one; with 1-naphthylsulfonyl chloride, 1- [4- (1-naphthylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl is obtained) phenyl] -ethan-1-one; With 2-naphthylsulfonyl chloride, 1- [4- (2-naphthylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl is obtained) phenyl] -ethan-1-one; with 5-dimethylamino-l-naphthylsulfonyl chloride, 1- [4- (5-dimethylamino-1-naphthylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -ethan-1-one; with 4-methylsulfony'l-phenylsulfonyl chloride, 1- [4- (4-methylsulfonyl-phenylsulfonyl) -piperazin-1-yl] -2- [4- (5-methyl- [1,2,4] oxadiazole-3- is obtained. il) -phenyl] -ethan-1-one.

Hydrogenation of the mentioned compounds yields the amidine derivatives indicated below: 4-. { 2-oxo-2- [4- (decylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 450; 4- . { 2-oxo-2- [4- (phenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 387; 4-. { 2-oxo-2- [4- (3,4-dichlorophenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 454; 4-. { 2-oxo-2- [4- (benzylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 401; 4- . { 2-OXO-2- [4- (3, 4-dimethoxyphenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 447; 4-. { 2-Oxo-2- [4- (isopropylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 353; 4-. { 2-oxo-2- [4- (canfo-10-ylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 353; 4-. { 2-Oxo-2- [4- (3-methoxy-4-methoxycarbonyl-1-2-thienylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 481; 4-. { 2-oxo-2- [4- (2,4-, 6-trimethylphenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 429; 4-. { 2-oxo-2- [4- (2-phenylvinylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 413; 4-. { 2-oxo-2- [4- (methylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 325; 4-. { 2-oxo-2- [4- (2, 3-diaminophenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 415; 4-. { 2-oxo-2- [4- (2,4-dichlorophenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 455; 4- . { 2-OXO-2- [4- (1-naphthylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 437; 4- . { 2-oxo-2- [4- (2-naphthylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 437; 4-. { 2-oxo-2- [4- (5-dimethylamino-1-naphthylsulfonyl) -pi? Erazin-1-yl] -ethyl} -benzamide, acetate, FAB 480; 4-. { 2-oxo-2- [4- (4-methylsulfonylphenylsulfonyl) -piperazin-1-yl] -ethyl} -benzamide, acetate, FAB 465; ' Example 7 By analogous reaction to that of Example 1 of "A" with 4-biphenylylcarbonyl chloride gives [4- (4-phenylbenzoyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) - phenyl] -methanone; With cyclopentylcarbonyl chloride, [4- (cyclopentylcarbonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -phenyl] -methanone is obtained; With phenoxyacetyl chloride, [4- (phenoxyacetyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -methanone is obtained; with [1-naphthylcarbonyl chloride] is obtained [4- (1-naphthylcarbonyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] - methanone; with 2-naphthylcarbonyl chloride, [4- (2-naphthylcarbonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] - is obtained. methanone; with nicotinoyl chloride, [4- (nicotinoyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone is obtained; with 3-nitro-benzoyl chloride, [4- (3-nitrobenzoyl) -piperazin-1-yl] - [4- (5-ethyl- [1, 2, 4] oxadiazol-3-yl) -phenyl is obtained ] -metanone; with benzo- [b] thiophene-2-carbonyl chloride, [4- (benzo- [b] thiophene-2-carbonyl) -piperazin-1-yl] - [4- (5-methyl- [1] is obtained. 2,4] oxadiazol-3-yl) -phenyl] -methanone; with 4-trifluoromethoxybenzoyl chloride gives [4- (4-trifluoromethoxybenzoyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] - methanone; with 2-5-dimethoxyphenylacetyl chloride, [4- (2,5-dimethoxy-ifylacetyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl is obtained. ) -phenyl] -metanone; With 4-chlorophenylacetyl chloride, [4- (4-chlorophenylacetyl) -piperazin-1-yl] - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] - is obtained. methanone; with 1,3-benzodioxol-5-carbonyl chloride, [4- (1,3-benzodioxol-5-carbonyl) -? iperazin-1-yl] - [4- (5-methyl- [1,2 , 4] oxadiazol-3-yl) -phenyl] -methanone; with 3-4-dichlorobenzoyl chloride gives [4- (3,4-dichlorobenzoyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -metanone; with isobutyl chloroformate, [4- (isobutyloxycarbonyl) -piperazin-1-yl] - [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -methanone is obtained.

By hydrogenation of these compounds, the following amldine derivatives are obtained: 4- [4- (4-phenylbenzoyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 413; 4- [4- (cyclopentylcarbonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 329; 4- [4- (phenoxyacetyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 367; 4- [4- (1-naphthylcarbonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 387; 4- [4- (2-naphthylcarbonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 387; 4- [4- (nicotinoyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 338; 4- [4- (3-aminobenzoyl) -piperazine-1-carbonyl] -benzamidine; 4- [4- (benzo- [b] thiophene-2-carbonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 393; 4- [4- (4-trifluoromethoxybenzoyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 421; 4- [4- (2, 5-dimethoxyphenylacety1) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 411; 4- [4- (4-chlorophenylacetyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 385; 4- [4- (1, 3-benzodioxol-5-carbonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 381; 4- [4- (3, 4-dichlorobenzoyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 381; 4- [4- (isobutyloxycarbonyl) -piperazin-1-car onyl] -benzamidine, acetate, FAB 333.

Example 8 By reaction with equimolar amounts of acetyl chloride in pyridine and catalytic amounts of dimethylaminopyridine and working the mixture in a usual manner is obtained, from 4- [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1 -carbonyl] -benzamidi a, the N-. { imidino-4- [4- (6-chloronaphthalene-2-sulfonyl) -piperazine-1-carbonyl] -phenylimethyl} -acetamide.

Example 9 By reaction of equimolar amounts of 4-cyanobenzyl bromide, BOC-piperazine and triethylamine in dichloromethane, l- (4-cyanobenzyl) -4- (t-butyloxycarbonyl) -piperazine is obtained. By reaction with a) hydroxylamine hydrochloride, triethylamine in ethanol and b) acetic anhydride, 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzyl] -4- (tert-butyloxycarbonyl) is obtained. ) -piperazine. After removing the BOC group with TFA in CH2C12 and by analogous reaction to that of examples 1 and 2 of 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] piperazine with 6-chloronaphthalene-2-sulfonyl chloride, subsequent hydrogenation and usual treatment of the reaction mixture gives 4- [(6-chloronaphthalene-2-sulfonyl) -piperazin-1-ylmethyl] -benzamidine. The following compounds are obtained analogously: 4- [(4-biphenylylsulfonyl) -piperazin-1-ymethyl] -benzamidine, 4- [(2-naphthylsulfonyl) -piperaz-1-ylmethyl] -benzamidine 4- [(4-propylphenylsulfonyl) -piperazin-1-ylmethyl] -benzamidine, 4- [(2-phenylvinylsulfonyl) -piperazin-1-y-methyl] -benzamidine Example 10 By reaction of equimolar amounts of 4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoic acid, diphenylphosphorylazide and triethylamine in DMF and after treating the reaction mixture in the usual manner 4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzoylazide. By heating with BOC-piperazine in toluene a rearrangement reaction occurs, and after treating the reaction mixture in a usual manner, 1-B0C-4- [4- (5-methyl- [1,2,4] is obtained. oxadiazol-3-yl) -phenylcarbamoyl] piperazine. After removing the BOC group with TFA in CH2C12, 4- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenylcarbamoyl] -piperazine ("C") is obtained. In a manner analogous to that of Examples 1 and 2, N- (4-amidinophenyl-4- (6-chloronaphthalene-2-sulphonyl) -piperazine-1-carboxamide is obtained by reaction of "C" with 6-chloronaphthalenesulfonyl chloride and subsequent hydrogenation. The following compounds are obtained analogously: N- (4-amidinophenyl) -4- (4-biphenylylsulfonyl) -piperazin-1 -carboxamide, N- (4-amidinophenyl) -4- (2-naphthylsulfonyl) -piperazine-1-carboxamide, N- (4-amidinophenyl) -4- (4-propylphenylsulfonyl) -piperazine-1-carboxamide and N- (4-amidinophenyl) -4- (2-phenylvinylsulfonyl) -? iperazin-1- carboxamide.

Example 11 By reaction of equimolar amounts of 1-BOC-4- [4- (5-methyl [1,2,4] oxadiazol-3-yl) -phenylcarbamoyl] -piperazine, methyl bromoacetate and potassium terbutoxide in DMF and after treating the reaction mixture in a usual manner, the is obtained. { (4-BOC-pi? Erazin-1-carbonyl) - [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -amino} -methyl acetate. By reaction with a) HCl / dioxane and b) NaOH the is obtained. { (piperazine-1-carbonyl) - [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -phenyl] -amino} -methyl acetate. By reaction with 6-chloronaphthalene sulfonyl chloride in a manner analogous to that of Example 1, the is obtained. { [4- (6-chloronaphthalene-2-sulfonyl) -piperazine-1-carbonyl] - [4 - (5-methyl- '[1, 2, 4] oxadiazol-3-yl) -phenyl] -amino} -methyl acetate. Hydrogenation of the latter compound with Raney nickel gives the. { [4- (6-chloronaphthalene-2-sulfonyl) -piperazine-1-carbonyl] - [4-amidinophenyl] -amino} -methyl acetate. The methyl ester is cleaved by treatment with NaOH in methanol / water. After treating the product in a usual manner, the acid is obtained. { [4- (6-chloronaphthalene-2-sulfonyl) -piperazine-1-carbonyl] - [4-amidinophenyl] -amino} -acetic. The compounds indicated below are obtained by proceeding analogously: acid. { [4- (4-biphenylylsulfonyl) -piperazin-1-carbonyl] - [4-amidinophenyl] -amino} -acetic, acid. { [4- (2-naphthylsulfonyl) -piperazin-1-carbonyl] - [4-amidinophenyl] -amino} -acetic, acid. { [4- (4-propylphenylsulfonyl) -piperazin-1-carbonyl] - [4-amidinophenyl] -amino} -acetic and acid. { [4- (2-phenyvinylsulfonyl) -piperazine-l-carbonyl] - [4-amidinophenyl] -amino} -acetic.

Example 12 By reaction of equimolar amounts of 4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenylacetic acid, methyl iodide and potassium carbonate 4- (5-methyl- [ 1, 2, 43 oxadiazol-3-yl) -phenylacetate methyl ("D"). By heating equimolar amounts of BOC-piperidine and chloroacetyl chloride in toluene and after treating the reaction mixture in a usual manner, l-BOC-4-chloromethylcarbonyl-piperazine ("E") is obtained.

By reaction of "D" and "E" with NaH in DMF and after treating the reaction mixture in a usual manner, 4- (4-BOC-piperazin-1-yl) -2- [4- (5- methyl- [1,2,4-oxadiazol-3-yl) -phenyl] -4-oxo-butyrate methyl. By reaction with a) HCl / dioxane and b) NaOH there is obtained 4- (piperazin-1-yl) -2- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] Methyl-4-oxo-butyrate. Reaction with 6-chloronaphthalenesulfonyl chloride analogously to Example 1 yields 4- [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1-yl] -2- [4- (5-methyl) - [1,2,4-Oxadiazol-3-yl) -phenyl] -4-oxo-butyrate methyl. Hydrogenation of the latter compound in a manner analogous to that of Example 2 yields 4- [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1-yl] -2- (4-amidinophenyl) -4-oxo -methyl butyrate. The methyl ester is cleaved by treatment with NaOH in methanol / water. After treating the product in the usual manner, 4- [4- (6-chloronaphthalene-2-sulfonyl) -piperazin-1-yl] -2- (4-amidinophenyl) -4-oxo-butyric acid is obtained.

The compounds indicated below are obtained analogously: 4- [4- (4-biphenylylsulfonyl) -piperazin-1-yl] -2- (4-amidinophenyl) -4-oxo-butyric acid, 4- acid [4- (2-naphthylsulfonyl) -piperazin-1-yl] -2- (4-amidinophenyl) -4-oxo-butyric acid, 4- [4- (4-propylphenylsulfonyl) -piperazin-1-yl] -2 - (4-amidinophenyl) -4-oxo-butyric acid and 4- [4- (2-phenylvinylsulfonyl) -piperazin-1-yl] -2- (4-amidinophenyl) -4-oxo-butyric acid.

EXAMPLE 13 By reaction at room temperature of equimolar amounts of "A" and of phenyl isocyanate in di-chloromethane and subsequently working the reaction mixture in a usual manner, the N-phenyl-4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoyl] -piperazine-1-carboxamide. By analogous reaction of "A" with 4-trifluoromethylphenyl isocyanate, N- (4-trifluoromethylphenyl) -4- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzoyl] is obtained. -piperazine-1-carboxamide; with butyl isocyanate, N-butyl-4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) • benzoyl] -piperazin-1 -carboxamide is obtained; with 1-naphthyl isocyanate, N- (l-naphthyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoyl] -piperazine-l-carboxamide is obtained; with 4-methoxyphenyl isocyanate, N- (4-methoxyphenyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoyl] -piperazine-1-carboxamide is obtained; with 4-nitrophenyl isocyanate, N- (4-nitrophenyl) -4- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzoyl] -piperazine-1-carboxamide is obtained; with cyclohexyl isocyanate, N-cyclohexyl-4- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzoyl] -piperazine-1-carboxamide is obtained; with 3-ethoxycarbonylphenyl isocyanate, N- (3-ethocarbonylphenyl) -4- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzoyl] -piperazine-1-carboxamide is obtained. .

By hydrogenating these compounds analogously to that described in example 2, the following amidine derivatives are obtained: N-phenyl-4- (4-amidinobenzoyl) -piperazine-l-carboxamide, acetate, FAB 352; N-butyl-4- (4-amidinobenzoyl) -piperazine-l-carboxamide, acetate, FAB 332; N- (1-naphthyl) -4- (4-amidinobenzoyl) -piperazine-1-carboxamide, acetate, FAB 402; N- (4-methoxyphenyl) -4- (4-amidinobenzoyl) -piperazine-l-carboxamide, acetate, FAB 382; N- (4-aminophenyl) -4- (4-amidinobenzoyl) -piperazine-1-carboxamide, acetate, FAB 367; N-cyclohexyl-4- (4-amidinobenzoyl) -piperazine-1-carboxamide, acetate, FAB 358; N- (3-ethoxycarbonylphenyl) -4- (4-amidinobenzoyl) -piperazine-l-carboxamide, acetate, FAB 424.

Example 14 The following compounds are prepared in a manner analogous to that described in Examples 1 and 2: 3- [4- (2-naphthylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 423; 3- [4- (3-Chloro-4-methyl-phenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 421; 3- [4- (2, 4, 6-trichlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 475, 477; 3- [4- (3-amino-4-chlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 422; 3- [4- (4-chlorophenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 407; 3- [4- (3-trifluoromethylphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 441; 3- [4- (4-biphenylylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 449; 4- [4- (3, 5-dimethoxyphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 433; 4- [4- (dibenzofuran-2-ylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 463; 4- [4- (3-fluoro-4-methoxyphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 421; 4- [4- (2,4-dichloro-6-methoxyphenylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 471; 4- (4-benzylpiperazine-1-carbonyl) -benzamidine, acetate, FAB 323; 4- [4- (2-naphthylmethyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 373; 4- [4- (4-methoxyphenylmethyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 353; 4- [4- (4-methoxycarbonylphenylmethyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 431; 4- [4- (4-propylphenylsulfonyl) -piperazine-1-carbonyl] -3-methylbenzamidine, acetate, FAB 429; 4- [4- (2-naphthylsulfonyl) -piperazine-1-carbonyl] -3-methylbenzamidine, acetate, FAB 437; 4- [4- (6-chloro-2-naphthylsulfonyl) -piperazine-1-carbonyl] -3-methylbenzamidine, acetate, FAB 471; 4- [4- (7-methoxy-2-naphthylsulfonyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 453; 4- [4- (3,5-dimethoxymethylmethyl) -piperazine-1-carbonyl] -benzamidine, acetate, FAB 383.

Example 15 The compounds indicated below are prepared in a manner similar to that described in Example 6 4-. { 3-oxo-3- [4- (butylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 381; 4-. { 3-oxo-3- [4- (4-propylphenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 443; 4-. { 3-oxo-3- [4- (6-chloro-2-naphthylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 485; 4-. { 3-oxo-3- [4- (2-naphthylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 451; 4-. { 3-oxo-3- [4- (3-chloro-4-methylphenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 449; 4-. { 3-oxo-3- [4- (4-chlorophenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 435; 4-. { 3-oxo-3- [4- (4-biphenylylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 477; 4- . { 3-oxo-3- [4- (2,4-, 6-trimethylphenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 443; 3-. { 3-oxo-3- [4- (butylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 381; 3-. { 3-oxo-3- [4- (4-methoxyphenylsulfonyl) -piperazin-1-Í13-propyl} -benzamidine, acetate, FAB 431; 3-. { 3-oxo-3- [4- (4-chlorophenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 435; 3-. { 3-oxo-3- [4- (4-isopropylphenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 443; 3-. { 3-oxo-3- [4- (2,4-, 6-trimethylphenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 443; 3-. { 3-oxo-3- [4- (3-chloro-4-methylphenylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 449; 3-. { 3-oxo-3- [4- (6-chloro-2-naphthylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 485; 3-. { 3-oxo-3- [4- (2-naphthylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 451; 3-. { 3-oxo-3- [4- (4-biphenylylsulfonyl) -piperazin-1-yl] -propyl} -benzamidine, acetate, FAB 477.

Example 16 By analogous reaction to that of example 13 of isocyanate of 4- (5-methyl- [1, 2, 4] -oxadiazol-3-yl) -phenyl ("F") with 1- (2-naphthylsulfonyl) -piperazine is obtains N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (2-naphthylsulfonyl) -piperazine-l-carboxamide; with 1- (2-phenylvinylsulfonyl) -piperazine the N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (2-phenylvinylsulfonyl) -piperazine- is obtained. l-carboxamide; with 1- (4-propylphenylsulfonyl) -piperazine the N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (4-propylphenylsulfonyl) -piperazine- is obtained. l-carboxamide; with 1- (4-chlorophenylsulfonyl) -piper'azine is obtained N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (4-chlorophenylsulfonyl) - piperazine-l-carboxamide; with 1- (2,4-, 6-trimethylphenylsulfonyl) -piperazine the N- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -4- (2.4 is obtained. , 6-trimethylphenylsulfonyl) -piperazine-l-carboxamide; with 1- (6-chloro-2-naphthylsulfonyl) -piperazine the N- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (6-chloro) is obtained -2-naphthylsulfonyl) -piperazine-l-carboxamide. By hydrogenating these compounds analogously to that described in Example 2, the following amidine derivatives are obtained: N- (4-amidinophenyl) -4- (2-naphthylsulfonyl) -piperazine-1-carboxamide, acetate, FAB 438; N- (4-amidinophenyl) -4- (2-phenylvinylsulfonyl) -piperazine-l-carboxamide, acetate, FAB 414; N- (4-amidi-phenyl) -4- (4-propylphenylsulfonyl) -piperazine-l-carboxamide, acetate, FAB 430; N- (4-amidinophenyl) -4- (4-chlorophenylsulfonyl) -pi? Erazin-1-carboxamide, acetate, FAB 422; N- (4-amidinophenyl) -4- (2,4-, 6-trimethylphenylsulphonyl) -piperazine-l-carboxamide, acetate, FAB 430; N- (4-amidinophenyl) -4- (6-chloro-2-naphthylsulfonyl) -piperazine-1-carboxamide, acetate, FAB 472.

Example 17 By reaction similar to that of Example 1 of 1- [4- (5-methyl [1, 2, 4] oxadiazol-3-yl) -benzyl] -piperazine ("G") with 4-pyrrolyl-phenylsulfonyl chloride 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] 4- (4-propylphenylsulfonyl) -piperazine; with 4-methoxyphenylsulfonyl chloride there is obtained 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzyl] -4- (4-methoxyphenylsulfonyl) -piperazine; with 4-biphenylylsulfonyl chloride there is obtained 1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -4- (4-biphenylylsulfonyl) -piperazine; with 2-naphthylsulfonyl chloride, 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzyl] -4- (2-naphthylsulfonyl) -piperazine is obtained; With 6-chloro-2-naphthylsulfonyl chloride there is obtained the 1- [4- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -4- (6-chloro-2- naphthylsulfonyl) -piperazine; with 7-methoxy-2-naphthylsulfonyl chloride, 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzyl] -4- (7-methoxy-2 is obtained. -naphthylsulfonyl) -piperazine; with 3,5-dimethoxybenzyl chloride there is obtained 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzyl] -4- (3, 5-dimethoxybenzyl) -piperazine; with 4-isopropylphenylsulfonyl chloride there is obtained 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -benzyl] -4- (4-isopropylphenylsulfonyl) -piperazine; with 4-biphenylylcarbonyl chloride there is obtained 1- [4- (5-methyl- [1,4] oxadiazol-3-yl) -benzyl 3-4- (4-biphenylylcaronyl) -piperazine; Ocon with 2-naphthylcarbonyl chloride gives 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] -4- (2-naphthylcarbonyl) -piperazine; with 2-naphthylmethyl chloride, 1- [4- (5-methyl- [1,2,4-oxadiazol-3-yl) -benzyl] -4- (2-naphthylmethyl) -piperazine is obtained. Hydrogenation of these compounds in a manner analogous to that described in example 2 yields the amidine derivatives indicated below: 1- (4-amidinobenzyl) -4- (4-propylphenylsulfonyl) -piperazine, acetate, FAB 401; 1- (4-amidinobenzyl) -4- (4-methoxyphenylsulfonyl) -piperazine, acetate, FAB 389; 1- (4-amidinobenzyl) -4- (4-biphenylylsulfonyl) -piperazine, acetate, FAB 435; 1- (4-amidinobenzyl) -4- (2-naphthylsulfonyl) -piperazine, acetate, FAB 409; 1- (4-amidinobenzyl) -4- (6-chloro-2-naphthylsulfonyl) -piperazine, acetate, FAB 443; 1- (4-amidinobenzyl) -4- (7-methoxy-2-naphthylsulfo-nyl) -piperazine, acetate, FAB 439; 1- (4-amidinobenzyl) -4- (3,5-dimethoxybenzyl) -piperazine acetate, FAB 369; 1- (4-amidinobenzyl) -4- (4-isopropylphenylsulfo-nyl) -piperazine, acetate, FAB 441; 1- (4-amidinobenzyl) -4- (4-biphenylylcarbonyl) -piperazine, acetate, FAB 399; 1- (4-amidinobenzyl) -4- (2-naphthylcarbonyl) -piperazine, acetate, FAB 373; l- (4-amidinobenzyl) -4- (2-naphthyl-ethyl) -piperazine, acetate, FAB 359; Example 18 By reaction of 4- [4- (6-chloro-2-naphthyl-sulfonyl) -piperazine-1-carbonyl] -3-methyl-benzamidine with methyl chloroformate in dichloromethane and after treating the reaction mixture in a usual manner, it obtains methyl (imino-. {4- [4- (6-chloro-2-naphthylsulfonyl) -piperazin-1-carbonyl-J-phenyl] -methyl) -carbamate, FAB 515.

Example 19 By reaction similar to that of Example 1 of l- [4- (5-methyl [1,2,4] oxadiazol-3-yl) -phenyl] -piperazine ("H") with 4-propylphenylsulfonyl chloride was obtains 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -4- (4-propylphenylsulfonyl) -piperazine; with 4-butylsulfonyl chloride, 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -4- (4-butylsulfonyl) -piperazine; with 4-methoxyphenylsulfonyl chloride there is obtained 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -4- (4-m-to-phenylsulfonyl) -piperazine; with 4-chlorophenylsulfonyl chloride, 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (4-chlorophenylsulfonyl) -piperazine; with 4-isopropylphenylsulfonyl chloride there is obtained 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (4-isopropylphenylsulfonyl) -piperazine; with 4-biphenylsulfonyl chloride there is obtained 1- [4- (5-methyl- [1, 2, 43 oxadiazol-3-yl) -phenyl] -4- (4-biphenylsulfonyl) -piperazine; with 2-, 4,6-trimethylphenylsulfonyl chloride, 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (2,4,6-trimethylphenylsulfonyl) is obtained. ) -piperazine; with 3-chloro-4-methylphenylsulfonyl chloride, 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (3-chloro-4-methylphenylsulfonyl) is obtained. ) -piperazine; with 2-naphthylsulfonyl chloride, 1- [4- (5-methyl- [1, 2, 4] oxadiazol-3-yl) -phenyl] -4- (2-naphthylsulfonyl) -piperazine; with 6-chloro-2-naphthylsulfonyl chloride, 1- [4- (5-methyl- [1,2,4] oxadiazol-3-yl) -phenyl] -4- (6-chloro-2-naphthylsulfonyl is obtained. ) -piperazine.

By hydrogenation of these compounds analogously to that described in Example 2, the amidine derivatives indicated below are obtained: 1- (4-amidinophenyl) -4- (4-propylphenylsulfonyl) -piperazine, acetate, FAB 387; 1- (4-amidinophenyl) -4- (4-butylsu'lfonyl) -piperazine, acetate, FAB 325; 1- (4-amidinophenyl) -4- (4-methoxyphenylsulfonyl) -piperazine, acetate, FAB 375; 1- (4-amidinophenyl) -4- (4-chlorophenylsulfonyl) -piperazine, acetate, FAB 379; 1- (4-amidinophenyl) -4- (4-i-sopro-phenylsulfo-nil) -piperazine, acetate, FAB 387; 1- (4-amidinophenyl) -4- (4-biphenylylphenylsulfo-nyl) -piperazine, acetate, FAB 421; 1- (4-amidinophenyl) -4- (2, 4, 6-trimethylphenylsul-fonyl) -piperazine, acetate, FAB 387; 1- (4-amidinophenyl) -4- (3-chloro-4-methylphenylsulfonyl) -piperazine, acetate, FAB 393; 1- (4-amidinophenyl) -4- (2-naphthylsulfonyl) -piperazine, acetate, FAB 395; 1- (4-amidinophenyl) -4- (6-chloro-2-naphthylsulfo-nyl) -piperazine, acetate, FAB 429. The following examples refer to pharmaceutical preparations: Example A: Injection bottles The pH of a solution of 100 g of an active substance of formula I and 5 g of disodium hydrogen phosphate in 3 liters of bidistilled water is adjusted to 6.5 with 2 N hydrochloric acid, then filtered under sterile conditions, the bottles are filled with The solution is lyophilized and the bottles are closed under sterile conditions. Each bottle for injection contains 5 mg of the active substance. Example B: suppositories A mixture composed of 20 g of an active substance of formula I, 100 g of soy lecithin and 1400 g of cocoa butter is melted, then the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of active substance. Example C: solution A solution is prepared with 1 g of an active substance of formula I, 9.38 g of NaH2P04 x 2H20, 28.48 g of Na2HP04 x 12 H20, 0.1 g of benzalkonium chloride and 940 ml of bidistilled water. The pH is adjusted to 6.8, brought to a volume of 1 liter and sterilized by irradiation. This solution can be used in the form of eye drops. Example D: Ointment In aseptic conditions 500 mg of an active substance of formula I are mixed with 99.5 g of Vaseline. Example E: tablets A mixture composed of 1 kg of an active substance of formula I, 4 kg of elactose, 1.2 kg of potato starch, 0.2 kg of talc and 0 kg, 1 kg of magnesium stearate is compressed into tablets, such that each tablet contains 10 mg of the active substance. Example F: Dragees The tablets are formed analogously to that described in Example E and then coated in a usual manner with a bath of sucrose, potato starch, talc, tragacanth and dye. Example G: capsules With 2 kg of an active substance of formula I, hard gelatin capsules are filled, so that each capsule contains 20 mg of the active substance. Example H: ampoules A solution of 1 kg of an active substance of formula I in 60 liters of bidistilled water is filtered under sterile conditions. The ampoules are filled with this solution and then lyophilized and closed under sterile conditions. Each ampoule contains 10 mg of the active substance.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (9)

R E I V I N D I C A C I O N S

1. Derivatives of benzamide, characterized by responding to formula I wherein R1 represents -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] n-Ar, -COOA, -OH or with a conventional amino protecting group, R2 represents H, A, OR6, N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr, NHS02A, NHS02Ar, COOR6, CON (R6) 2, CONHAr, COR6, COAr, S (0) nA or S ( 0) nAr, R-2 represents A, cycloalkyl, - [C (R) 2] nAr, [C (R6) 23n-0-Ar, - [C (R6) 23nHet or -C (R6) 2 = C (R6) 2-Ar, R represents H, A or benzyl, X is absent or represents -CO- , 'C (R' Z ~ i • C (R6) 2-C (R6) 2-, -C (R6) 2 -CO-, -C (R6) 2-C (R6) 2 -CO-, -C (R6) = C (R6) -CO-, NR6CO-, -N. { [C (R6) 2] n-COOR6} -CO- or -C (COOR6) R6-C (R6) 2-CO-, Y represents, -C (R6) 2-, -S02-, -CO-, -COO- or CONR6-, A represents alkyl of 1 to 20 carbon atoms in which one or two CH groups may be replaced by O or S atoms or by groups of CRb = CRb and / or 1 7 H atoms may be replaced by F, Ar represents phenyl or naphthyl unsubstituted or mono, di or trisubstituted with A, Ar ', OR6, N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr ', NHS02A, NHS02Ar', COOR6, CON (R6) 2, CONHAr ', COR6, COAr', S (0) nA or S (0) nAr, Ar 'represents phenyl or naphthyl or substituted or mono, di or trisubstituted with A, OR6, N (R6) 2, N02, CN, Hal, NHCOA, COOR6, CON (R6) 2, COR6 or S (0) nA, Het represents a monocyclic or bicyclic, saturated or unsaturated heterocyclic system, containing one, two, three or four identical or different heteroatoms such as nitrogen, oxygen and sulfur and which is unsubstituted or mono- or polysubstituted with Hal, A, Ar ', COOR6, CN, N (R6) 2 , N02, Ar-CONH-CH2 and / or carbonyloxy, Hal represents F, Cl, Br or I, n is 1, 1 or 2, and the salts of these compounds.

2. Compounds according to claim 1, characterized by responding to the following designations: a) 4- [4- (4-propylphenylsulfonyl) -1-piperazinylcarbonyl] -benzamidine; b) 4- [4- (3-amino-4-chlorophenylsulfonyl) -1-piperazinylcarbonyl] -benzamidine; c) 4- [4- (6-chloronaphthalene-2-sulfonyl) -1-piperazinylcarbonyl] -benzamidine; d) 4- [4- (2-phenylvinylsulfonyl) -1-piperazinylcarbonyl-3-benzamidine; and the salts of these compounds.

3. Process for preparing the compounds of formula I, according to claim 1, and their salts, characterized in that a) they are released from one of the functional derivatives by treatment with a sovolysis or hydrogenolysis agent, i) by hydrogenolysis releasing a group of amidino of its oxadiazole derivative, ii) replacing a conventional amino protecting group with hydrogen by treating it with a solvolysis or hydrogenolysis agent or releasing an amino group which is protected with a conventional protecting group, b) because to prepare compounds of formula I wherein R1 represents X represents -CO- or -C (R6) 2-CO-, and R2, R3 and Y have the meanings indicated in claim 1, a compound of formula II is reacted HN N-Y-R3 (II), wherein R3 and Y have the meanings indicated in claim 1, with a compound of formula III < where R1 is X represents -CO- or -C (R6) 2-CO-, R2 has the meaning indicated in claim 1 and L represents Cl, Br, I or a free OH group or functionally transformed into a reactive group, or c) because for preparing compounds of formula I wherein R1 is Y represents -S02-, -CO-, -COO- or -C (R6) 2-, and R2 and X have the meanings indicated in claim 1, a compound of formula IV -Y-R3 (IV) is reacted wherein Y represents -S02-, -C0-, -C00- or -C (R6) 2-, RJ has the meaning indicated in claim 1 and L represents Cl, Br, I or a free OH group or functionally transformed a reactive group, with a compound of formula V where R1 e: and R2 and X have the meanings indicated in claim 1, or d) because to prepare compounds of formula I wherein R1 is Y represents -CONH- and R2 and X have the meanings indicated in claim 1, a compound of formula VI is reacted R, 3-N = C = 0 (VI) wherein R has the meaning indicated in claim 1, with a compound of formula V where R is and R and X have the meanings indicated in claim 1, e) because to prepare compounds of formula I, wherein R 1 represents -C (= NH) -NH 2, a cyano group is transformed into an amidino group, f) and / or because it is a compound of formula I is transformed (n) ) one or more residues R1, R2 and / or R3 in one or more different radicals R1, R2 and / or R3, for example, i) hydrolyzing an ester group to a carboxyl group, ii) reducing a nitro group, iii) acylating an amino group, and / or converting a base or an acid of formula I into one of its salts.

4. A process for obtaining pharmaceutical preparations based on the compounds of claim 1, characterized in that a compound of formula I and / or one of its physiologically acceptable salts is brought into a suitable dosage form, together with at least one excipient or solid, liquid or semi-liquid auxiliary product.

Pharmaceutical preparation based on the compounds of claim 1, characterized in that it contains at least one compound of formula I and / or one of its physiologically acceptable salts.

6. Compounds of formula I, according to claim 1, and their physiologically acceptable salts, characterized in that they combat thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication.

7. Medicaments of formula I, according to claim 1, and their physiologically acceptable salts, characterized as being inhibitors of the coagulation factor Xa.

8. Compounds of formula I, according to claim 1, and / or their physiologically acceptable salts, characterized in that they are used to prepare a medicament.

9. Compounds of formula I, according to claim 1, and / or their physiologically acceptable salts, characterized in that they are used to combat thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina of chest, restenosis after angioplasty and intermittent claudication. BENZAMIDINE DERIVATIVES AS INHIBITORS OF THE FACTOR XA SUMMARY OF THE INVENTION The invention relates to novel compounds of the formula (I), wherein X, Y, R1, R2 and R3 have the meanings given in claim 1, are inhibitors of coagulation factor Xa and can be used to prevent or treat diseases thromboembolic