MXPA00010416A - Biphenyl derivatives - Google Patents

Abstract

The invention relates to novel compounds of formula (I), wherein X, R1, R2, R3, R4 and R5 have the meanings cited in Patent Claim No. 1. Said compounds are inhibitors of the coagulation factor Xa and can be used for prophylaxis and/or for treating thromboembolic disorders.

Description

BIFENYL DERIVATIVES The invention relates to the compounds of formula I (I) wherein R1, R4 independently represent -C (= NH) -NH2 which may also be monosubstituted with -COA, -CO- [C (R6) 2] n-Ar, -COOA, -OH or with an amino protecting group conventional, NH-C (= NH) -NH2, -CO-N = C (NH2) 2 Ref. 123311 R3, independently represent H, A, OR N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr, NHS02A, NHS02Ar, COOR6, CON (R6) 2, CONHAr, COR6, COAr, S (0) nA, S (0) nAr, -O-. { C (R6) 2] m-COOR6, - [C (R6) 2] p-COOR6, -O- [C (R6) 2] m-CON (R6) 2, [C (R6) 2] p-C0N (R6) 2, -0- [(R6) 2] m-CONHAr, or - [C (R6) 2] p-CONHAr, X represents - [C (R6) 2] n-, -CR6 = CR6-, - [C (R6) 2] n- O-, -O- [C (R6) 2] n-, -COO-, -OOC-, -CONR6- or -NR6CO-, Rl represents H, A or benzyl, 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 trisustiidated with A, Ar ', OR6, OAr', N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr ', NHS02A, NHS02Ar', COOR6, CON (R6) 2, CONHAr ', COR6, COAr', S (0) nA, s (0) "Ar ', Ar1 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, or S (0) nA, Hal represents F, Cl, Br or I, n is 0, 1 or 2, m is 1 or 2 , p is 1 or 2, and the salts of these compounds. The invention also relates to the hydrates and solvates of these compounds. The aim 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, restonosis after angioplasty and intermittent claudication.

Aromatic derivatives of amidine having an antithrombotic action are disclosed, for example, in European Patent No. 0 540 051 Bl. The cyclic guanidines which are intended for the treatment of thromboembolic diseases are described, for example, in the world patent No. 97/08165. Aromatic heterocycles that exhibit an inhibitory activity of factor Xa are disclosed, for example, in 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 intervene in the blood coagulation process by inhibiting factor Xa, and thus repress thrombus formation. 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 that described, for example, J. Hauptmann 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. That 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, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication. The object of the invention is constituted by the compounds of 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 released from one of their functional derivatives by treatment with a sovolysis or hydrogenolysis agent, either i) by hydrogenolysis releasing an amidino group of its oxadiazole derivative, ii) replacing a conventional amino protecting group with hydrogen by treating it with a solvolysis or hydrogenolysis agent or releasing a amino group that is protected with a conventional protective group, b) because in one compound of formula I one or more residues R1, R2, R3, R4 and / or R5 are transformed into one or more different residues R1, R2, R3, R4 and / or R5 either by example, i) hydrolyzing an ester group to a carboxyl group, ii) transforming a hydroxylated amidino group into an amidino group, iii) reducing a nitro group, iv) acylating an amino group, and / or c) converting 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. Hydrates and solvates are understood, for example, as hemi, mono or dihydrates, and solvates are, for example, compounds obtained by the addition of alcohols, such as, for example, methanol or ethanol. In the formulas indicated above, A represents straight or branched chain alkyl and 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, secbutyl 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-l-methyl-propyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2, -trimethyl-propyl, heptyl, octyl, nonyl or decilo. A also represents, for example, trifluoromethyl, pentafluoroethyl, alido or crotyl. COR6 is acyl and preferably represents formyl, acetyl, propionyl, then also butyryl, pentanoyl or hexanoyl. COOR6 preferably represents methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butocarbonyl. Hal preferably represents F, Cl, or Br, but also I.R2, R3 and R5 independently and preferably represent H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ethylamino , diethylamino, acetamido, sulfonamido, methylsulfonamido, phenylsulfonamido, methylthio, ethylthio, meth ylsulfinyl, ethylsulfinyl, metiisulfonilo, etiisulfonilo, phenylsulfinyl, phenylsulfonyl, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, carboxymethoxy, methoxycarbonylmethoxy, carboxymethyl, methoxycarbonylmethyl, aminocarboniÍmetoxi, aminocarbonylmethyl, N- phenylaminocarbonylmethoxy, N-phenylaminocarbonylmethyl, then also acyl or benzoyl. R2, R5 represent, in particular, H. R3 preferably represents, for example, H, COOA or -CH2COOR6, wherein R6 represents H or alkyl of 1 to 4 carbon atoms. R6 represents H, A or benzyl, but mainly H or alkyl of 1 to 4 carbon atoms. X preferably represents, for example, -CH2-, -CH = CH-, -CH20-, -0-CH2- -COO-, -OOC-, -CONH- or -NHCO -; X represents even more preferably -CH20-, -0-CH2 or -CH2-CH2-. Ar preferably represents phenyl or unsubstituted naphthyl, then preferably phenyl or mono, di or trisus naphthyl, for example with A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxo, benzyloxy. , phenethyloxy, methylthio, ethylthio, methyl-sulfinyl, ethylsulfinyl, metiisulfonilo, etiisulfonilo, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, phenylsulfonamido , (4-methylphenyl) -sulfonamido, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonyl letoxy, 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-terbutyl phenyl, 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-carboxy phenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- 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, o-, m- or p-methylthiophenyl, then preferably 2,3-, 2 , 4-, 2,5-, 2,6-, 3,4- or 3,5-difluor-ofenyl, 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-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3-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-nor tro-4-N, N-dimethylane- or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4- , 2,3,5-, 2,3,6-, 2,4,6- or 3, 4, 5-trichloropheni lo, 2, 4, 6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bro-ofhenyl , 2, 5-di-fluoro-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 2,5-dimethyl-4-chloro-phenyl.

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-propyl enyl, or -, m- or p-isopropyl phenyl, 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-, m- 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, or- , m- or p-bromophenyl, o-, m- or p-chlorophenyl or o-, m- or p-methylsulfonylphenyl. Accordingly, first and foremost object of the present invention are those compounds of formula I in which at least one of the mentioned moieties has one of the preferred meanings indicated above. Some preferred groups of compounds may be represented by the partial formulas ai I indicated below, which correspond to formula I and in which the radicals which are not explicitly stated have the meaning indicated for formula I, namely: in R1, R4 independently represent -C (= NH) -NH2 which may also be monosubstituted with OH, or -CO-N = C (NH2) 2; in Ib R2, R5 represent H; in R1, R4 independently represent -C (= NH) -NH2 which may also be monosubstituted with OH, or -CO-N = C (NH2) 2, R2, R5 represent H and R3 represent H or COOR6; Id R1, R4 independently represent -C (= NH) -NH2 which may also be monosubstituted with OH, or -CO-N = C (NH2) 2, R2, R5 represent H and R3 represent H, COOR6 or -O- (CH2) COOR6; in X represents -CH2-0- or -0-CH2-; in If R1, R4 independently represent -C (= NH) - NH2 which may also be monosubstituted with OH, or -C0-N = C (NH2) 2, R2, R5 represent H, Rc represent H or COOR and X represents - CH2-0- or -0-CH2-; in ig R4 independently represent C (= NH) -NH2 which may also be monosubstituted with OH, or -CO-N = C (NH2) 2, R2, R5 represent H, R3 represent H, COOR6 or -O- (CH2) COOR6, and X represents -CH2-0-, -0-CH2- or -CH2- CH2- in Ih R1, R4 independently represent -C ( = NH) -NH2 which may also be monosubstituted with OH, or -CO-N = C (NH2) 2, R¿R- represent H, R represent H, COOR6, -O- (CH2) COOR6, CH2-COOR6, -0-CH2-CON (R6) 2, CH2- CON (R6) 2, -0-CH2-CONHAr or CH2-CONHAr, X represents -CH2-0-, -0-CH2- or -CH2- CH2-R6 represent H or A, A represent alkyl of 1 to 4 C atoms; in I i R1, R4 independently represent C (= NH) - NH2 which can also be monosubstituted with OH, or -CO- N = C (NH2) 2 / R2, Rc represent H, R- represent H, COOR6, -O - (CH2) COOR6, CH2-COOR6, -0-CH2-CON (R6) 2, or CH2- CON (R6) 2, X represents -CH2-0-, -0-CH2- or -CH2- CH2-, They represent H or A, A represent alkyl of 1 to 4 carbon atoms. 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 ( example, in certain standard works such as those of Houben-eyl, "Methoden der organischen 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, substances which correspond to formula I are preferred, but instead of one or more free amino groups and / or free hydroxyl groups contains correspondingly protected amino and / or hydroxyl groups, preferably those which instead of an H atom attached to an N atom carry a amino-protecting group, in particular those which instead of a group of NH carry a group of R '-N, where R' is an amino-protecting group, and / or those which instead of the H-atom of the hydroxyl group carry a hydroxyl protecting group, for example, those which respond to formula I, but which instead of a -COOH group carry a -COOR group, with R "being a hydroxyl protecting group. Oxadiazole derivatives which can be transformed into the corresponding amidino compounds are also preferred among the starting materials. The introduction of the oxadiazole group can be carried out, for example, by reaction of the cyano compounds with hydroxylamine and by reaction with phosgene, dialkano carbonate, chloroformic acid ester, N, N'-carbonyldiimidazole or acetic anhydride. There may 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 groups of this type are the 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 arylsulfonyl 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 do not constitute a critical point because they re-excise once the desired chemical reaction (or the sequence of chemical reactions) has been completed; however, groups from 1 to 20, in particular from 1 to 10, carbon atoms are preferred Examples of hydroxyl protecting groups are, among others, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tertbutyl and acetyl, with benzyl being and the terbutyl 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, may be used. 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 suitably comprised between ca. 0 and 50 ° C, preferably between 15 and 30 ° C (room temperature). The groups BOC, OBut and Mtr can be cleaved preferably with, for example, TFA in dichloromethane or with HCl approx. 3N to 5N in dioxane, at a temperature 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. Protective groups that are separated by hydrogenolysis (for example CBZ, benzyl or the release of the amidino group from its 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, suitably a support such as carbon, or as wet Raney nickel in the presence, for example, of acetic acid). 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. The 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 R1 and R4 represent -C (= NH) -NH2 can be prepared preferably from the corresponding cyano compounds. The transformation of a cyano group to an amidino group is carried out, for example, by reaction with hydroxylamine and by subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd / C or nickel-Raney. 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 steps by means of a process in which, in a manner known per se a), the nitrile is converted with H2S to a thioa-ida 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 it is then treated with ammonia, or c) the nitrile is reacted with lithium bis- (trimethylsilyl) -amide and then the product obtained is hydrolyzed. The preparation of the cyano compounds is carried out according to known methods. The compounds of formula I, in which R1 and R4 represent -CON (= NH) -NH2, can be prepared preferably by reacting the corresponding alkoxycarbonyl compounds with guanidine. 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, acylating an amino group or reducing nitro groups to amino groups (for example, by hydrogenation with nickel-Raney 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 a conventional manner with an acid chloride or anhydride, 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 °. 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 time is comprised, depending on the conditions used, between a few minutes and 14 days, the reaction temperature is between approx. 0 ° and 150 °, usually between 20 ° and 130 °. 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 sulfide; 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. 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, acids which form acceptable salts from a physiological point of view are particularly suitable. Therefore, inorganic acids such as, for example, sulfuric acid, nitric acid, hydrocides such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulphamic acid, then also organic acids can be used. , in particular the aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulphonic or sulfuric acids such as, for example, formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulonic, benzenesulfonic, p-toluene-sulphonic, naphthalene-magnesium, 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. , the sodium or potassium hydroxide or carbonate) in their respective metal salts, in particular in their alkali metal or alkaline earth metal salts, or in their respective ammonium salts. Organic bases that are physiologically acceptable such as, for example, ethanolamine. The invention also relates to the use of the compounds of formula I and / or their physiologically acceptable salts in the preparation of pharmaceutical preparations, in particular by a non-chemical route. For this purpose, 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 (eg 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, tablets, pills, capsules, powders, granules, syrups, juices or drops are used in particular for rectal administration, suppositories for parenteral administration, solutions, preferably oily solutions 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 comprised between ca. 1 and 500 mg, in particular between 5 and 100 mg per dosage unit. The daily dose is preferably comprised between ca. 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 it is adjusted, according to the constitution of the final product, to pH values comprised 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. Mass spectrometry (MS): The (ionization by electronic impact) M + FAB (Fast Atom Bombardment) (rapid bombardment of atoms) (M + H) + Example 1 A solution of 2.06 g of 3-bromobenzonitrile and 1.50 g of 3-toliboric acid in 50 ml of dimethoxyethane is mixed with 247 mg of palladium (II) acetate, 335 mg of trio-tolifosphine, 20 ml of water and 954 mg of anhydrous sodium carbonate and heating for 18 hours at 100 ° C with continuous stirring. The mixture is then worked up in a usual manner, the residue is chromatographed on a column of silica gel using petroleum ether / ethyl acetate 9: 1 as eluent, and 3'-methylbiphenyl-3-carbonitrile is obtained at the colorless solid ("A"), 193. A solution of 1.17 g of "A" in 10 ml of carbon tetrachloride is mixed with 1.09 g of N-bromosuccinimide (NBS) and 60 mg of azobisisobutyronitrile, and it is heated for 18 hours at 70 ° C. The mixture is worked up in a usual manner, the residue is chromatographed on a column of silica gel using petroleum ether / ethyl acetate 9: 1 as eluent, and 3'-bromomethylbiphenyl-3-carbonitrile is obtained at the colorless solid ("B"). A solution of 500 mg of "B" and 238 mg of 3-hydroxybenzonitrile in 10 ml of acetonitrile is mixed with 652 mg of cesium carbonate, stirred for 40 hours at room temperature. After working the mixture in a usual manner, the residue is chromatographed on the column in a reversed phase using acetonitrile / water 65:35 as the eluent. The 3 '- (3-cyanophenoxymethyl) -biphenyl-3-carbonitrile ("C"), FAB 311, is obtained in the state of a colorless solid. A solution of 90 mg of "C" and 125 mg of hydroxylammonium chloride in 10 ml of ethanol is mixed with 1.2 g of bound dimethyl aminopyridine as a polymer (DMAP) and stirred for 18 hours at room temperature. It is then filtered, the solvent is removed and the N-hydroxy-3 '- [3- (N-hydroxycarbamimidoyl) -phenoxymethyl] -biphenyl-3-carboxamidine ("D") is obtained at the solid state. A solution of 76 mg of "D" in 10 ml of methanol is mixed with 100 mg of Raney nickel moistened with water and 30 mg of acetic acid, and the mixture is hydrogenated for 18 hours at room temperature and normal pressure. It is then filtered, the solvent is removed and the 3 '- (3-carbamimidoyl-phenoxymethyl) -biphenyl-3-carboxamidine, acetate, 327 (M + - NH3), 310 (M + - 2 NH3) is obtained.

The compounds indicated below are obtained in a manner analogous to that described above: 3 '- (3-carbamimidoyl-phenoxymethyl) -bifeni-4-carboxamidine, diacetate, FAB 345; 3 '- (4-carbamimidoyl-phenoxymethyl) -biphenyl-4-carboxamidine, diacetate, FAB 345; 3 '- (4-carbamimidoyl-phenoxymethyl) -biphenyl-3-carboxamidine, diacetate, FAB 345; 4 '- (4-carbamimidoyl-phenoxymethyl) -biphenyl-4-carboxamidine; 4 '- (4-carbamimidoyl-phenoxymethyl) -bifeni 1-3 -carboxamidine; 4 '- (3-carbamimidoi 1-phenoxymethyl) -biphenyl-3-carboxamidine and 4' - (3-carbamimidoyl-phenoxymethyl) -bifeni 1-4 -carboxamidi a.

Example 2 By analogous reaction to Example 1 of 3-bromobenzonitrile with 3-methoxyphenylboronic acid, 3'-methoxybiphenyl-3-carbonitrile is obtained.

Subsequent cleavage of the ether with aluminum triiodide in acetonitrile and reaction with 3-bromomethyl-benzonitrile affords 3 '- (3-cyanobenzyloxy) -bipheni-3-carbonitrile. 3'- (3-carbamimidoyl-benzyloxy) -biphenyl-3-carboxamidine is obtained by reaction with hydroxylamine and reduction with hydrogen using Ni-Ra as a catalyst.

The following compounds are obtained analogously: 4'- (4-carbamimidoyl-benzyloxy) -biphenyl-4-carboxamidine, diacetate, FAB 345; 4'- (3-carbamimidoyl-benzyloxy) -biphenyl-4-carboxamidine, diacetate, FAB 345. EXAMPLE 3 By analogous reaction to that of example 1 of 3-cyanophenylboronic acid with methyl 3-bromo-5-methyl-benzoate was it obtains methyl 3'-cyano-5-methyl-biphenyl-3-carboxylate. By bromination with NBS and reaction with 3-hydroxybenzonitrile, 3 '-cyano-5- (3-cyano-phenoxymethyl) -biphenyl-3-carboxylic acid methyl ester is obtained. By reaction with hydroxylamine and reduction with H2 / Ni-Ra, 3 '-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) -biphenyl-3-carboxylic acid methyl ester is obtained. Saponification of the ester with aqueous NaOH affords 3'-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) -biphenyl-3-carboxylic acid.

By chromatography on a reversed-phase column, using a mixture of acetonitrile / water / TFA as eluent, 3'-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) -biphenyl-3-carboxylic acid bistrifluoroacetate is obtained. . The compounds indicated below are obtained analogously: 4'-methylcarbamimidoyl-4- (4-carbamimidoyl-phenoxymethyl) -biphenyl-3-carb-carbylate, FAB 403; 4 '-carbamimidoyl-4- (3-carbamimidoi-1-phenoxymethyl) -biphenyl-2-carboxylic acid methyl ester, FAB 403; 3 '-carbamimidoyl-4- (-carbamimidoyl-phenoxymethyl) -biphenyl-2-carboxylic acid methyl ester, FAB 403; 3 '-carbamimidoyl-4- (3-carbamimidoyl-phenoxymethyl) biphenyl-2-carboxylic acid methyl ester, FAB 403; 4 '-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxylic acid methyl ester, FAB 403; 3 '-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) biphenyl-4-carboxylic acid methyl ester, FAB 403; Example 4 By a reaction analogous to Example 1 of methyl 3-bromobenzoate with 3-tolylboronic acid, methyl 3'-methylbiphenyl-3-carboxylate is obtained. By bromination with NBS and reaction of the latter compound with methyl 3-hydroxy-benzoate, methyl 3 '- (3-methoxycarbonyl-phenoxymethyl) -biphenyl-3-carboxylate is obtained. By reaction of the latter with guanidine hydrochloride in methanolic sodium methoxide solution, N- [3 '- (3-guanidinocarbonyl-phenoxymethyl) -biphenyl-3-carbonyl] -guanidine is obtained.

Proceeding analogously, the N- [4 '- (4-guanidinocarbonyl-phenoxymethyl) -biphenyl -carbonyl] -guanidine compound is obtained.

Example 5 A solution of 7.0 g of 3-bromo-5-methylphenol, 5.97 g of methyl bromoacetate and 13 g of cesium carbonate in 100 ml of acetonitrile is stirred overnight at room temperature. After working the reaction mixture in a usual manner, 9.70 g of methyl (3-bromo-5-methylphenoxy) -acetate ("AB") are obtained. A suspension of 2.0 g of "AB", 100 mg of tetrakis (triphenylphosphine) -palladium and 0.85 g of sodium carbonate in 50 ml of toluene is heated to boiling. Then a solution of 2.94 g of 3-cyanophenylboronic acid in 30 ml of methanol is added dropwise and heated at reflux for 14 hours. The reaction mixture is worked up in the usual manner and 2.17 g of methyl (3'-cyano-5-methyl-biphenyl-3-yloxy) -acetate ("AC") are obtained. A solution of 1.2 g of "AC" and 0.765 g of NBS in 50 ml of carbon tetrachloride is illuminated with UV light at room temperature. After working the product in the usual manner, 1.54 g of methyl (3'-cyano-5-bromomethyl-biphenyl-3-yloxy) -acetate ("AD") are obtained.

A solution of 185 mg of "AD", 63.1 mg of 4-hydroxybenzonitrile and 172.7 mg of cesium carbonate in 10 ml of acetonitrile is stirred at room temperature for 4 days. After working the mixture in the usual way, [3'-cyano-5- (4-cyanophenoxymethyl) -biphenyl-3-yloxy] -acetic acid methyl ester ("EA") is obtained. A solution of 60 mg of "EA", 69.5 mg of hydroxylammonium chloride and 101 mg of triethylamine in 10 ml of methanol is refluxed for 14 hours at reflux. After removing the solvent, the residue is taken up with water. It is separated and 70 mg of [3'-N-hydroxyamidino-5- (4-N-hydroxyamidino-phenoxymethyl) -biphenyl-3-yloxy] -acetic acid methyl ester ("AF"). Reduction of the latter compound with H2 / nickel-Raney gives [3'-amino-5- (4-amidinophenoxymethyl) -biphenyl-3-yloxy] -acetic acid methyl ester, FAB 433.

The compounds listed below are obtained analogously: [4'-amino-5- (4-amidinophenoxymethyl) -biphenyl-3-yloxy] -acetic acid methyl ester, FAB 433 [3 '-amidino-5- (3-amidinophenoxymethyl) -biphenyl-3-yloxy] -methyl acetate, FAB 433 [4 '-amidino-5- (3-amidinophenoxymethyl) -biphenyl-3-yloxy] -acetic acid methyl ester, FAB 433. If methyl bromoacetate is replaced in the first stage with tert-butyl bromoacetate, the esters can be cleaved terbuthics which are obtained in the last step with trifluoroacetic acid to obtain the corresponding carboxylic acids [3'-amidino-5- (4-amidinophenoxymethyl) -biphenyl-3-yloxy] -acetic acid, bistri-fluoroacetate, FAB 419; [4 '-amidino-5- (4-amidinophenoxymethyl) -biphenyl-3-yloxy] -acetic acid; [3 '-amidino-5- (3-amidinophenoxymethyl) -biphenyl-3-loxy] -acetic acid; [4 '-amidino-5- (3-amidinophenoxymethyl) -biphenyl-3-yloxy] -acetic acid.

Example 6 .0 g of 3 '-bromomethyl-biphenyl-3-carbonitrile and 5 ml of triethyl phosphite are combined and the solution is heated slowly to 150 °. It is stirred for 6 hours at 150 ° and after working the reaction mixture in a usual manner, 6.05 g of diethyl (3'-cyano-biphenyl-3-ylmethyl) phosphonate ("BA") are obtained. To a solution of 1.0 g of "BA" and 3-cyanobenzaldehyde in 20 ml of ethylene glycol dimethyl ether are added, with ice bath and nitrogen atmosphere, 150 mg of sodium hydride. The mixture is stirred for 4 hours, the mixture is worked up in the usual manner and 0.93 g of 3 '- [2- (3-cyanophenyl) -vinyl] -biphenyl-3-carbonitrile ("BB") is obtained. After hydrogenation of 360 mg of "BB" with Pd-C-5% in methanol, 360 mg of 3 '- [2- (3-cyanophenyl) -ethyl] -biphenyl-3-carbinitrile ("BC") is obtained. As in Example 1, it is then reacted with hydroxylammonium chloride and hydrogenated with Raney-nickel to obtain 3 '- [2- (3-amidinophenyl) -ethyl] -biphenyl-3-carboxamidine, FAB 343.

Proceeding in an analogous manner, 3 '- [2- (4-amidine phenyl) -ethyl] -biphenyl-3-carboxamidine, FAB 343. The following examples relate 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 1 of bidistilled water is adjusted to 6.5 with 2 N hydrochloric acid, then filtered under sterile conditions, the jars with the solution, lyophilize and close the bottles under sterile conditions. Each bottle for injection contains 5 mg of the active substance.

Example B: suppositories A compound mixture is melted with 20 mg of an active substance of formula I, 100 g of soy lecithin and 1400 g of cocoa butter, then the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of the 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 1 1 volume and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment Under 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 lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 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 they are coated in the 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 in such a way 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 1 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 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)

1. - Compounds of formula I (I) characterized in that: R ^ R4 independently represent -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, NH-C (= NH) -NH2, -CO-N = C (NH2) 2 R2, R3, R5 independently represent H, A, OR6, N (R6) 2, N02, CN, Hal, NHCOA, NHCOAr, NHS02A, NHS02Ar, COOR6, CON (R6) 2, CONHAr, COR6, COAr, S (0) nA, s (0) nAr, -O- f C (R6) 2] m-COOR6, - [C (R6) 2] p-COOR6, -0- [C (R6) 2] m-CON (R6) 2, [C (R6) 2] p-CON (R6) 2, -Ot (R6) 2] m-CONHAr, [C (R6) 2] p-C0NHAr, X represents - [C (R6) 2] n-, -CR6 = CR6-, - [C ( R6) 2] n- O-, -O- [C (R6) 2] n-, -COO-, -OOC-, -CONR6- or -NR6CO-, Re represents H, A or benzyl, A represents alkyl of 1 to 20 carbon atoms in which one or two CH2 groups can 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 trisus substituted with A, Ar ', OR6, OAr', N (R6) 2 / N02, CN, Hal, NHCOA, NHCOAr ', NHS02A, NHS02Ar', COOR6, CON (R6) 2, CONHAr ', COR6, COAr', S (0) nA, s (0) nAr ', Ar' represents phenyl or naphthyl unsubstituted or mono, di or trisubstituted with A, OR6, N (R6) 2, N02, CN, Hal, NHCOA, COOR6, CON (R6) 2, COR6, or S (0) nA, Hal represents F, Cl, Br or I, n is 0, 1 6 2, m is 1 or 2, is 1 or 2, the salts of these compounds

2. - Compounds according to claim 1 a) 3 '- (3-carbamimidoyl-phenoxymethyl) -biphenyl-3-carboxamidine; b) 3 '- (3-carbamimidoyl-benzyloxy) -biphenyl-3-carboxamidine; c) 3 '-carbamimidoyl-5- (3-carbamimidoyl-phenoxymethyl) -biphenyl-3-carboxylic acid; d) N- [3 '- (3-guanidinocarbonyl-phenoxymethyl) -biphenyl-3-carbonyl] -guanidine; e) [3 '-amidino-5- (-amidiñofenoximetil) -biphenyl-3-yloxy] -acetic acid methyl ester; f) [3 '-amino-5- (4-amidinophenoxymethyl) -bipheni-3-yloxy] -acetic acid 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 their functional derivatives by treatment with a sovolysis or hydrogenolysis agent, either i) releasing by hydrogenolysis an amidino group 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, or b) because in a compound of formula I, one or more radicals R1, R2, R3, R4 and / or R5 are transformed into one or more different radicals R1, R2, R3, R4 and / or R5, for example, i ) hydrolyzing an ester group to a carboxyl group, ii) transforming a hydroxylated amidino group into an amidino group, iii) reducing a nitro group. iv) by acylating an amino group, and / or c) a base or an acid of formula I is converted to one of its salts.

4. - Process for obtaining pharmaceutical preparations, characterized in that a compound of formula I according to claim 1 is carried, and / or one of its salts physiologically acceptable to a suitable dosage form, together with at least one excipient or solid, liquid or semi-liquid auxiliary product.

5. - Pharmaceutical preparation, characterized in that it contains at least one compound of formula I, according to claim 1, and / or one of its salts acceptable from the physiological point of view.

6. - Compounds of formula I, according to claim 1, and their physiologically acceptable salts, intended to combat thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, restonosis after of angioplasty and intermittent claudication.

7. Medicaments of formula I, according to claim 1, and their physiologically acceptable salts, characterized in that they act as inhibitors of coagulation factor Xa.

8. Use of the compounds of formula I, according to claim 1, and / or their physiologically acceptable salts for preparing a medicament.

9. Use of the compounds of formula I, according to claim 1, and / or of their physiologically acceptable salts to combat thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris , restenosis after angioplasty and intermittent claudication.