MXPA01006942A - Imidazo[4,5-c]-pyridine-4-on-derivatives - Google Patents

Abstract

The invention relates to novel compounds of formula (I) wherein R, R1, R2, R3 and n have the meaning given in Claim 1. Said compounds are inhibitors of the coagulation factor Xa and can be used for the prophylaxis and/or therapy of thrombo-embolic diseases.

Description

DERIVATIVES OF THE IMIDAZO [4,5 C] -PIRIDIN-4 -ONA FIELD OF THE INVENTION The invention relates to the compounds of formula wherein R represents H, alkyl of 1 to 6 carbon atoms and straight or branched chain or cycloalkyl of 3 to 6 carbon atoms, R1 represents Ar, R2 represents Ar ', R3 represents H, R, R4, Hal, CN , COOH, COOA or CONH2, Ar, Ar 'independently represent phenyl, naphthyl or biphenyl unsubstituted or mono, di or trisubstituted with R, OH, Hal, CN, N02, CF3, NH2, NHR, NR2, pyrrolidin-1-yl , piperidin-1-yl, Ref: 130024 benzyl oxy, S02NH2, S02NHR, S02NR2, -CONHR, -C0NR2, - (CH2) n-NH2, - (CH2) n -NHR, - (CH2) n-NR2, -O- (CH2) n- NH2, -O- (CH2) n-NHR, -O- (CH2) n-NR2, R4 or substituted together with -O- (CH2) m-0-, or isoquinolinyl substituted with NH2, R * represents - C (= NH) -NH2 or -NH-C (= NH) -NH2 or -C (= 0) -N = C (NH2) 2 unsubstituted or monosubstituted with -COR, -COOR, -OH or with a group conventional amino protector, A represents alkyl of 1 to 4 carbon atoms, Hal represents F, Cl, Br or I, m is 1 or 2, n is 0 or 1, and to the salts and solvates of these compounds. The invention also relates to the optically active forms, the racemates, the diastereomers, the hydrates and the solvates, for example the alkoxides, 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. .5 It was discovered that the compounds of formula I and their salts exhibit very 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 diseases thromboembolic events such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication. The compounds of the invention, of formula I, also '15 can act as inhibitors of coagulation factors VIla and IXa and thrombin, which are substances that are involved in the process of blood coagulation. The aromatic derivatives of amidine having an antithrombotic action are disclosed, for example, in • 20 European document 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 inhibit factor Xa are disclosed, for example, in the patent • 25 world number 96/10022. In World Patent No. 96/40679 there are described substituted N- [(aminoiminomethyl) phenylalkyl] -azaheterocyclylamides which act as factor Xa inhibitors. 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, or to the inhibition of other activated serineprdteases such as factor Vlla, Factor IXa or thrombin. 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. The latter separates fibrinogen into fibrin monomers which, after crosslinking, essentially contribute to the formation of thrombi. An activation of thrombin can cause the onset of thromboembolic diseases. However, an inhibition of thrombin can inhibit the formation of fibrin that participates in the formation of thrombi. The inhibition of thrombin can be measured, for example, according to the method of G.F.Cousins et al. which is described in "Circulation" 1996, 94, pgs. 1705 to 1712. Thus, 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 process of blood coagulation by inhibiting factor Xa and, therefore, inhibit 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 that described, for example, J. Hauptmann et al. in Thrombosis and Haemostasis, 1990, 63, p. 220 to 223. The inhibition of factor Xa can also be determined, for example, according to the method of T. Hará et al. which is described in Thromb. Haemostas 1994, 71, pgs. 314 to 319. The factor VIla of blood coagulation initiates the extrinsic pathway of blood coagulation by binding to tissue factor, and leads to the formation of factor Xa by activation of factor X. Consequently, the inhibition of factor VIla inhibits the formation of factor Xa and also the subsequent formation of thrombi. The inhibition of factor Vlla 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 method usually employed to measure inhibition of factor Vlla is that described, for example, by H.F. Ronning et al. in "Thrombosis Research" 1996, 84, pgs. 73 to 81. The clotting factor IXa is generated in the intrinsic mechanism of blood coagulation and also participates in the activation of factor X to form the factor For. Therefore, an inhibition of factor IXa is another way to prevent the formation of factor Xa. The inhibition of factor IXa 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. Chang et al. in "Journal of Biological Chemistry" 1998, 273, pgs. 12089-, 15 12094. 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, 2nd myocardial infarction, arteriosclerosis, inflammation, 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 The 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 or solvolysis an amidino group of its oxadiazole derivative or its oxazolidinone derivative, ii) replacing an amino protecting group Conventional by hydrogen by treating it with a solvolysis or hydrogenolysis agent or by releasing an amino group which is protected with a conventional protecting group, or B) because in one compound of formula I one or more radicals R, R1, R2 and / or R3 are transformed into one or more different radicals R, 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, vi) transforming a cyano group into an amidino group, and / or • 25 c) 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 are independent of each other. The residues or parameters R, R1, R2, R3 and n that are indicated in this text have the meanings indicated for formula I, unless otherwise indicated. R represents straight chain (linear) or branched alkyl and from 1 to 6, preferably from 1, 2, 3, 4, 5 or 6 carbon atoms. Preferred meanings of R are methyl, then ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or terbutyl, and then also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 3-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-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. R also represents cycloalkyl and represents preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. A represents alkyl of 1, 2, 3 or 4 C atoms and preferably means methyl, then ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. Hal preferably represents F, Cl or Br, but also I. Ar and Ar 'independently represent phenyl, benzodiozol-5-yl, naphthyl or biphenyl unsubstituted or mono, di or trisubstituted with R, OH, OR, Hal, CN, N02, CF3, NH2, NHR, NR2, pyrrolidin-1- ilo, piperidin-1-yl, benzyloxy, S02NH2, S02NHR, S02NR2, phenylsulfonamido, - (CH2) n-NH2, - (CH2) n -NHR, - (CH2) n -NR2, -O- (CH2) n- NH2, -O- (CH2) n-NHR, -O- (CH2) n-NR2, -0- (CH2) m-0- or R4, among which is preferred naphthyl or biphenyl monosubstituted with amidino. Preferred substituents for the biphenyl are amidino, fluoro, S02N? 2 or S02NHR. Ar and Ar 'independently represent phenyl, naphthyl or unsubstituted biphenyl, preferably preferably phenylmono, di or trisubstituted naphthyl or biphenyl, for example, with methyl, ethyl, propyl, isopropyl, butyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, bu-ilsulfonamido, dimethylsulfonamido, phenylsulfonamido, aminomethyl, aminoethyl, N -methylaminomethyl, N-ethylaminomethyl, N, N-dimethylaminomethyl, aminomethyloxy, aminoethyloxy or R4, then also benzodioxolyl. Therefore, the particularly preferred meanings of Ar and Ar 'are independently, 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- (N-meylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p- methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) -phenyl, o- , m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-fluorophenyl, o-, m- or p- bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p-amidinophenyl, 7-amidino-2-naphthyl, 2'-amidino- biphenyl-3-yl, 3-fluoro-2'-sulfamoyl-biphenyl-4-yl, 3-fluoro-2'-N-tert-butyl-sulfamoyl-biphenyl-4-yl, 2'-sulphamoyl-biphenyl-4-yl , 2'-N-tert-butyl-sulfamoyl-biphenyl-4-yl, or-, m- p- (pyrrolidin-1-yl) -phenyl, o-, m- or p- (piperidin-1-yl) -phenyl, o-, m- or p-. { 5-methyl- [1, 2, 4] -oxadiazol-3-yl)} -phenyl, 7-. { 5-methyl- [1, 2, 4] -oxadiazol-3-yl)} -2-naphthyl, o-, m- or p-. { 5-oxo- [1,2,4] -oxadiazol-3-yl)} -phenyl, 7-. { 5-oxo- [1,2,4] -oxadiazol-3-yl)} -2-naphthyl, 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-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-di-methoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-ami-no-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 -di-methylaminophenyl, 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 2,5-dimethyl-4-chlorophenyl. R3 preferably represents, for example, H, Hal, COOH, COOA or C0NH2. R 4 preferably represents, for example, -C (= NH) -NH 2, -NH-C (= NH) -NH 2, C (= 0) -N = C (NH 2) 2 unsubstituted, which may also be monosubstituted with OH , and even more preferably represents -C (= NH) -NH2 unsubstituted or substituted with OH or CH, .m is 1 or 2. n is preferably O or 1 The compounds of formula I can have one or more chiral atoms and, therefore, have different stereoisomeric forms. Formula I covers all these forms. Consequently, compounds of formula I in which at least one of the aforementioned residues has one of the preferred meanings indicated above are first and foremost objects of the present invention. Some preferred groups of compounds may be represented by the partial formula ai I 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 the Ar represents phenyl, naphthyl or biphenyl monosubstituted with R 4; in Ib Ar 'represents phenyl, naphthyl or biphenyl monosubstituted with S02NH2 or R4; in Ar, Ar 'independently represent phenyl, naphthyl or biphenyl monosubstituted with S02NH2 or R4; in Id Ar, Ar 'independently represent phenyl, naphthyl or biphenyl monosubstituted with -C0NR2, S02NH2 or R4; in the RJ represents H, R, Hal, COOH or COOA; in If R * represents S02NH2 or -C (= NH) -NH2 or in R 1 represents alkyl of 1 to 6 straight or branched chain C atoms or cycloalkyl of 3 to 6 C atoms; R1 represents Ar, R2 represents Ar ', R3 represents H, R, Hal, COOH or COOA, Ar, Ar' independently represent phenyl, naphthyl or biphenyl monosubstituted with -CONR2, S02NH2 or R4, represents -C (= NH) -NH2 or A represents alkyl of 1 to 4 C atoms, Hal represents F, Cl, Br or I, m is 1 or 2, n is 0 or 1; R represents H, alkyl of 1 to 6 straight or branched chain C atoms or cycloalkyl of 3 to 6 C atoms; R1 represents Ar, R * represents Ar ', RJ represents H, R, Hal, COOH or COOA, Ar, Ar' independently represent phenyl, naphthyl or biphenyl monosubstituted with S02NH2 or R4, R * represents -C (= NH) -NH2 or A represents alkyl of 1 to 4 C atoms, Hal represents F, Cl, Br, or I, m is 1 or 2, n is 0 or 1; represents H, alkyl of 1 to 6 straight or branched chain C atoms or cycloalkyl of 3 to 6 C atoms; R1 represents Ar, R2 represents Ar ', R3 represents H, R, Hal, COOH or COOA, Ar, Ar' independently represent phenyl, naphthyl or biphenyl monosubstituted with S02NHR or R4, or isoquinolinyl substituted with NH2, R * represents -C ( = NH) -NH2 unsubstituted or substituted with OH or A represents alkyl of 1 to 4 C atoms, Hal represents F, Cl, Br or I, m is 1 or 2, n is 0 or 1.

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-eyl, "Methoden der organischen Chemie "(Methods of Organic Chemistry), Georg-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 that are not detailed in this text. If desired, the starting materials can also be prepared in situ, but in such a way that instead of isolating them from the reaction mixture they are immediately reacted, then to form the compounds of formula I. The compounds of formula I can be preferably released from one of their 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 instead of one or more free amino groups and / or free hydroxyl groups they contain amino and / or hydroxyl groups correspondingly protected, preferably those which instead of an H atom attached to an N atom contain an amino protecting group, in particular those which instead of an NH group carry a group of R'-N, where R1 is an amino protecting group, and / or those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protecting group, for example, those which correspond to formula I, but instead of a group of -COOH carry a group of -C00R ", where R" is a hydroxyl protecting group. Oxadiazole derivatives which can be transformed into the corresponding amidino compounds are also preferred among the starting materials. The release of an amidino group from its oxadiazole derivative can be carried out, for example, by treatment with hydrogen in the presence of a catalyst (for example, Raney nickel). As the solvent, those indicated below are suitable, in particular alcohols such as methanol or ethanol, organic acids such as acetic or propionic acid or mixtures thereof. In general, the hydrogenolysis is carried out at temperatures between approximately 0 and 100 ° and pressures between approximately 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar. 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, dialkyl carbonate, chloroformic acid ester, N, N'-carbonyldiimidazole or acetic anhydride. 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 widely known and refers to groups that are suitable to protect (block) an amino group from chemical reactions, but which can easily be cleaved after the chemical reaction has been carried out desired elsewhere 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 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 oxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tertiary butyloxycarbonyl (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 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), hydrocarbons can be preferably used. halogenated 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 about 0 and about 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 comprised 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. 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. 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, trifluoromethylbenzene, 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 bu-tanone, 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. The biphenyl-S02NH2 group is preferably introduced in the form of its terbutyl derivative. The cleavage of the terbutyl group is carried out, for example, with TFA and with or without the addition of an inert solvent, preferably by adding a small amount of anisole (1% by volume). The transformation of a cyano group into an amidino group is carried out, for example, by reaction with hydroxylamine and 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 (for example, Ar = phenyl monosubstituted with -C (= NH) -NH2), ammonia can also be added to a nitrile. 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 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. The introduction of the residue R1 (when n = 0) or R2 to the system of the dihydro-imidazo [4, 5-c] -pyridin-4-one is carried out by N-arylation (Lit: Chan et al., Tetrahedron Letters 1998, 39, pp. 2933 and subsequent and 2941 et seq.). For example, in order to prepare compounds of formula (IA), a compound of formula II can be reacted wherein R has the meaning indicated in claim 1 and R1 and R3 individually represent a non-alkylatable moiety such as, for example, for R1 a phenyl, benzyl or naphthyl moiety substituted with a group with a compound of formula III Thus, compounds of formula IV are obtained These compounds are then reacted to obtain the compounds of the invention. Suitable solvents are those mentioned above. The reaction is carried out in the presence of, for example, Cu (II) (0Ac) 2. The reaction times are comprised, depending on the conditions employed, between a few minutes and 14 days, and the reaction temperatures range from about 0 ° to 150 °, usually between 15 ° and 80 °.

Analogously, it is also possible to first introduce a radical R2 in the system of dihydro-imidazo [4, 5-c] -pyridin-4-one and then react a compound of formula V wherein R has the meaning indicated in claim 1 and R2 and R3 individually represent a non-alkylatable moiety, with a compound of formula VI R1- (CH2) n-L VI. In the compounds of formula VI n is 1, R 1 represents a non-alkylating residue such as, for example, a phenyl residue substituted with a group of 5-methyl- [1, 2, 4] oxadiazol-3-yl and L represents Cl, Br, I or a free OH group or functionally transformed into a reactive group. L preferably represents Cl, Br, I or a group OH functionally transformed into a reactive group such as, for example, an activated ester, an imidazolide or an alkylsulfonyloxy group of 1 to 6 carbon atoms (preferably a methylsulfonyloxy group) or an alkylsulfonyloxy group of 6 to 10 carbon atoms. (preferably a phenyl-sulfonyloxy or p-tolylsulfonyloxy group). With this process, compounds of formula (IA) and / or (IB) are obtained. When compounds of formula II are reacted, wherein n is 0, with compounds of formula VII compounds of formula VIII are obtained By subsequent reaction of the compounds of formula VIII with compounds of formula IX -20 compounds of formula X are obtained The compounds of formula I are then obtained by cleavage of the terbutyl group and by transformation of the oxadiazole moiety to an amidino group. It is also possible to convert a compound of formula I into another compound of formula I by transforming one or more radicals R, R1, R2 and / or R3 into one or more different radicals R, R1, R2 and / or R3, for example by acylating a amino group or by 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 and working at temperatures between 0 ° and 100 ° C. 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 °. 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 monobasic or polybasic aliphatic carboxylic, sulfonic or sulfuric acids, alicyclic, araliphatic, aromatic or heterocyclic 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, ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene-sulfonic, naphthalenedisulphonic 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 corresponding metal salts, in particular in their alkali metal or alkaline earth metal salts, or in their respective ammonium salts. Organic bases which are physiologically acceptable such as, for example, ethanolamine can also be used. 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 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 can be obtained 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, amino acids suitably protected in nitrogen (for example, N) are suitable. -benzoylproline or N-benzenesulfonylproline) or the various optically active canphosulphonic acids. It is also convenient to separate the enantiomers by chromatography using an optically active separation agent (for example, dinitrobenzo-ilphenylglycine, cellulose triacetate or other derivatives of carbohydrates 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 object of the invention is also the use of the compounds of formula I and / or their physiologically acceptable salts for preparing pharmaceutical compositions, in particular, by a non-chemical route. To this end, the compounds of formula I 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 compositions containing at least one compound of formula I and / or one of its physiologically acceptable salts.

These compositions 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, for 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 mentioned compositions can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, pH regulating substances, dyes, flavor correction 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 the form of administration, of the The rate of excretion, the combination of medications and 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 "work (or treat) in the usual way" means the following: if necessary, water is added, if necessary it is adjusted, according to the constitution of the final product, to pH values between 2 and 10, extract with ethyl acetate or dichloromethane, separate the phases and dry the organic phase over sodium sulfate, concentrate by evaporation and purify by chromatography 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 (electronic impact ionization) M + FAB (Fast Atom Bombardment) (rapid bombardment of atoms) (M + H) + Example 1 15 A 50.0 g of 3,4-diamino-2 -chloropyridine are added 140 ml of isobutyric acid and 250 ml of fuming hydrochloric acid. The reaction mixture is refluxed for 7 days. It is then poured into ice water, the precipitate formed is separated and the 2-isopropyl-3,5-dihydro-imidazo [4,5-c] -pyridin-4-one ("AB"), m.p. 310-311 ° (decomposition), The 177. -25 A mixture of "AB" and 4-chloro-2-isopropyl-3H-imidazo [4] is found in the mother liquor., 5-c] -pyridine. A solution of 0.877 g of "AB" and 0.691 g of potassium carbonate in 30 ml of DMF is stirred for 30 minutes at room temperature. 1.5 g of 3- (3-bromo-methylphenyl) -5-methyl- [1, 2, 4] oxadiazole are added, the mixture is stirred for 16 hours and the mixture is worked up in the usual manner. After chromatography on silica gel, in addition to the two dialkylation regioisomers, 2-isopropyl -3- [3- (5-methyl- [1, 2, 4] oxa-diazol-3-yl) -benzyl is obtained ] -5H-imidazo [4, 5-c] pyridin-4-one ("CA").

The following is an alternative procedure that also allows obtaining "CA" (analogously to that of Mederski et al in J. Med. Chem., 1994, pp. 1632 et seq.). 3, 4-diamino-2-chloropyridine is reacted with isobutyric anhydride to obtain N- (4-amino-2-chloro-pyridin-3-yl) -isobutyramide. Subsequent reaction with 3- (3-bromomethyl-phenyl) -5-methyl- [1, 2, 4] oxadiazole gives a mixture composed of 4-chloro-2-isopropyl-3- [3 - (5-methyl- [1, 2, 4] oxadia-zol-3-yl) -benzyl] -3H-imidazo [4, 5-c] pyridine and N- (4-amino-2-chloro-pyridin-3-yl) -N - [3- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl)] -isobutyramide. Both compounds are transformed into "CA".

To a solution of 0.4 g of "CA" in 10 ml of DMF is added 0.5 g of the compound of formula III, 258 mg of Cu (II) (OAc) in 50 ml of dichloromethane and 1 g of molecular sieve. (0.4 nm), and stirred at room temperature for 4 days. After separating the molecular sieve and working the reaction mixture in a usual manner, 2-isopropyl-3 - [(5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] -5- is obtained. (3-cyanophenyl) -3,5-dihydro-imidazo [4, 5-c] -pyridin-4-one ("BC1"), 345 mg, mp 168 °, The 450. 330 mg of BC1 are suspended in 20 ml of ethanol and then 490 mg of sodium bicarbonate and 407 mg of hydroxylammonium chloride are added consecutively. Then add 2 ml of water and heat the mixture to reflux for 5 hours. 50 ml of ice water are added, the mixture is worked up in the usual manner and 280 mg of 2-isopropyl-3 - [(5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] - are obtained. 5- (3-N-hydroxy-amidinophenyl) -3,5-dihydro-imidazo [4,5-c] -pyridin-4-one ("BC2"), 483. By analogous reaction of "AB" with 2 -bromomethyl-7-cyano-naphthalene and subsequent purification gives 2-isopropyl-3- (7-cyano-2-naphthylmethyl) -5H-imidazo [4,5-c] -pyridin-4-one. By analogous reaction with the compound of formula III, as described above, 2-isopropyl-3- (7-cyano-naphth-2-ylmethyl) -5- (3-cyanophenyl) -3,5 is obtained dihydroimidazo [4,5-c] pyridin-4-one, El: [M +] 443 (74%), 166 (100%). ao By subsequent reaction with hydroxylammonium chloride, 2-isopropyl-3- (7-N-hydroxyamidino-naphth-2-ylmethyl) -5- (3-N-hydroxyamidinophenyl) -3,5-dihydro-imidazo [4] is obtained. , 5- c] pyridin-4-one, El: [M +] 509 (8%), 166 (100%). , 5 Ei emplo 2 A solution of 0.27 g of "BC2" in 20 ml of methanol is mixed with 1 drop of acetic acid and with 100 mg of Raney-nickel, and hydrogenated for 8 hours at room temperature. -20 The catalyst is removed by filtration, the solvent is removed and the following compound is obtained: 2-isopropyl-3- (3-amidinobenzyl) -5- (3-amidinophenyl) -3,5-dihydro-imidazo [4, 5-c] pyridin-4-one, FAB 428.

The compounds 2-65 of formula IA which are indicated in table 1 are obtained in a manner analogous to that described in examples 1 and / or 2 Table 1 (1) = 3-amidinophenyl; (2) = 2-amidinosulfonyl; (3) = 7-amidino-2-naphthyl-; (6) = 3- [(5-methyl- [1, 2,4] -oxadiazol-3-yl) -phenyl; (7) = 2- (N-tert-butyl-aminosulfonyl) -phenyl; (8) = 3-aminocarbonylphenyl; (9) = 3-cyanophenyl; (10) = 7- [(5-methyl- [1,2,4] -oxadiazol-3-yl) -2-naphthyl; (11) = 4-bromophenyl; (12) = 3- (N-tert-butyl-aminosulfonyl) -phenyl; (13) = 3-amino sulfonylphenyl; (14) = cyclopentylmethyl; (15) = l-amino-isoquinoline-7-yl-; (16) = 3-N-hydroxyamidino-phenyl; Me = methyl; Et = ethyl; i-Pr = isopropyl; Bu = n-butyl; t-Bu = tertbutyl; iso-Bu = isobutyl; Pe = pentyl The following examples refer to pharmaceutical compositions: Example A: vials for injections 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 2N hydrochloric acid, then filtered in sterile conditions, fill 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 mixture composed of 20 g of an active substance of formula I is melted, 100 g of soy lecithin and 1400 g of cocoa butter, then pour the melt into the molds and let it 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 1 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 lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablet form, 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 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 gelatine 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 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 known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. - Compounds of formula I characterized in that: R represents H, alkyl of 1 to 6 carbon atoms and straight or branched chain or cycloalkyl of 3 to 6 carbon atoms, R1 represents Ar, R2 represents Ar ', R3 represents H, R, R4, Hal, CN, COOH, COOA or C0NH2, Ar, Ar 'independently represent phenyl, naphthyl or biphenyl unsubstituted or mono, di or trisubstituted with R, OH, Hal, CN, N02, CF3, NH2, NHR, NR2, pyrrolidin-1- ilo, piperidin-1-yl, benzyloxy, S02NH2, S02NHR, S02NR2, -CONHR, -CONR2, - (CH2) p-NH2, - (CH2) n -NHR, - (CH2) n-NR2, -O- ( CH2) n-NH2, -0- (CH2) p-NHR, -O- (CH2) n-NR2, R4 or substituted together with -O- (CH2) m-0-, or isoquinolinyl substituted with NH2, R * represents -C (= NH) -NH2, -NH-C (= NH) -NH2 or -C (= 0) -N = C (NH2) 2 unsubstituted or monosubstituted with -COR, -COOR, -OH or with a conventional amino protecting group,
1. A represents alkyl of 1 to 4 carbon atoms, Hal represents F, Cl, Br or I, m is 1 or 2, n is 0 or 1, and the salts and solvates of these compounds.
2. 2. - Compounds according to claim 1 a) 2-isopropyl-3- (3-amidinobenzyl) -5- (3-amidinophenyl) -3,5-dihydro-imidazo [4, 5-c] -pyridin-4-one; and the salts and solvates of these compounds.
3. 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 or solvolysis an amidino group of its oxadiazole derivative or its oxazolidinone derivative, ii) replacing a conventional amino protecting group with hydrogen by treating it with a solvolysis or hydrogenolysis agent or releasing an amino group that is protected with a group conventional protector, or b) because in a compound of formula I one or more radicals R, R1, R2 and / or R3 are transformed into one or more different radicals R, 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, vi) transforming a cyano group into an amidino group, and / or transforming a base or an acid from Formula I in one of its salts.
4. 4. - Process for preparing pharmaceutical compositions, 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 vehicle or solid, liquid or semi-liquid excipient.
5. 5. - Pharmaceutical composition, 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. 6. - Compounds of formula I, according to claim 1, and their physiologically acceptable salts or their solvates as active substances of drugs.
7. 7. - Compounds of formula I, according to claim 1, and their physiologically acceptable salts, to combat thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication.
8. 8. Medicaments of formula I, according to claim 1, and their physiologically acceptable salts, as inhibitors of the coagulation factor Xa.
9. 9. Use of the compounds of formula 1, according to claim 1, and / or their physiologically acceptable salts for preparing a medicament.
10. 10. Use of the compounds of formula 1, according to claim 1, and / or of their physiologically acceptable salts, to combat thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina chest, restenosis after angioplasty and intermittent claudication.