SK9442001A3 - Imidazo[4,5-c]-pyridine-4-on-derivatives, process for the preparation thereof, use thereof and pharmaceutical composition comprising same - Google Patents

Abstract

The invention relates to novel compounds of formula (I) wherein R, R<1>, R<2>, R<3> 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

Technical field

The invention relates to compounds of the general formula I wherein

R a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, R ¹ Ar group R ² Ar ', R ³ hydrogen, R, R ⁴ , Hal, CN, COOH, COOA or conh ₂ ,

Ar, Ar ^z each, independently of one another phenyl, naphthyl, or biphenyl, or one, of the type which are independently unsubstituted, or two to three substituents, the group R, OH, Hal, CN,

NO ₂ , CF ₃ , NH ₂ , NHR, NR ₂ , pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO ₂ NH ₂ , SO ₂ NHR,

SO ₂ NR ₂ , -CONHR, -CONR ₂ , - (CH ₂ ) _n "NH ₂ - (CH ₂ ) _n - NHR, - (CH ₂ ) _n -NR ₂ , -O- (CH ₂ ) _n " NH ₂ , -O- (CH ₂ ) _n -NHR, -O- (CH ₂ ) _n -NR ₂ and R ^4, or together -O- (CH ₂ ) _Π -Ο-, or an isoquinolinyl group substituted with NH ₂ ,

R ^{4 is} -C (= NH) -NH ₂ , which is unsubstituted or in-substituted by -COR, -COOR, -OH, or by conventional amino protecting groups or is -NH-C (= N) -NH ₂ , -C ( = O) -N = C (NH ₂ ) ₂ ,

O-NH p O or N = N, N CH ₃ A (C 1 -C 4) alkyl group; Hal a fluorine, chlorine, bromine or iodine atom, m 1 or 2 a n 0, 1, 2 or 3

and salts and solvates thereof.

The invention also relates to optically active forms, racemates of diastereomers as well as hydrates and solvates, for example alcoholates of these compounds.

TJl'óhôu-you-náXe.zu_je finding novel compounds having hair otnými Hodja + t p where no ____ £ i_ desirably be - more particularly, L ''^'==: ^ naIIZvýrobu pharmaceutical ppostriedkov.

BACKGROUND OF THE INVENTION

Aromatic amidine derivatives having antithrombotic activity are known, for example, from European Patent Specification No. 0 540051 B1. Cyclic guanidines for the treatment of thromboembolic diseases are described, for example, in WO 97/08165. Aromatic heterocyclic compounds effective for inhibiting factor Xa are known, for example, from WO 96/10022. Substituted N [(aminoiminomethyl) phenylalkyljazaheterocyclylamides as Factor Xa inhibitors are disclosed in WO 96/40679.

The antithrombotic and anticoagulant activity of the compounds of the invention is attributed to their inhibitory action against the activated clotting protease known as factor Xa, or to the inhibition of other activated serine proteases such as factor VIIa, factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin cleaves fibrinogen into fibrin monomers which, once crosslinked, contribute to thrombus formation. Thrombin activation may lead to thromboembolic diseases. However, inhibition of thrombin may inhibit the formation of fibrin involved in thrombus formation. Inhibition of thrombin can be measured, for example, by the method of G. F. Cousins et al. (Circulation 94: 1705-1712, 1996).

Thus, inhibition of factor Xa can prevent the formation of thrombin. The compounds of the formula I according to the invention and their salts are involved in the blood coagulation process by inhibiting factor Xa and can therefore prevent thrombus formation.

The inhibition of factor Xa by the compounds of the invention and the measurement of the antithrombotic and anticoagulant activity of the compounds of the invention in vitro and in vivo are possible as described by J. Hauptmann et al. (Thrombosis and Haemostasis 63: 220-223, 1990).

For example, T. Hara et al. (Thrombosis and Haemostasis 71: 314-319, 1994).

The clotting factor VIIa, upon binding to the tissue factor, initiates its own acting fraction of the blood clotting cascade and contributes to the activation of factor X to factor Xa. Inhibition of factor VIIa prevents this

The formation of factor Xa and consequently the formation of thrombin.

í i

Inhibition of Factor VIIa by the Compounds of the Invention and Measurement

I; anticoagulant and antithrombotic effects are possible by conventional in vitro and in vivo methods. A conventional method for measuring factor VIIa inhibition is described, for example, by H. F. Ronning et al. (Thrombosis Research 84: 73-81, 1996).

The clotting factor IXa is generated in the intrinsic clotting cascade and is also involved in the activation of factor X to factor Xa. Therefore, inhibition of factor IXa can be prevented in another way by producing factor Xa.

Inhibition of factor IXa by the compounds of the invention and measurement

X anticoagulant and antithrombotic effects are possible by conventional in vitro and in vivo methods. A suitable measurement method is described, for example, by J. Chang et al. (Journal of Biological Chemistry 273, pp. 12089-12094, 1998).

SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds having valuable properties, particularly suitable for the manufacture of pharmaceutical compositions.

SUMMARY OF THE INVENTION

The present invention provides the compounds of formula I as defined above and their salts.

It has surprisingly been found that the compounds of the formula I and their salts have very valuable pharmacological properties when well tolerated. In particular, they exhibit Factor Xa inhibitory properties and may therefore be used to treat and prevent thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angioplasty restenosis and gastric pain in walking.

The compounds of the formula I according to the invention can also be used as inhibitors of blood coagulation factors VIIa, IXa and thrombin in a blood coagulation cascade.

The compounds of the formula I according to the invention can be used as therapeutic agents in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and pain. in the calf muscles while walking.

The process for the preparation of the compounds of the formula I, in which the individual symbols are as defined above, and their salts according to the invention, consists in

(a) released from their functional derivatives by treatment with a solvolysing or hydrogenolysing agent,

(i) the amidino group is liberated from its oxadiazole derivative or oxazolidine derivative by hydrogenolysis or solvolysis; one or more R, R ¹ , R ² or R ³ groups are converted to one or more other R, R ¹ , R ² or R ³ groups by hydrolyzing the i / ester group to a carboxyl group, ii) the nitro group is reduced, iii) the amino group is acylated, iv) the cyano group is converted to the amidino group and / or c) the base or acid of formula I is converted to its salt.

The individual symbols, which appear repeatedly in the general formula, have the meanings indicated.

All symbols and optional indices R, R ¹ , R ² , R ³ and n are as defined in formula I unless otherwise stated.

The symbol R represents an alkyl group having a straight or branched chain of 1 to 6 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. Preferably R is methyl, further ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 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. The symbol R is also a cycloalkyl r t < _c > t < _c > CCf group and preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

A is alkyl having 1, 2, 3 or 4 carbon atoms, and preferably A is methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

Hal is preferably fluorine, chlorine or bromine, but also iodine.

Ar and Ar * are phenyl, benzodoxix-5-yl, naphthyl or biphenyl, which are each independently unsubstituted or have one, two or three substituents from the group consisting of R, OH, OR, Hal, CN, NO ₂ , CF ₃ , NH ₂ , NHR, NR ₂ , pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO ₂ NH ₂ , SO ₂ NHR, SO ₂ NR ₂ , phenylsulfonamido, - (CH ₂ ) _n -NH ₂ , - (CH ₂ ) _n -NHR, (CH ₂ ) _n -NR ₂ , -O- (CH ₂ ) _n -NH ₂ , -O- (CH ₂ ) _n -NR ₂ -O- (CH _{2) n} - NR _2, -0- _{(CH2) In} -0- and R ^4, the group is preferably naphthyl or biphenyl, which is mono-substituted amidino group, preferred substituents of the biphenyl are amidino, fluorine, SO ₂ NH ₂ or SO ₂ NHR.

Ar and Ar 'are phenyl, naphthyl or biphenyl, which are independent of unsubstituted, or phenyl, biphenyl, preferably having one, preferably naphthyl or two or three substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butyloxy, pentyloxy, hexyloxy, cyano, methoxy, nitro, amino, amino, amino, 1-yl, piperidin-1-yl, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, methylmethylaminomethyl, N-methylmethylaminomethyl, N-methylmethylaminomethyl, N-methylmethylaminomethyl, N-methylmethyl ,, Ν, dim-dimethylaminomethyl, aminomethyloxy, aminoethyloxy, and R ^4, and benzodioxolyl.

Thus, Ar and Ar 'in each case are independently and particularly preferably, for example, o-, m- or ptolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m-, or p- isopropylphenyl, o-, male 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 o-, m- or pN- (methylaminocarbonyl) -phenyl, o-, male- 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-, male- or p- (methylsulfonamido) phenyl, o-, m- or β-aminophenyl, 7-amidino-2-naphthyl, 2'-amidinobiphenyl-3-yl, 3-fluoro- ^27- sulfamoylbiphenyl-4 -yl, 3-fl fluoro-2'-N-tert-butylsulfamoylbiphenyl-4-yl, 2 * -sulfamoylbifenyl-4-yl, ^2? -N-tert-butylsulfamoylbiphenyl-4-yl, o-, m- or p- (pyrrolidin-1-yl) phenyl, o-, m- or p- (piperidin-1-yl) phenyl, o-, m - or .beta.-S-methyl-1,2,

4-oxadiazol-3-yl-phenyl, 7- (5-methyl-1,2,4-oxodiazole)

-3-yl) naphth-2-yl, ο-, m- or p- (5-oxo 1,2,4-oxadiazol-3-yl) phenyl, 7- (5-oxo [1,2,4] oxadiazol-3) -yl-naphth-2-yl and also 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-, 2- , 5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chlorophenyl, 2-amino-3-chlorophenyl, 2-amino-4-chlorophenyl, 2- amino-5-chlorophenyl or 2-amino-6-chlorophenyl, 2-nitro-4-Ν, N-dimethylaminophenyl or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4 -, 2,3, 5-,

2,3,6 or 3,4,5-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.

symbol R ³ is preferably, for example, H, Hal, COOH, COOA or CONH ₂ . symbol R ⁴ is preferably unsubstituted, for example

-C (= NH) -NH ₂ , -NH-C (= NH) -NH ₂ , -C (= O) -N = C- (NH ₂ ) ₂ , optionally monosubstituted with a hydroxyl group or a group of formula

particularly preferably unsubstituted or hydroxyl-substituted -C (= NH) -NH 2 or a group of formula

M is preferably 1 or 2.

The index n is preferably 0 or 1.

can be

(IB)

Compounds of formula (I) may have several chiral centers and may be in stereoisomeric forms.

I may have one or be therefore in different The invention includes all these forms.

The invention thus relates in particular to compounds of the formula I in which at least one of the symbols has the meaning given above. Some preferred groups of compounds of general interest

of formula (I) are the following compounds of formulas (Ia) to (Ii), wherein not particularly indicated are as defined in formula (I), wherein in formula (Ia) Ar is phenyl, naphthyl or biphenyl which are monosubstituted with R ⁴ , 1b) Ar * phenyl, naphthyl or biphenyl which are monosubstituted with SO ₂ NH ₂ or R ⁴ , 1c) Ar and Ar are phenyl, naphthyl or biphenyl which are independently monosubstituted with SO ₂ NH ₂ or R ⁴ , 1d) Ar and Ar 'is phenyl, naphthyl or biphenyl, each of which is independently mono-substituted by CONR _2, SO ₂ NH ₂ or R ^4, le) ^R3 is H, group R, Hal, COOH or COOA, If) R ⁴ SO ₂ NH ₂ or -C (= NH) -NH ₂ or

M CH ₃ g) R a linear or branched alkyl group having 1 to 6 carbon atoms or cycloalkyl

group with 3 to 6 carbon atoms, R ¹ group Ar, R ² group Ar, R ³ H, group R, Hal, COOH or COOA

Ar Ar'skupinu a phenyl, naphthyl or biphenyl, each of which is independently mono-substituted by -CONR 2, ^S0 2 ^NH 2 ^{and e} ^ ^{-'-) m.p.}

R ^{4 is} -C (= NH) -NH 2 or

ch ₃

A (C1-C4) alkyl,

Hal is fluorine, chlorine, bromine or iodine, m 1 or 2,

n 0 or 1 Ih) R H, straight or branched chain alkyl C 1 -C 6 (C 3 -C 6) -alkyl; R ¹ Ar group R ² Group ¹ kr. R ³ H, R, Hal, COOH or COOA Ar and Ar 'is phenyl, naphthyl or biphenyl, which are independently monosubstituted with SO ₂ NH ₂ or R ⁴ , R ⁴ -C (= NH) -NH 2;

ch ₃

A (C1-C4) alkyl,

Hal is fluorine, chlorine, bromine or iodine, m 1 or 2, n 0 or 1,

Ii) R is H, straight or branched (C 1 -C 6) alkyl or (C 3 -C 6) cycloalkyl,

R ¹ is Ar,

R ² is Ar,

R ³ is H, group R, Hal, COOH or COOA,

Ar and Ar 1 are phenyl, naphthyl or biphenyl, which are independently monosubstituted with SO ₂ NHR or R ⁴ , or an isoquinolinyl group substituted with NH ₂ ,

R ⁴ unsubstituted or hydroxyl substituted by -C (= NH) -NH ₂ or

CH ₃

A (C1-C4) alkyl,

Hal is fluorine, chlorine, bromine or iodine, m 1 or 2, n 0 or 1.

The compounds of formula (I) and the starting materials for their preparation are prepared by known methods described in the literature (for example, in standard publications such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme Verlag, Stuttgart), and this is done under reaction conditions which are known and suitable for the above reactions. It is also possible to use known variants not described here in greater detail.

The starting materials may optionally be formed in situ, i.e. they are not isolated from the reaction mixture, but are immediately used to prepare the compounds of formula I.

The compounds of formula (I) may be prepared by liberating from their functional derivatives by solvolysis, in particular by solvolysis or hydrogenolysis agents.

The starting materials of the hydrogenolysis are the compounds of the general formula for solvolysis, optionally for which they otherwise correspond to the above I, but instead have free amino or hydroxyl groups corresponding to protected amino or hydroxy groups, preferably compounds which have a group instead of a hydrogen atom. amino protecting group, especially compounds having an R group ^from -X in place of the HN group, wherein r 'is an amino protecting group and / or compounds which have a hydroxyl protecting group instead of a hydrogen atom in a hydroxyl group, for example compounds which instead of -COOH they have a -COOR group, wherein R is a hydroxyl protecting group.

Preferred starting materials are also the oxadiazole derivatives which are used in the synthesis. can be converted to the corresponding amidino compounds.

The amidino group liberation from the oxadiazole derivative can be effected, for example, by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel). Suitable solvents for this reaction are set forth below, with alcohols such as methanol or ethanol, organic acids such as acetic or propionic acid or mixtures thereof being particularly suitable as solvents. Hydrogenolysis is generally carried out

C '·' f. * T - r '(· r is carried out at a temperature of 0 to 100 ° C at a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30 ^° C (at room temperature) and at a pressure of 0.1 up to 1 MPa.

The oxadiazole group is introduced, for example, by reacting the cyano compound with hydroxylamine and reacting with phosgene, dialkyl carbonate, chloroformic acid ester, N, N'-carbonyldiimidazole or acetic anhydride.

There may be several identical or different amino protecting groups and / or hydroxyl groups in the molecule of the starting material. If the protecting groups are different from each other, they can in many cases be selectively cleaved.

The term amino protecting group is well known and refers to groups which are suitable for protecting (blocking) the amino group from chemical reactions but which are readily removable when the desired reaction is carried out elsewhere in the molecule. Typically such groups are especially unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are not critical. However, groups having 1 to 20, and especially 1 to 8, carbon atoms are preferred. The term acyl group is always understood here in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, but in particular alkoxycarbonyl, aryloxycarbonyl and in particular aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butyryl, aralkanoyl, such as phenylacetyl, aroyl such as benzoyl or toluyl, aryloxyalkanoyl, such as phenoxyacetyl (POA), alkoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, , 2-trichloroethoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl, aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorophenylmethoxycarbonyl, (FMOC) group and a. Preferred amino protecting groups are BOC and Mtr, CBZ, Fmoc, benzyl and acetyl.

Depending on the protecting group used, the release of the compounds of the formula I takes place, for example, with strong acids, preferably trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acid. acids such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are, for example, organic carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as methylene chloride, and also alcohols such as methanol, ethanol or isopropanol. as well as water. Mixtures of these solvents may also be suitable. Trifluoroacetic acid is preferably used in excess without addition of other solvents, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The cleavage reaction temperature is suitably about 0 to about 50 ^° C, preferably 15 to 30 ° C (room temperature).

For example, the BOC, OBut, and Mtr groups may be conveniently cleaved with trifluoroacetic acid in methylene chloride or about 3-5% hydrochloric acid in dioxane at 15 to 30 ° C, FMOC with a 5 to 50% solution of dimethylamine, diethylamine or piperidine in dimethylformamide at 15 to 30 ° C. 30 ° C.

The cleavage of the hydrogenolytically removable protecting group (e.g. CBZ or benzyl group), or the liberation of the amidino group from their oxadiazole derivatives may be effected, for example, by treatment with hydrogen in the presence of a catalyst (e.g. noble metal catalyst such as palladium, suitably on a support such as coal). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol, or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group, for example, performs well on 5-10% palladium on carbon in methanol or on ammonium formate (instead of hydrogen) in the presence of palladium on carbon in a methanol / dimethylformamide system at 20-30 ° C.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene, chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, trifluoromethylbenzene, chloroform or methylene chloride, alcohols such as methanol, ethanol, isopropanol, n-propanol, n-propanol butanol or tert-butanol, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane, glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene 17 glycol dimethyl ether (diglyme), ketones such as acetone or acetone; , N-methylpyrrolidone (NNP), dimethylformamide (DMF), nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide (DMSO), carbon disulphide, organic carboxylic acids such as formic or acetic acid, nitro compounds such as nitromethane or nitrobenzene, esters such as ethyl acetate, or mixtures of these solvents.

The biphenyl -SO ₂ NH ₂ group is preferably used in the form of its tert-butyl derivatives. The tert-butyl group is removed, for example, using trifluoroacetic acid without or with the addition of an inert solvent, preferably with the addition of a small amount of anisole (1% v / v).

Conversion of the cyano group to the amidino group is accomplished by reaction with, for example, hydroxylamine and subsequent reduction of N-hydroxyamidine with hydrogen in the presence of a catalyst, such as palladium on carbon.

To prepare an amidine of the formula I (R naprikld Ar is phenyl which is monosubstituted by C (-NH) _-NH2), it is also possible addition of ammonia to the nitrile. The addition reaction is preferably carried out in several stages in a known manner: a) the nitrile is converted to thioamide with hydrogen sulfide, the thioamide is converted with an alkylating agent, for example methyl iodide, to the corresponding S-alkylimidothioester, which is reacted with ammonia to give amidine; , for example with ethanol, in the presence of hydrogen chloride to the corresponding imidoester, which is treated with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and hydrolyzing the product obtained.

The group R ¹ (if n is zero) or R ² is introduced into the dihydroimidazole-4,5-pyridin-4-system by known methods of N-arylation (Chan et al., Tetrahedron Letteres 39, from pp. 2933 and 2941, 1998) ).

Thus, for example, a compound of formula II is reacted to prepare formula IA

- R ³

H N (II) _{(CH2) n-R} <

wherein R is as defined above and R ¹ and R ³ are each non-alkylable, for example R ¹ is phenyl, benzyl or naphthyl substituted by ^C ₃ H with a compound of formula III (iii)

In this way, compounds of formula IV are obtained

R ³ which are then reacted: for obtaining the compounds of the present invention.

The above solvents are used. The reaction is carried out in the presence of, for example, copper (II) acetate. The reaction time is, depending on the reaction conditions, a few minutes to 14 days and the reaction temperature is 0 to 150 ° C, generally 15 to 80 ° C.

Similarly, the R ² group may also be first introduced into the dihydroimidazole-4,5-pyridopyridine-4-system followed by reaction of the compound of formula V

(V) p 3 wherein R is as defined above and R and R are each non-alkylable, with a compound of formula VI

R ¹ - (CH ₂ ) _n -L (VI) wherein n is 1

An R ¹ group that cannot be alkylated, for example, a phenyl substituted group with 5-methyl-1,2,4-oxadiazol-3-yl, and

L is a chlorine, bromine or iodine atom or a free or reactively functionally modified hydroxyl group.

L is preferably chlorine, bromine, iodine or ηϊηύ or a reactively functionally modified hydroxyl group, for example, an ester, imidazolide or alkylsulfonyloxy group (preferably methylsulfonyloxy) or arylsulfonyloxy group of 6 to 10 carbon atoms (preferably 6 to 10 carbon atoms) tolylsulfonyloxy).

In this way, compounds of the general formula are obtained

IA or IB.

By reaction of the compounds of of formula II wherein n is n zero, with compounds of of formula VII ΓΤ .b (oh, ₂ br ^ at (VII) to give compounds of of formula VIII

Subsequent reaction of compounds of formula VIII with compounds of formula IX

Χ ^ / Β (° Η) ₁ (IX)

SO.NHtBu

are obtained compound of of formula X R ³ N ΓΥΎ --R N \ (X) ⁰ R ¹ ^ SO ₂ NHtBu compounds of formula I are then obtained cleavage a tert-butyl group and reaction oxadiazole rest on amidine group.

Further, it is possible to convert a compound of formula I to another compound of formula I by converting one or more R, R, R or R groups to another R, R ¹ , R ² or R ^{3 group,} for example by acylating an amino group or reducing nitro groups to amino groups (for example, by hydrogenation in the presence of Raney nickel or palladium on carbon in an inert solvent such as methanol or ethanol).

Esters may be saponified, for example, with acetic acid or sodium or potassium hydroxide in water or in a mixture of water and tetrahydrofuran and aleno-points and dioxane at a temperature of 0 to 100 ° C.

The free amino groups may further be acylated in a known manner with acid chlorides or anhydrides, or may be alkylated with an unsubstituted or substituted alkyl halide suitably in an inert solvent such as methylene chloride, tetrahydrofuran and / or in the presence of a base such as triethylamine or pyridine at -60 to + 30 ° C.

The base of formula (I) may be converted into an appropriate acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and subsequently evaporating the solvent. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids may be used, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monohydric or sulfonic or sulfuric acids , pival, fumaric, gluconic, methanesulfonic, 2-hydroxyethanesulfonic, naphthalene-monosulfonic acetic, propionic, succinic, pimelic, malic, citric, isonicotinic, ethanedisulfonic, p-toluenesulfonic, phonic and laurylsulfonic acid. Non-fatty acid carboxylic salts such as formic, diethylacetic, malonic, maleic, lactic, tartaric, ascorbic nicotinic, ethanesulfonic, benzenesulfonic, and naphthalenedisuls physiologically unacceptable acids, e.g. picrates, can be used to isolate or purify the compounds of Formula I.

On the other hand, the compounds of the formula I can be converted into the corresponding metal salts by reaction with a base (for example sodium or potassium hydroxide or carbonate), in particular alkali metal or alkaline earth metal salts or the corresponding ammonium salts. Physiologically acceptable organic bases such as ethanolamine can also be used.

Since the compounds of formula (I) may be chiral for their molecular structure, they may be in different enantiomeric forms. They may be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers of the compounds of the invention may vary, the use of enantiomers may be required. In such cases, the gluten product or the intermediate may be separated into enantiomeric compounds by chemical or physical methods known to the art, or the enantiomeric compounds may only be used for synthesis.

racemic amines, diastereomers may be mixed from the mixture by reaction with an optically active resolving agent. Examples of such resolving agents include the R and S forms of tartaric acid, mandelic acid, nitrogen atom.

The N-benzoylproline of various optics is chromatographic

In the case of preparing with an agent, optically active acids such as diacetyltartaric, dibenzoyltartaric or lactic, suitably for amino acids (e.g.

N-benzenesulfonylproline) or camphorsulfonic acids. Preferred apple protected or active resolution of enantiomers by optically active resolving agents (such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers fixed on silica gel). Suitable mobile phases are aqueous or alcoholic solvent mixtures, for example hexane / isopropanol / acetonitrile, for example in a 82: 15: 3 by volume ratio.

The compounds of formula I and their physiologically acceptable salts can be used for the manufacture of pharmaceutical compositions, in particular by a non-chemical route. Therefore, they can be converted into a suitable dosage form with at least one solid or liquid or semi-liquid carrier or excipient and optionally in admixture with one or more other active ingredients.

The invention therefore also relates to compositions, in particular pharmaceutical compositions, comprising at least one compound of the formula I or a physiologically acceptable salt thereof.

The compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration or for administration in the form of inhalation sprays and which do not react with compounds of the formula I, such as water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are suitable for oral use; ointments, creams or powders. The compounds of the invention may also be lyophilized and the resulting lyophilizates used, for example, for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more other active ingredients. such as vitamins.

The compounds of formula I and their physiologically acceptable salts can be used for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angioplasty restenosis and gastric walking pain.

The compounds of the formula I according to the invention are generally employed in doses of approximately 1 to 500 mg, in particular 5 to 100 mg per dosage unit. The daily dose is preferably about 0.02 to 10 mg / kg body weight. The dose for each individual depends on a variety of factors, such as the efficacy of the particular compound employed, age, body weight, general health, sex, diet, time and route of administration, elimination rate, combination of drugs and severity of the particular compound. disease. Oral administration is preferred.

The invention is illustrated by, but not limited to, the following examples. Temperatures are always given in degrees Celsius. The expression processing in the usual manner in the following examples of practical implementation means:

Optionally, water is added or, depending on the constitution of the final product, the pH is adjusted. The Rf values are at 2 to 10, the methylene chlorophases are sulfate on silica gel on silica gel, the mobile phase is an ethyl acetate / methanol system in a 9: 1 by volume ratio. Mass spectrometry (MS): EI (electron impact ionization) M ⁺

FAB (fast atom bombardment (M + H) ⁺ )

DETAILED DESCRIPTION OF THE INVENTION

Example 1

140 ml of isobutyric acid are added to 250 ml of fuming hydrochloric acid and 50.0 g of 3,4-diamino-2-chloropyridine are added. The reaction mixture was heated at reflux for 7 days. Pour into ice-water, the precipitate formed is collected to give 2-isopropyl-3,5-dihydroimidazof-4,5-cyclopyridin-4-one (AB), m.p. 310-311 ^° C (dec.). EI 177.

ABOUT

The mother liquor contains a mixture of AB and 4-chloro-2-isopropyl-3H-imidazo 4,5-clpyridine. A solution of 0.877 g AB and 0.691 g potassium carbonate in 30 ml dimethylformamide was stirred at room temperature for 30 minutes. 1.5 g of 3- (3-bromomethylphenyl) -5-methyl-1,2,4J oxadiazole are added and the mixture is stirred for 16 hours, then worked up in a manner known per se. Chromatography on silica gel affords 2-isopropyl-3- 3- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl-5H-imidazo-4,5-clpyridin-4-one (both regioisomeric dialkylation products) ( CA).

Yet another method leads to CA (similar to Mederski et al., J. Med. Chem., Since 1632, 1994): reaction of 3,4-diamino-2-chloropyridine with isobutyric anhydride gives N- ( 4-amino 2-chloropyridine-3-yl) -isobutyramide. Subsequent reaction with 3- (3-bromomethylphenyl) -5-methyl [1,2,4] oxadiazole results in a mixture of 4-chloro-2-isopropyl-3C- (5-methyl-1,2,4) oxadiazol-3-yl benzyl] -3H-imidazo-4,5-cis-pyridine and N- (4-amino-2-chloropyridin-3-yl) -N- 3- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl) isobutyramide. Both compounds react to obtain CA.

To a solution of 0.4 g of CA in 10 ml of dimethylformamide was added 0.5 g of the compound of formula III, 258 mg of copper acetate in 50 ml of dichloromethane, 1 g of molecular sieve (0.4 nm) was added and stirred for four days at room temperature.

After removal of the molecular sieves, 2-isopropyl-3 - [(5-methyl [1,2,4-oxadiazol-3-yl) benzyl] -5- (3-cyanophenyl) -3,5-dihydroimidazo [4,5] is obtained by conventional work-up. -pyridin-4-one (BC1) 345 mg, mp 168 ° C. EI 450.

330 mg of BC1 is suspended in 20 ml of ethanol and 490 mg of sodium bicarbonate and 407 mg of hydroxylamine chloride are immediately added. After a further addition of 2 ml of water, the mixture was refluxed for 5 hours. 50 ml of ice-water was added and worked up in the usual manner to give 280 mg of 2-12-propyl-3- (5-methyl-1,2,4-oxadiazol-3-yl) benzyl] -5- (3- N-hydroxyamidinophenyl) -3,5-dihydroimidazo [4,5,5-c] pyridin-4-one (BC2). EI 483.

Similarly, it is obtained by reacting AB and 2-bromomethyl-7-cyanophthalene followed by purification of 2-isopropyl-3- (7-cyanophth-2-ylmethyl) -5H-imidazole / 4,5-c] pyridin-4.one. A similar reaction with the compound of formula III as described above gives 2-isopropyl-3- (7-cyanophth-2-ylmethyl) -5- (3-cyanophenyl) 3,5-dihydroimidazo [4,5-c] pyridine- 4-one. EI / M ⁺ / 443 (74%)

166 (100%).

Subsequent reaction with hydroxylammonium chloride yields

2-Isopropyl-3- (7-N-hydroxyamidinonaft-2-ylmethyl) -5- (3-N-hydroxyamidinophenyl) -3,5-dihydro-imidazo 4,5-£ c3Jpyridin-4.One. EI / M &lt; ^{+ &gt;} / 509 (8%), 166 (100%).

Example 2

To a solution of 0.27 g of BC2 in 20 mL of methanol was added 100 mg of Raney nickel and one drop of acetic acid and hydrogenated for eight hours at room temperature. The catalyst was filtered off, the solvent was removed to give 2-isopropyl-3- (3-amidinobenzyl) -5- (3-amidinophenyl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one. FAB 428.

Like the. according to Example 1 of compound 2 to 65 of formula IA (m.p. in steps C in column I of the table).

and / or 2 are given in Table I of the compound, temperature

Table I

R R ¹ R ² R ³ n Temperature top. EI (FAB 2 H (1) (1) H 1 119 to 120 3 He (1) (1) H 1 4 et (1) (1) H 1 5 t - Bu (1) (1) H 1 > 300

6 H (1) (1) H 0 7 Me (1) (1) H 0 8 et (1) (1) H 0 9 i - Pr (1) (1) H 0 10 tBu (1) (1) H 0

11 H (1) (2) H 0 12 Me (1) (2) H 0 13 et (1) (2) H 0 14 i - Pr (1) (2) H 0 15 tBu (1) (2) H 0

16 Η (1) (2) H 1 149 to 150 17 Me (1) (2) H 1 18 et (1) (2) H 1 19 i - Pr (1) (2) H 1 20 tBu (1) (2) H 1

21 H (3) (1) H 1 [M + H] 437 (1%) 130 (100%) 22 Me (3) (1) H 1 23 et (3) (1) H 1 [M + H] 464 (9%) 92 (100%) 24 i - Pr (3) (1) H 1 [M + H] 478 (10%) 130 (100%) 25 tBu (3) (1) H 1

26 H (1) (4) H 0 27 Me (1) (4) H ' 0 23 et (1) (4) H 0 29 i - Pr (1) (4) H 0 30 t - Bu (1) (4) H 0

31 Η (1) (4) H 1 32 He (1) (4) H 1 33 et (1) (4) H 1 34 i - Pr (1) (4) H 1 35 tBu (1) (4) H 1

36 H (1) (5) H 0 37 Me (1) (5) H 0 38 et (1) (5) H 0 39 i - Pr (1) (5) H 0 40 tBu (1) (5) H 0

41 H (1) (5) H 1 42 no (1) (5) H 1 43 et (1) (5) H ' 1 44 i - Pr (1) (5) H 1 45 tBu (1) (5) H 1

46 H (3) (2) H 1 47 He (3) (2) H 1 48 et (3) (2) H 1 49 i - Pr (3) (2) H 1 50 tBu (3) (2) H 1 51a izo, _ _Bu (10) (9) H 1 IM + H] '514 (16%). 222 (100%) 51b i-Bu (10) (16) H 1 [M + H] 547 (38%) 165 (100%) 51c izo -Bu (3) (1) H 1 244

52 i - Pr (6) 7 H 1 188 [M + H] 560 (53%) 424 (100%) 53 Bu (1) (1) H 1 214 until 215 54 BU (6) (8) H ' 1 220 until 221 55 Bu (9) (9) H 1 166 until about 167

56 Bu (3) (1) H 1 244 to 245 57 Bu (10) (8) H 1 169 to 170

58 Bu (1) (4) H 1 128 (Rozk1. [M + H] 555 (94%) .) 91 (100%) 59 Bu (6) (11) H 1 and 175 60 Pe (1) (1) H 1 about 191 61 Bu (12) (8) H 1 187 až 188

62 Bu (13) (8) H 1 120 to 121 63 Bu (13) (1) H 1 137 to 138

64 (14) (15) (1) H 1 88 to 89 65 Pe (15) (1) H 1 about 145

notes:

(dec) denotes with decomposition (1) = 3-amidinophenyl, (2) = 2-aminosulfonylphenyl, (3) = 7-amidinonaphth-2-yl, (4) =

(6) = 3 - [(5-methyl- [1,2,4] oxadiazol-3-yl) phenyl, (7) = 2- (N-tert-butylaminosulfonyl) phenyl, (8) = 3-aminocarbonylphenyl, (9) = 3-cyanophenyl, (10) = 7 - [(5-methyl- [1,2,4] oxadiazol-3-yl) naphth-2-yl, (11) = 4-bromophenyl, (12) = 3- (N-tert-butylamino-sulfonyl) phenyl, (13) = 3-amino-sulfonylphenyl, (14) = cyclopentylmethyl, (15) = 1-aminoisoquinolin-7-yl, (16) = 3-N-hydroxyamidinophenyl,

Me = methyl, Et = ethyl, i-Pr-isopropyl, Bu = n-butyl, t-Bu = tert-butyl, iso-Bu = isobutyl, Pe = pentyl.

The following resources.

examples relate to pharmaceutical

Example A. Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 .mu.g of disodium hydrogen phosphate in 3 l of double-distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and filled into injection vials, lyophilized under sterile conditions and vials closed. Each vial contains 5 mg of active ingredient.

Example B. Lace

A mixture of 20 g of an active compound of the formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C. Solution

A solution of 1 g of an active compound of the formula I, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of sodium hydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH of the solution was adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used as eye drops.

Example D. Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E. Tablets

Tablets are compressed in a known manner from a mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate, each tablet containing 10 mg of active ingredient.

Example F. Dragees

Similar to Example E, tablets are compressed and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G. Capsules

In a known manner, 2 kg of active ingredient of the formula I are filled into hard gelatin capsules such that each capsule contains 20 mg of active ingredient.

Example H. Ampoules

A solution of 1 kg of an active compound of the formula I in 60 l of double-distilled water is sterile filtered and filled into ampoules, lyophilized under sterile conditions and the ampoules are sealed. Each ampoule contains 10 mg of active ingredient.

Industrial usability

The imidazo [4,5-c] pyridin-4-one derivative and its pharmaceutically acceptable salts are useful as inhibitors of coagulation factor Xa for the manufacture of a medicament for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arethriosclerosis, inflammation, apoplexia, angina pectoris. restenosis after angioplasty and pain in the calf muscles while walking.

7½

Claims (5)

PATENT CLAIMS CLAIMS 1. Compounds of formula (I) EMI3.0 wherein is R is a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, R ¹ is Ar, R ² Ar ' R ³ is H, R, R ^4, Hal, CN, COOH, COOA or _CONH2, Ar, Ar ^{1 are} each independently phenyl, naphthyl or biphenyl, unsubstituted independently of one another or with one, two or three substituents from the group consisting of R, OH, Hal, CN, NO 2, CF 3, NH 2, NHR, NR 2, pyrrolidine- 1-yl, piperidin-1-yl, benzyloxy, SO2NH2, SO2NHR, SO2NR2, -CONHR, -CONR 2, - (CH 2) n NH 2, - (CH2) n-NHR, ^{_ (CH 2)} n ^NR 2 ' “° ^(CH2 > n“ ^NH2 > ~ 0- (CH2) _n -NHR, -O- (CH ₂ ) _n -NR ₂ and R ^4, or together -O- (CH ₂ ) _m -O-, or an isoquinolinyl group substituted with NH ₂ , R ^{4 is} -C (= NH) -NH ₂ , which is unsubstituted or monosubstituted with -COR, -COOR, -OH, or conventional amino protecting groups or -NH-C (= N) -NH ₂ , -C (= O) -N = C (NH ₂ ) ₂ , or A (C 1 -C 4) -alkyl; Hal a fluorine, chlorine, bromine or iodine atom, m ' 1 or 2, n 0,1,2 or 3 and salts and solvates thereof. Compounds according to claim 1 a) 2-Isopropyl-3- (3-amidinobenzyl) -5- (3-amidinophenyl) -3,5-dihydroimidazo [4,5-c] pyridin-4-one, and salts and solvates thereof. A process for the preparation of compounds according to claim 1, wherein the individual symbols are as defined above and their salts, characterized in that: (a) released from their functional derivatives by treatment with a solvolysis or hydrogenolysis agent, whereby r p- (i) the amidino group is liberated from its oxadiazole derivative by hydrogenolysis or solvolysis; or (ii) the conventional amino-protecting group is replaced by hydrogen by treatment with a solvolysing or hydrogenolysing agent, or the conventional amino-protecting group is removed from the amino group; (b) in a compound of formula (I), one or more R, R ¹ , R ² or R ³ groups are converted into one or more other R, R ¹ , R ² or R ³ groups by: i) the ester group is hydrolyzed to a carboxyl group, ii) the nitro group is reduced, iii) the amino group is acylated, iv) the cyano group is converted to the amidino group, or c) converting a base or an acid of formula i into its salt. A process for the manufacture of a pharmaceutical composition, characterized in that the compound according to claim 1 of general formula I and / or its physiologically acceptable salt is formulated in a dosage form with at least one solid, liquid or semi-solid carrier or excipient. 5. A pharmaceutical composition comprising as active ingredient at least one compound according to claim 1 and / or a physiologically acceptable salt thereof. A compound according to claim 1 of the formula I and its physiologically acceptable salts or solvates as pharmaceutical active substances. tenoza after angiop walking. Compound according to claim 1 and its physiologically acceptable prevention of myocardial infarction pectoris zorca I for treatment and diseases such as thrombosis, erosion, inflammation, apoplexia, angina pain in the calf y. Medicaments of the formula I according to claim 1 and their physiologically acceptable salts as coagulation factor Xa inhibitors. Use of the compounds according to claim 1 of the formula I or their physiologically acceptable salts for the manufacture of medicaments. angina carry in calf muscles at I and / or thrombosis, Lyte myocardial salts, arteriosclerosis, restenosis after zi. zoro treatment of inflammation, angioplasty and