WO2000051989A1

WO2000051989A1 - Pyrazole-3-on-derivative as factor xa inhibitors

Info

Publication number: WO2000051989A1
Application number: PCT/EP2000/001695
Authority: WO
Inventors: Dieter Dorsch; Horst Juraszyk; Werner Mederski; Christos Tsaklakidis; Hanns Wurziger; Sabine Bernotat-Danielowski; Guido Melzer
Original assignee: Merck Patent Gmbh
Priority date: 1999-03-03
Filing date: 2000-02-29
Publication date: 2000-09-08
Also published as: EP1157010A1; NO20014234L; MXPA01008844A; CZ20013164A3; PL350941A1; KR20010102428A; CN1342148A; NO20014234D0; BR0008608A; CA2364908A1; JP2002538143A; ZA200108064B; RU2001126566A; HUP0200242A2; SK12152001A3; AU2916500A; HUP0200242A3; DE19909237A1

Abstract

The invention relates to novel compounds of formula (I) wherein R?1, R2, R3, R4¿, X and Y 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

PYRAZOLE-3-ON DERINATES AS FACTOR XA INHIBITORS

The invention relates to compounds of the formula I.

wwoorriinn

R ¹ , R ² each independently of one another H, A, cycloalkyl- [C (R ⁷ R ⁷ )] _π - or Ar- [C (R ⁷ R ^{7 '} )] _n -,

R ³ , R ^{4 are} each independently of one another H, Ar, Het, R ⁵ , where at least 5 of the two radicals is R,

R ⁵ by -C (= NH) -NH _2l also simply by -COA,

Ar- [C (R ⁷ R ^{7 '} )] _π -CO-, COOA, OH or by a conventional one

Amino protecting group may be substituted, -NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl, which are optionally additionally mono- or disubstituted by A, Ar ', Het, OR ⁵ , NR ⁶ R ^6' , N0 ₂ , CN, Hai, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ S0 ₂ A,

NR ⁶ S0 ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , COR ⁷ , CO-Ar, S0 ₂ NR ⁵ R ^{6 '} ,

S (0) _π Ar 'or S (0) _n A can be substituted, R ⁶ , R ^5' each independently of one another H, A, CR ⁷ R ^{7 '} -Ar' or CR ⁷ R ^{7 '} -

Het, R ⁷ , R ⁷ each independently of one another H or A, X, Y each independently of one another (CR ⁷ R ⁷ ) _n , A alkyl having 1-20 C atoms, in which one or two CH ₂ groups are represented by O or S atoms and / or through -CH = CH groups and / or 1-7 H atoms can be replaced by F, Ar unsubstituted or one, two or three times by A, Ar ', Het,

OR ⁶ , NR ⁶ R ^{6 '} , N0 ₂ , CN, Hai, NR ⁶ COA, NR ⁶ COAr', NR ⁶ S0 ₂ A, NR ⁶ S0 ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , CON ⁶ Ar ', COR ⁷ , COAr',

S0 ₂ NR ⁶ R ^{6 '} , S (0) _n Ar' or S (0) _n A substituted phenyl,

Naphthyl or biphenyl, Ar 'unsubstituted or one, two or three times by A, OR ⁷ , NR ⁷ R ^7' , N0 ₂ , CN, Hai, NR ⁷ COA, NR ⁷ S0 ₂ A, COOR ⁷ , CO-NR ⁷ R ^{7 '} ,

COR ⁷ , S0 ₂ NR ⁷ R ^{7 '} or S (0) _n A substituted phenyl or

Naphthyl, Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N-, O- and / or S-

Atoms that are unsubstituted or one, two or three times by

A, OR ⁷ , NR ⁷ R ^{7 '} , N0 _2l CN, shark, NR ⁷ COA, NR ⁷ S0 ₂ A, COOR ⁷ ,

CO-NR ⁷ R ^{7 '} , COR ⁷ , S0 ₂ NR ⁷ R ^7' , S (0) _n A and / or carbonyl oxygen can be substituted, Hai F, CI, Br or I, n 0, 1 or 2 mean, and their pharmaceutically acceptable salts and solvates.

The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. Alcohololates, these compounds.

The object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic Diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication are used.

The compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade.

Aromatic amidine derivatives with antithrombotic activity are e.g. known from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are e.g. described in WO 97/08165. Aromatic heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022. Substituted N - [(aminoimino-methyl) phenylalkyl] azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.

The antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory activity against the activated coagulation protease, known under the name factor Xa, or to the inhibition of other activated serine proteases such as factor VIII, 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 after cross-linking make an elementary contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. However, inhibition of thrombin can inhibit fibrin formation involved in thrombus formation. The measurement of the inhibition of thrombin can e.g. using the method of G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent thrombin from being formed. The compounds of formula I according to the invention and their salts interfere with the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.

The inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is e.g. by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.

The measurement of the inhibition of factor Xa can e.g. using the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.

The coagulation factor VIa initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus the subsequent formation of thrombin. The inhibition of factor VIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A common method for measuring the inhibition of factor VIIa is e.g. by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.

Coagulation factor IXa is generated in the intrinsic coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed. The inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is described, for example, by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094. The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate .

The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that

a) liberates them from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, by

i) releases an amidino group from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis,

ii) a conventional amino protecting group by treatment with a solvolysing or hydrogenolysing agent

Replaces hydrogen or releases an amino group protected by a conventional protective group, or

b) in a compound of the formula I, one or more radicals R ¹ , R ² , R ³ and / or R ^{4 are converted} into one or more radicals R ¹ , R ² , R ³ and / or R ⁴ ,

for example by

i) hydrolyzing an ester group to a carboxy group,

ii) reducing a nitro group,

iii) acylating an amino group, iv) a cyano group in an amidino group

and or

c) converts a base or acid of the formula I into one of its salts.

For all radicals that occur several times, the meaning is independent of one another.

Above and below, the radicals or parameters R ¹ , R ² , R ³ , R ⁴ , X and Y have the meanings given in formula I, unless expressly stated otherwise.

A means Al yi, is unbranched (linear) or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermore 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, more preferably e.g. Trifluoromethyl. A very particularly preferably denotes alkyl having 1-6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

Cycloalkyi preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Shark preferably means F, Cl or Br, but also I.

Ar means unsubstituted or single, double or triple by A, Ar ', Het, OR ⁶ , NR ⁶ R ^6' , N0 ₂ , CN, Hai, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ S0 ₂ A, NR ⁶ S0 ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , CON ⁶ Ar ', COR ⁷ , COAr', S0 ₂ NR ⁶ R ^{6 '} , S (0) _n Ar' or S (0) _π A substituted phenyl, naphthyl or biphenyl. Preferred substituents for biphenyl are fluorine, S0 ₂ NH ₂ or S0 ₂ NHA. Ar 'means unsubstituted or single, double or triple by A, Het, OR ⁶ , NR ⁶ R ^6' , N0 ₂ , CN, Hai, NR ⁶ COA, NR ⁶ S0 ₂ A, NR ⁶ S0 ₂ Ar \ COOR ⁶ , CO- NR ⁶ R ^{6 '} , COR ⁷ , S0 ₂ NR ⁶ R ^6' or S (0) _n A substituted phenyl or naphthyl.

Ar preferably denotes unsubstituted phenyl, naphthyl or biphenyl, further preferably e.g. by methyl, ethyl, propyl, isopropyl, butyl, fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyan, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino , Pyrrolidin-1-yl, piperidin-1-yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, tert.-butylsulfonamido, tert.-butylaminosulfonyl, dimethylsulfonamido, phenylsulfylamino-carboxyl, methoxy , Phenylaminocarbonyl, acetyl, propionyl, benzoyl, methylsulfonyl or phenylsulfonyl mono-, di- or tri-substituted phenyl, naphthyl or

Biphenyl.

Ar 'is preferably unsubstituted phenyl or naphthyl, more preferably e.g. by methyl, ethyl, propyl, isopropyl, butyl, fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyan, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidine-1 -yl, piperidin-1-yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, methoxycarbonyl, carboxy, dimethylaminocarbonyl, phenylaminocarbonyl, acetyl or propylyl, methylsulfonyl, methylsulfonyl, propylyl, methylsulfonamyl trisubstituted phenyl or naphthyl.

Ar particularly preferably means, for example, phenyl, naphthyl, biphenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl , o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylaminocarbonyl) 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, 3-fluoro-2'-sulfamoyl-biphenyl-4-yl, 3-fluoro-2'-N-tert-butyl-sulfamoyl -biphenyl-4-yl, 2'-sulfamoyl-biphenyl-4-yl, 2'-N-tert-butyl-sulfamoyl-biphenyl-4-yl, o-, m- or p- (pyrrolidin-l-yl ) - phenyl, o-, m- or p- (piperidin-1-yl) phenyl, more 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-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino -4-chloro, 2-amino-3-chloro, 2-amino-4-chloro, 2-amino-5-chloro or 2-amino-6-chlorophenyl, 2-nitro-4-N, N -dimethylamino- or 3-nitro-4-N, N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3.6 -Dichlor-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.

Ar ¹ is preferably, for example, phenyl, naphthyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o -, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylaminocarbonyl) 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, 3-fluoro-2'-sulfamoyl-biphenyl-4-yl, 3-fluoro-2'-N-tert-butyl- sulfamoyl-biphenyl-4-yl, 2'-sulfamoyl-biphenyl-4-yl, 2'-N-tert-butylsulfamoyl-biphenyl-4-yl, o-, m- or p- (pyrrolidin-1- yl) phenyl, o-, m- or p- (piperidin-1-yl) phenyl.

Het preferably means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5 -Pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4- , 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5-yl, 1 - or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yl, 1, 3,4-thiadiazol-2- or - 5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-

Thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1- , 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4 -, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-,

4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8- 2H-benzo [1, 4] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl, 2,1, 3-benzothiadiazol-4- or -5-yl or 2, 1,3-benzoxadiazol-5-yl.

The heterocyclic radicals can also be partially or completely hydrogenated.

Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,

2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3 -thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4 - or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4 Tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, Tetrahydro-2-, -3- or -4- pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4- pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3- , -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, - 2 -, - 3-, -4-, -5- , -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8- 3,4-dihydro-2H-benzo [1, 4] oxazinyl, more preferably 2 , 3-

Methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2nd -Oxo-methylenedioxy) phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further preferably 2,3-dihydro-benzofuranyl or 2,3-dihydro-2-oxo -furanyl. Het is unsubstituted or one, two or three times by A, OR ⁷ , NR ⁷ R ^{7 '} , N0 ₂ , CN, Hai, NR ⁷ COA, NR ⁷ S0 ₂ A, COOR ⁷ , CO-NR ⁷ R ^7' , COR ⁷ , S0 ₂ NR ⁷ R ^{7 '} , S (0) _π A and / or carbonyl oxygen substituted.

Het means very particularly preferably e.g. Furyl, thienyl,

Thiazolyl, imidazolyl, [2,1,3] benzothiadiazolyl, oxazolyl, pyridyl, indolyl, piperidinyl or pyrrolidinyl.

R ¹ is preferably, for example, H, A, cycloalkyl-CH ₂ - or Ar-CH ₂ -, particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-

Butyl or tert-butyl, 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, more preferably for example Trifluoromethyl. H, methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl is very particularly preferred.

R ² preferably denotes, for example, H, A, cycloalkyl-CH ₂ - or Ar-CH ₂ -, very particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, 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, more preferably for example trifluoromethyl. H. is particularly preferred.

R ³ preferably denotes, for example, H, Ar, Het, by -C (= NH) -NH ₂ , which can also be simply substituted by -COA, Ar-CH ₂ -CO-, COOA, OH or by a conventional amino protecting group,

substituted phenyl, naphthyl or biphenyl. R ³ very particularly preferably denotes, for example, H, phenyl, by NH ₂ S0 ₂ - monosubstituted phenyl, naphthyl or biphenyl, by -C (= NH) -NH ₂ ,

substituted phenyl, naphthyl or biphenyl.

R is preferably, for example, H, Ar, Het, 0 through -C (= NH) -NH ₂ , which is also simply by -COA, Ar-CH ₂ -CO-, COOA,

OH or can be substituted by a conventional amino protecting group,

-NH-C (= NH) -

substituted phenyl, naphthyl or biphenyl.

R ⁴ very particularly preferably denotes H, phenyl, phenyl, naphthyl or biphenyl which is monosubstituted by NH ₂ S0 _2-0 ,

5 substituted phenyl, naphthyl or biphenyl.

R ⁶ , R ⁶ each independently of one another preferably mean, for example, H, methyl, ethyl, propyl, butyl or benzyl, very particularly preferably H, methyl, ethyl, propyl or butyl. 0

R ⁷ , R ⁷ each independently mean, for example, preferably H, methyl, ethyl or propyl, very particularly preferably H.

X, Y each independently mean, for example, preferably (CH ₂ ) _n , where n very particularly preferably denotes 0 or 1. The compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I encompasses all of these forms.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas la to le, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

in la R ¹ , R ² each independently denotes H or A; in Ib R ³ , R ⁴ each independently of one another H, Ar or R ⁵ , where at least one of the two radicals is R ⁵ ,

R ⁵ by -C (= NH) -NH ₂ , which is also simply by -COA

Ar- (CH ₂ ) _n -CO-, COOA, OH or can be substituted by a conventional amino protecting group, -NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl;

R ³ , R ⁴ each independently of one another H, Ar or R ⁵ , where at least one of the two radicals R ⁵ , R ⁵ by -C (= NH) -NH ₂ , which is also simply by -COA

Ar- (CH ₂ ) _n -CO-, COOA, OH or can be substituted by a conventional amino protecting group,

-NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl; in Id R ¹ A,

R ² H,

R ³ , R ⁴ each independently of one another are H, Ar or R ⁵ , where ^ is at least one of the two radicals R ⁵ ,

R ⁵ by -C (= NH) -NH ₂ , which is also simply by -COA

Ar- (CH ₂ ) _n -CO-, COOA, OH or can be substituted by a conventional amino protecting group, 5 -NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

0 substituted phenyl, naphthyl or biphenyl,

A alkyl with 1-6 C atoms,

X, Y each independently represent (CH ₂ ) _n ; in le R ¹ A, 5

R ² H,

R ³ , R ⁴ are each independently of one another H, Ar or R ⁵ , where at least one of the two radicals is R ⁵ ,

0 R "by -C (= NH) -NH ₂ or

substituted phenyl, naphthyl or biphenyl, Ar by S0 ₂ NR ⁶ R ^{6 '} simply substituted biphei

35 R ⁶ , R ⁶ each independently of one another H or A,

Alkyl with 1-6 C atoms, X, Y are each independently of one another (CH ₂ ) _n .

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.

Compounds of formula I can preferably be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group, and / or those which have one instead of the H atom Hydroxy group carry a hydroxy protecting group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group. Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.

The amidino group can be released from its oxadiazole derivative, for example, by treatment with hydrogen in the presence of a catalyst (e.g. water-moist Raney nickel) can be split off. Suitable solvents are those specified below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof. The hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar.

The introduction of the oxadiazole group succeeds e.g. by reacting the ° cyan compounds with hydroxylamine and reacting with phosgene, dialkyl carbonate, chloroformate, N, N'-carbonyldiimidazole or acetic anhydride.

There may also be several - identical or different - protected amino ^η 5 and / or hydroxyl groups in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.

The term "amino protecting group" is well known and refers to

2 ° on groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl

25 or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. He um-

30 includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl like ben-

35 zoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyl- oxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The liberation of the compounds of formula I from their functional derivatives succeeds - depending on the protective group used - z. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 -30 °.

Hydrogenolytically removable protective groups (e.g. CBZ, benzyl or the release of the amidino group from their oxadiazole derivative) can, for. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal). Suitable solvents are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably carried out at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. well on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Suitable inert solvents are e.g. 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 or monoethyl ether (methyl glycol or 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 disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

The biphenyl-SO ₂ NH ₂ group is preferably used in the form of its tert-butyl derivative. The tert-butyl group is split off, for example, using TFA with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1-10% by volume).

The conversion of a cyano group into an amidino group takes place by reaction with e.g. Hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. Pd / C. To produce an amidine of formula I (e.g. Ar = simply by

C (= NH) -NH ₂ substituted phenyl) can also add ammonia to a nitrile. The addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H ₂ S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH ₃ I, which in turn contains NH ₃ reacts to the amidine, b) the nitrile with an alcohol, for example ethanol in the presence of HCl converted into the corresponding imidoester and treated with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and then hydrolyzing the product.

The introduction of the radical -XR ³ into the pyrazolone system, with X = CH ₂ , is carried out, for example, by reacting compounds of the formula II

wherein R ¹ , R ² and R ⁴ each denote those radicals according to claim 1 which are not alkylatable and Y has the meaning given in claim 1, with a compound of formula III

R ³ -CH ₂ -L.

In the compounds of formula III, R represents a radical which cannot be alkylated according to claim 1, e.g. a phenyl radical which is substituted by 5-methyl- [1, 2,4] oxadiazol-3-yl and in which L is Cl, Br, I or a free or functionally modified OH group.

L is preferably Cl, Br, I or a reactive modified one

OH group such as an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The pyrazolone ring system is built up according to known methods by reacting a suitable β-keto ester with hydrazine or a hydrazine dehvate.

It is also possible to convert a compound of formula I into another compound of formula I by using one or more R ¹ , R ² , R ³ and / or R ^{4 is converted} into one or more R ¹ , R ² , R ³ , and / or R, for example by acylating an amino group or nitro groups (for example reduced to amino groups by hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanol).

Esters can e.g. are saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.

Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as ethylamine or pyridine at temperatures between -60 and

+ 30 °.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon or sulfone - or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, ethanoic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, methonic acid sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and / or purification of the compounds of the formula I.

On the other hand, compounds of formula I with bases (e.g. sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.

Also physiologically harmless organic bases, e.g. Ethanolamine can be used.

Compounds of the formula I according to the invention can be chiral due to their molecular structure and can accordingly occur in various enantiomeric forms. They can therefore be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or the stereo isomers of the compounds according to the invention can differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or can already be used as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Chromatographic separation of enantiomers with the aid of an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers fixed on silica gel) is also advantageous. Suitable solvents are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example in a ratio of 82: 15: 3. The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. Here, they can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more further active ingredients.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, e.g. one or more vitamins.

The compounds of the formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclero- se, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication can be used.

The substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of excretion and on the combination of drugs and severity of the respective disease, whichever therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Eluent: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): El (electron impact ionization) M ⁺ FAB (Fast Atom Bombardmeπt) (M + H) ⁺

example 1

4.3 g of cesium carbonate are added to 4.0 g of 3- (7-bromomethyl-naphthalin-2-yl) -5-methyl- [1, 2,4] oxadiazole and 2.1 g of ethyl isobutyrylacetate in 50 ml of acetonitrile . The suspension is stirred for 20 hours at room temperature. The mixture is filtered, the solvent is removed and the residue is chromatographed on a silica gel column. 4-Methyl-2- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] -3-oxopentanoic acid ethyl ester ("AA") is obtained as a colorless oil , FAB 381

A solution of 1.30 g of "AA" and 0.62 ml of hydrazinium hydroxide in 10 ml of acetic acid is heated to boiling for 24 hours. After customary working up, 5-isopropyl-4- [7- (5-methyl- [1, 2,4] oxadiazol-3-yl) naphthalin-2-ylmethyl] -1, 2-dihydro-pyrazol-3- on ("AB"), FAB 349

A solution of 60 mg "AB" in 5 ml of methanol is mixed with 60 mg of Raney nickel and 30 mg of acetic acid and hydrogenated for 18 hours at room temperature. The catalyst is filtered off, the solvent is removed and the compound is obtained

7- [5-Isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-4-ylmethyl] -2-aminonaphthalene, diacetate, FAB 309.

Example 2

A solution of 100 mg of "AB" and 68 mg of 3- (3-bromomethyl-phenyl) -5-methyl- [1, 2,4] oxadiazole in 10 ml of acetonitrile is mixed with 94 mg of cesium carbonate and stirred for 20 hours at room temperature. After customary working up and chromatography on silica gel, 5-isopropyl-2- [3- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] -4- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) -naphthalen-2-ylmethyl] -1, 2-dihydro-pyrazol-3-one, FAB 521.

Analogously to Example 1, the compound is obtained therefrom by hydrogenation

3- [4- (7-Amidino-naphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazoi-2-ylmethyl] benzamidine, diacetate, FAB 441

The connection is obtained analogously

4- [4- (7-Amidino-naphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] benzamidine.

The compound is obtained analogously by reacting "AB" with 3- (7-bromomethyl-naphthalin-2-yl) -5-methyl- [1, 2,4] oxadiazole and subsequent hydrogenation

7- [4- (7-Amidino-naphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidino-naphthalene, diacetate, FAB 491

Example 3

Analogously to Example 1, reaction of 3- (5-methyl- [1, 2,4] oxadiazol-3-yl) benzyl bromide with methyl isobutyrylacetate gives the compound 4-methyl-2- [3- (5-methyl- [1 , 2,4] oxadiazol-3-yl) benzyl] -3-oxopentanoic acid ethyl ester ("AC") as a colorless oil, FAB 317

By reaction with hydrazinium hydroxide, 5-isopropyl-4- [3- (5-methyl- [1, 2,4] oxadiazol-3-yl) -benzyl] -1, 2-dihydro-pyrazol-3-one is obtained therefrom, FAB 299 ("AD")

The compound 3- [5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-4-ylmethyl] benzamidine is obtained therefrom by hydrogenation.

Analogously, you get by implementing "AD"

3- (3-bromomethyl-phenyl) -5-methyl- [1, 2,4] oxadiazole,

3- (7-bromomethyl-naphthalen-2-yl) -5-methyl- [1, 2,4] oxadiazole,

2- (tert-Buty! Aminosulfonyl) -4'-bromomethyl-biphenyl

and after subsequent hydrogenation the compounds

3- [4- (3-Amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethylj-benzamidine, triacetate, FAB 391;

7- [4- (3-Amidino-beπzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidino-naphthalene, diacetate, FAB (M + 2H) 2+ m / z 221;

4 '- [4- (3-amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2- (tert-butylaminosulfonyl) biphenyl, and therefrom the compound 4 '- [4- (3-amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-1 / - / - pyrazol-2-ylmethyl] by splitting off the tert-butyl group -2-aminosulfonyl-biphenyl, trifluoroacetate, FAB 504.

The connections are obtained analogously 7- [4- (4-Amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidino-naphthalene and

3- (2-benzyl-5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-4-ylmethyl) benzamidine, FAB 349.

Example 4

Analogously to Example 1, reaction of 5-isopropyl-1,2-dihydro-pyrazol-3-one with 3- (7-bromomethyl-naphthalen-2-yl) -5-methyl-

[1, 2,4] oxadiazole and subsequent hydrogenation of the compound

5-isopropyl-2- [7-amidino-naphthalen-2-ylmethyl] -1, 2-dihydro-pyrazol-3-one ("AB"), diacetate, FAB 309.

Example 5

Analogously to Example 1, starting from 3- (7-bromomethyl-naphthalen-2-yl) -5-methyl- [1, 2,4] oxadiazole and 3-oxobutyric acid ethyl ester, reaction with hydrazine and subsequent reaction with 3- ( 7-bromomethyl-naphthalin-2-yl) -5-methyl- [1, 2,4] oxadiazole and hydrogenation of the compound

7- [4- (7-Amidino-naphth-2-ylmethyl) -5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidino-naphthalene.

If ethyl 3-oxo-butyrate is replaced by ethyl 3-oxo-heptanoate, the compound is obtained analogously

7- [4- (7-Amidino-naphth-2-ylmethyl) -5-butyl-3-oxo-2,3-dihydro-1 / - / - pyrazol-2-ylmethyl] -2-amidino-naphthalene.

Example 6

Analogously to Example 1, starting from 2- (tert-butylaminosulfonyl) -4'-bromomethyl-biphenyl and ethyl isobutrylacetate, reaction with hydrazine and subsequent reaction with 3- (3-bromomethyl-phenyl) -5-methyl- [1 , 2,4] oxadiazole, hydrogenation and ap-cleavage of the tert-butyl group the compound 3- [4- (2-aminosulfonyl-biphenyl-4'-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] benzamidine, trifluoroacetate, FAB 504.

The connection is obtained analogously

7- [4- (2-Aminosulfonyl-biphenyl-4'-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidinonaphthalene, trifluoroacetate, FAB 554 .

Example 7

The following compounds are obtained analogously to Examples 1 and 2

7- (4-benzyl-5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl) -2- amidino-naphthalene,

7- [2-benzyl-5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-4-ylmethyl] -2-amidino-naphthalene.

Example 8

Analogously to Example 1, the compound is obtained when hydrazine is replaced by phenylhydrazine

7- [5-Isopropyl-3-oxo-2-phenyl-2,3-dihydro-1 / - / - pyrazol-4-ylmethyl] -2-amidino-naphthalene.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

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

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g of soy 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 ingredient is prepared of the formula I, 9.38 g of NaH ₂ P0 ₄ ^• 2 H ₂ 0, 28.48 g Na ₂ HP0 ₄ • 12 H ₂ 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

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

Example E: tablets

A mixture of 1 kg of active ingredient 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 is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient. Example F: coated tablets

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

Example G: capsules

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

Example H: ampoules

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

Claims

claims

1. Compounds of formula I.

wherein

R ¹ , R ² each independently of one another H, A, cycloalkyl

[C (R ⁷ R ^{7 '} )] _n - or Ar- [C (R ⁷ R ^7' )] _n -,

R ³ , R ⁴ each independently of one another H, Ar, Het, R ⁵ , where 5 denotes at least one of the two radicals R,

R ⁵ by -C (= NH) -NH ₂ , which is also simply by -COA,

Ar- [C (R ⁷ R ^{7 '} )] _n -CO-, COOA, OH or can be substituted by a conventional amino protecting group, -NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl, which are optionally additionally mono- or disubstituted by A, Ar ', Het, OR ⁶ , NR ⁶ R ^6' , N0 ₂ , CN, Hai, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ S0 ₂ A, NR ⁶ S0 ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , COR ⁷ , CO-Ar ', S0 ₂ NR ⁶ R ^6' , S (0) _n Ar 'or S (0) _n A can be substituted,

R ⁶ ,, R ^{6 '} each independently of one another H, A, CR ⁷ R ⁷ -Ar' or

CR ⁷ R ^{7 '} -Het,

R ⁷ , R ^{7 '} each independently of one another H or A,

X, Y each independently of one another (CR ⁷ R ⁷ ) _n ,

AA alkyl with 1-20 C atoms, in which one or two CH ₂ -

Groups by O or S atoms and / or by -CH = CH groups and / or 1-7 H atoms can be replaced by F, Ar unsubstituted or one, two or three times by A, Ar ',

Het, OR ⁶ , NR ⁶ R ^{6 '} , N0 ₂ , CN, Hai, NR ⁶ COA, NR ⁶ COAr', NR ⁶ S0 ₂ A, NR ⁶ S0 ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , CON ⁶ ares,

COR ⁷ , COAr ', S0 ₂ NR ⁶ R ^6' , S (0) _rl Ar ^, or S (0) _n A substituted phenyl, naphthyl or biphenyl,

Ar 'unsubstituted or single, double or triple by A,

OR ⁷ , NR ⁷ R ^{7 '} , N0 ₂ , CN, Hai, NR ⁷ COA, NR ⁷ S0 ₂ A, COOR ⁷ , CO-NR ⁷ R ^7' , COR ⁷ , S0 ₂ NR ⁷ R ^{7 '} or S ( 0) _n A substituted phenyl or naphthyl, Het is a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, 0 and / or S atoms which is unsubstituted or mono-, di- or triple by A, OR ⁷ , NR ⁷ R ^{7 '} , N0 ₂ , CN, Hai, NR ⁷ COA, NR ⁷ S0 ₂ A, COOR ⁷ , CO-NR ⁷ R ^7' , COR ⁷ , S0 ₂ NR ⁷ R ^{7 '} , S ( 0) _π A and / or carbonyl oxygen can be substituted, Hai F, Cl, Br or I, n mean 0, 1 or 2, and their pharmaceutically acceptable salts and solvates.

2. Compounds according to claim 1

a) 7- [5-Isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidino-naphthalene; b) 7- [4- (7-Amidino-naphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidino-naphthalene; c) 3- [4- (3-Amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] benzamidine; d) 3- [4- (7-Amidino-naphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] benzamidine; e) 7- [5-isopropyl-3-oxo-2,3-dihydro-1 / - / - pyrazol-4-ylmethyl] -2-amidino-naphthalene

as well as their pharmaceutically acceptable salts and solvates.

3. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that

a) they from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent in

Set freedom by

ii) replacing a conventional amino protecting group with hydrogen by treatment with a solvolysing or hydrogenolysing agent or releasing an amino group protected by a conventional protecting group,

or

for example by

i) hydrolyzing an ester group to a carboxy group,

ii) reducing a nitro group,

iii) acylating an amino group,

iv) a cyano group in an amidino group and or

c) converting a base or acid of the formula I into one of its salts.

4. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I according to Claim 1 and / or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid carrier or auxiliary.

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

6. Compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as active pharmaceutical ingredients.

7. Compounds of formula I according to claim 1 and their physiologically acceptable salts for combating thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.

8. Medicament of the formula I according to claim 1 and their physiologically acceptable salts as inhibitors of the coagulation factor Xa.

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

10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the fight development of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.