DE19909237A1 - Pyrazol-3-one derivatives - Google Patents

Abstract

The invention relates to novel compounds of formula (I) wherein R<1>, R<2>, R<3>, R<4>, 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

The invention relates to compounds of the 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 are H, Ar, Het, R ⁵ , where at least one of the two radicals is R ⁵ ,
R ⁵ by -C (= NH) -NH ₂ , which can also be simply substituted by -COA, Ar- [C (R ⁷ R ^{7 '} )] _n -CO-, COOA, OH or by a conventional amino protecting group, NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

Substituted phenyl, naphthyl or biphenyl, if necessary additionally or once by A, Ar ', Het, OR ⁶ , NR ⁶ R ⁶ , NO ₂ , CN, Hal, NR ⁶ COA, NR ⁶ COAr', NR ⁶ SO ₂ A, NR ⁶ SO ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ⁶ , COR ⁷ , CO-Ar', SO ₂ NR ⁶ R ⁶ , S (O) _n Ar 'or S (O) _n A substituted could be,
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 ,
A alkyl with 1-20 C atoms, in which one or two CH ₂ groups can be replaced by O or S atoms and / or by -CH = CH groups and / or also 1-7 H atoms by F. ,
Ar unsubstituted or single, double or triple by A, Ar ', Het, OR ⁶ , NR ⁶ R ^6' , NO ₂ , CN, Hal, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ SO ₂ A, NR ⁶ SO ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , CON ⁶ Ar ', COR ⁷ , COAr', SO ₂ NR ⁶ R ^{6 '} , S (O) _n Ar' or S (O) _n A substituted phenyl, naphthyl or biphenyl,
Ar 'unsubstituted or single, double or triple by A, OR ⁷ , NR ⁷ R ^7' , NO ₂ , CN, Hal, NR ⁷ COA, NR ⁷ SO ₂ A, COOR ⁷ , CO-NR ⁷ R ^{7 '} ,, COR ⁷ , SO ₂ NR ⁷ R ^{7 '} , or S (O) _n A substituted phenyl or naphthyl,
Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by A, OR ⁷ , NR ⁷ R ^{7 '} , NO ₂ , CN, Hal, NR ⁷ COA, NR ⁷ SO ₂ A, COOR ⁷ , CO-NR ⁷ R ^{7 '} , COR ⁷ , SO ₂ NR ⁷ R ^7' , S (O) _n A and / or carbonyl oxygen can be substituted
Hal F, Cl, Br or I,
n is 0, 1 or 2,
as well as their pharmaceutically acceptable salts and solvates.

The invention also relates to the optically active forms, the Ra cemates, the diastereomers and the hydrates and solvates, e.g. B. Alcohol late, of these connections.

The invention was based on the object, new compounds with valuable len properties to find, especially those that are used to manufacture of drugs can be used.

It has been found that the compounds of formula I and their salts good tolerance very valuable pharmacological properties Zen. 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, ent ignitions, apoplexy, angina pectoris, restenosis after angioplasty and Intermittent claudication can be used.

The compounds of formula I according to the invention can also Inhi Bittern of the coagulation factors factor VIIa, factor IXa and thrombin der Blood coagulation cascade.

Aromatic amidine derivatives with antithrombotic activity are e.g. B. from EP 0 540 051 B1. Cyclic guanidines for treatment thromboembolic diseases are e.g. B. in WO 97108165 be wrote. Aromatic heterocycles with factor Xa inhibitory activity are z. B. from WO 96/10022. Substituted N - [(aminoimino methyl) phenylalkyl] azaheterocyclylamide as factor Xa inhibitors are in WO 96/40679.

The antithrombotic and anticoagulant effect of the ß compounds is on the inhibitory effect against the acti fourth coagulation protease, known as factor Xa, or on the inhibition of other activated serine proteases such as factor VIIa, Factor IXa or thrombin is attributed.

Factor Xa is one of the proteases involved in the complex process of blood coagulation is involved. Factor Xa catalyzes the conversion of Pro thrombin in thrombin. Thrombin cleaves fibrinogen into fibrin monomers that after cross-linking make an elementary contribution to thrombus formation. A Ak Activation of thrombin can lead to the occurrence of thromboembolic er lead illnesses. An inhibition of thrombin can, however, in the Inhibit thrombus formation involved fibrin formation. The measurement of the inhibition of thrombin can e.g. B. by the method by G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent thrombin is forming.  

The compounds of formula I according to the invention and their salts grei intervene in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.

The inhibition of factor Xa by the compounds of the invention gene and the measurement of anticoagulant and antithrombotic actions vity can be determined using conventional in vitro or in vivo methods. A suitable method is e.g. B. by J. Hauptmann et al. in thrombosis and Haemostasis 1990, 63, 220-223.

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

Coagulation factor VIIa initiates ex after binding to tissue factor trinsic part of the coagulation cascade and contributes to the activation of the Factor X to factor Xa. Inhibition of factor VIIa prevented thus the emergence of factor Xa and thus a subsequent one Thrombin formation. The inhibition of factor VIIa by the verbin according to the invention and the measurement of anticoagulant and antithrombotic Activity can be determined by conventional in vitro or in vivo methods the. A common method for measuring the inhibition of factor VIIa z. B. by H.F. Ronning et al. in Thrombosis Research 1996, 84, 73-81 described.

The coagulation factor IXa is ge in the intrinsic coagulation cascade neriert and is also on the activation of factor X to factor Xa be shares. An inhibition of factor IXa can therefore ver prevent factor Xa from being formed. The inhibition of factor IXa by the compounds of the invention gene and the measurement of anticoagulant and antithrombotic actions vity can be determined using conventional in vitro or in vivo methods. A suitable method is e.g. B. by J. Chang et al. in Journal of Biolo gical Chemistry 1998, 273, 12089-12094.  

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used, especially for loading fighting and preventing thromboembolic disorders such as Thrombosis, myocardial infarction, arteriosclerosis, inflammation, apo plexia, angina pectoris, restenosis after angioplasty and claudication in mid term.

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
  • a) releases an amidino group from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis,
  • b) 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
• 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 by, for example
  • a) hydrolyzing an ester group to a carboxy group,
  • b) a nitro group is reduced,
  • c) acylating an amino group,
  • d) 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 residues that occur more than once, the meaning is irrelevant are dependent on each other.

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 is alkyl, 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 means before preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec.- Butyl or tert-butyl, 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. B. trifluoromethyl. A very particularly preferably denotes alkyl having 1-6 C atoms, preferably wise methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert.- Butyl, pentyl or hexyl.

Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cy clohexyl or cycloheptyl.

Hal is preferably 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' , NO ₂ , CN, Hal, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ SO ₂ A, NR ⁶ SO ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , CON ⁶ Ar ', COR ⁷ , COAr', SO ₂ NR ⁶ R ^{6 '} , S (O) _n Ar' or S (O) _n A substituted phenyl, naphthyl or biphenyl. Preferred substituents for biphenyl are fluorine, SO ₂ NH ₂ or SO ₂ NHA.

Ar 'means unsubstituted or single, double or triple by A, Het, OR ⁶ , NR ⁶ R ^6' , NO ₂ , CN, Hal, NR ⁶ COA, NR ⁶ SO ₂ A, NR ⁶ SO ₂ Ar ', COOR ⁶ , CO- NR ⁶ R ^{6 '} , COR ⁷ , SO ₂ NR ⁶ R ^6' or S (O) _n A substituted phenyl or naphthyl.

Ar preferably denotes unsubstituted phenyl, naphthyl or biphen yl, further preferably z. B. by methyl, ethyl, propyl, isopropyl, Bu tyl, fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pen tyloxy, hexyloxy, cyan, nitro, trifluoromethyl, amino, methylamino, ethyl amino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, sulfo namido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butyl sulfonamido, tert-butylsulfonamido, tert-butylaminosulfonyl, dimethylsul fonamido, phenylsulfonamido, methoxycarbonyl, carboxy, dimethylamino carbonyl, phenylaminocarbonyl, acetyl, propionyl, benzoyl, methylsulfonyl or phenylsulfonyl mono-, di- or tri-substituted phenyl, naphthyl or Biphenyl.

Ar 'preferably means unsubstituted phenyl or naphthyl hin preferably z. B. by methyl, ethyl, propyl, isopropyl, butyl, fluorine, Chlorine, bromine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, He xyloxy, cyan, nitro, trifluoromethyl, amino, methylamino, ethylamino, di methylamino, diethylamino, pyrrolidin-1-yl, piperidin-1-yl, sulfonamido, Methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfone amido, dimethylsulfonamido, phenylsulfonamido, methoxycarbonyl, Car boxy, dimethylaminocarbonyl, phenylaminocarbonyl, acetyl, propionyl, Benzoyl, methylsulfonyl or phenylsulfonyl mono-, di- or trisub substituted phenyl or naphthyl.

Ar particularly preferably means z. B. 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-methylamino carbonyl) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxy phenyl, 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, 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-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.

Ar 'preferably means z. B. 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-hydroxy phenyl, 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- (methyl sulfonamido) 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-1-yl) -phenyl, o-, m- or p- (piperidin-1-yl) phenyl.

Het preferably means z. B. 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 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, further before adds 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 his.

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-dioxo lan-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-pyrrole dinyl, 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-dihydro benzofuran-5- or 6-yl, 2,3- (2-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 '} , NO ₂ , CN, Hal, NR ⁷ COA, NR ⁷ SO ₂ A, COOR ⁷ , CO-NR ⁷ R ^7' , COR ⁷ , SO ₂ NR ⁷ R ^{7 '} , S (O) _n A and / or carbonyl oxygen substituted.

Het means very particularly preferably z. B. furyl, thienyl, Thiazolyl, imidazolyl, [2,1,3] benzothiadiazolyl, oxazolyl, pyridyl, indolyl, Piperidinyl or pyrrolidinyl.

R ¹ preferably means z. B. 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 e.g. B. trifluoromethyl. H, methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl is very particularly preferred.

R ² preferably means z. B. 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-tri methylpropyl, more preferably e.g. B. trifluoromethyl. Especially preferred is H.

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

substituted phenyl, naphthyl or biphenyl.  

R ³ very particularly preferably denotes z. B. H, phenyl, by NH ₂ SO ₂ - monosubstituted phenyl, naphthyl or biphenyl, by -C (= NH) -NH ₂ ,

substituted phenyl, naphthyl or biphenyl.

R ⁴ preferably means z. B. 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, NH-C ( = NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl.

R ⁴ very particularly preferably means z. B. H, phenyl, by NH ₂ SO ₂ - monosubstituted phenyl, naphthyl or biphenyl, by -C (= NH) -NH ₂ ,

substituted phenyl, naphthyl or biphenyl.

R ⁶ , R ^{6 '} each independently, preferably preferably z. B. H, methyl, ethyl, propyl, butyl or benzyl, very particularly preferably H, methyl, ethyl, propyl or butyl.

R ⁷ , R ^{7 'are} each independently of one another, preferably z. B. H, methyl, ethyl or propyl, very particularly preferably H.

X, Y are each independently, preferably z. B. (CH ₂ ) _n , where n very particularly preferably denotes 0 or 1.

The compounds of formula I can have one or more chiral centers possess and therefore occur in different 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 said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ie, 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 Ia R ¹ , R2 each independently represent 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 can also be substituted simply by -COA Ar- (CH ₂ ) _n -CO-, COOA, OH or by a conventional amino protecting group, NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl;
in Ic R ¹ A,
R ² H,
R ³ , R ⁴ each independently of one another are H, Ar or R ⁵ , where at least one of the two radicals is R ⁵ ,
R ⁵ by -C (= NH) -NH ₂ , which can also be substituted simply by -COA Ar- (CH ₂ ) _n -CO-, COOA, OH or 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 at least one of the two radicals is R ⁵ ,
R ⁵ by -C (= NH) -NH ₂ , which can also be substituted simply by -COA Ar- (CH ₂ ) _n -CO-, COOA, OH or by a conventional amino protecting group, NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl,
A alkyl with 1-6 C atoms,
X, Y each independently of one another (CH ₂ ) _n ,
means;
in Ie R ¹ A,
R ² H,
R ³ , R ⁴ each independently of one another are H, Ar or R ⁵ , where at least one of the two radicals is R ⁵ ,
R ⁵ by -C (= NH) -NH ₂ or

substituted phenyl, naphthyl or biphenyl,
Ar is simply substituted biphenyl by SO ₂ NR ⁶ R ^{6 '} ,
R ⁶ , R ^{6 '} each independently of one another H or A,
A alkyl with 1-6 C atoms,
X, Y each independently of one another (CH ₂ ) _n ,
means.

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) be are written, namely under reaction conditions that are genan Implementations are known and suitable. You can also from known variants not mentioned here in detail use ma chen.

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

Compounds of formula I can preferably be obtained by compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing Set the means free.

Preferred starting materials for solvolysis or hydrogenolysis are those that otherwise correspond to formula I, but instead of one or more protected free amino and / or hydroxyl groups Contain amino and / or hydroxyl groups, preferably those which are place an H atom connected to an N atom, an Ami wear protective group, especially those that replace an HN Group carry an R'-N group, wherein R 'be an amino protecting group indicates, and / or those instead of the H atom of a hydroxy group carry a hydroxy protecting group, e.g. B. those that correspond to formula I. chen, but instead of a group -COOH carry a group -COOR ", wherein R "represents a hydroxy protecting group. Preferred starting materials are also the oxadiazole derivatives, which are in the corresponding amidino compounds can be transferred.

The release of the amidino group from its oxadiazole derivative can e.g. B. by treatment with hydrogen in the presence of a catalyst (e.g.  water-moist Raney nickel) can be split off. As a solvent the following, especially alcohols such as Methanol or ethanol, organic acids such as acetic acid or propion acid or mixtures thereof. Hydrogenolysis is usually done with Temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar guided.

The introduction of the oxadiazole group succeeds, for. B. by implementing the Cyan compounds with hydroxylamine and reaction with phosgene, Dialkyla carbonate, chloroformate, N, N'-carbonyldiimidazole or acetane hydride.

Several - identical or different - protected amino and / or hydroxyl groups present in the molecule of the starting material his. If the existing protecting groups are different from each other, they can be split off selectively in many cases.

The term "amino protecting group" is well known and refers to on groups that are suitable, an amino group before chemical order to protect (block) settlements that are easily removable, after the desired chemical reaction elsewhere in the Molecule has been carried out. Typical of such groups are esp special unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups according to the desired Reaction (or sequence of reactions) to be removed is their type and size the rest not critical; however, those with 1-20 are preferred, in particular their 1-8 C atoms. The term "acyl group" is related to to understand the present procedure in the broadest sense. He around includes aliphatic, araliphatic, aromatic or hetero cyclic carboxylic acids or sulfonic acids derived acyl groups so such as especially alkoxycarbonyl, aryloxycarbonyl and especially aral koxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl like Ben zoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxy carbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyl  oxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("Carbo benzoxy "), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr. Be preferred amino protecting groups are BOC and Mtr, also CBZ, Fmoc, Ben zyl and acetyl.

The liberation of the compounds of formula I from their functional len derivatives succeed - depending on the protective group used - e.g. B. with star ken acids, suitably with TFA or perchloric acid, but also with their strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acid ren such as benzene or p-toluenesulfonic acid. The presence of an additional Chen inert solvent is possible, but not always necessary. As 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, fer ner also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably in excess without the addition of another solution means used, perchloric acid in the form of a mixture of acetic acid right and 70% perchloric acid in a ratio of 9: 1. The reaction temperature ren for the cleavage are advantageously between about 0 and about 50 °, preferably one works between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in Di chloromethane or with about 3 to 5N HCl in dioxane at 15-30 ° be the FMOC group with an approximately 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 its oxadiazole derivative)) can, for. B. by treatment with hydrogen in the presence of a catalyst (e.g. a noble metal catalyst such as palladium, advantageously on a support like coal) can be split off. Suitable solvents are specified above, in particular z. B. alcohols such as methanol or etha nol or amides such as DMF. Hydrogenolysis is usually done at Tempe 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 the CBZ group succeeds e.g. B. good at 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in metha nol / DMF at 20-30 °.

Suitable inert solvents are, for. B. hydrocarbons such as hexane, Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, trifluoromethylbene zole, chloroform or dichloromethane; Alcohols such as methanol, ethanol, iso propanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, Diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ether like 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 Amei sensic acid or acetic acid; Nitro compounds such as nitromethane or nitro benzene; Esters such as ethyl acetate or mixtures of the solutions mentioned tel.

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. B. with TFA with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1-10 vol%).

The conversion of a cyano group into an amidino group is carried out by Implementation with z. B. hydroxylamine and subsequent reduction of the N- Hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. B. Pd / C.

To produce an amidine of the formula I (for example Ar = phenyl substituted simply by C (= NH) -NH ₂ ), ammonia can also be added to a nitrile. The addition is preferably carried out in several stages by a) converting the nitrile with H ₂ S into a thioamide in a manner known per se, which is reacted with an alkylating agent, for. B. CH ₃ I, is converted into the corresponding S-alkyl imidothioester, which in turn reacts with NH ₃ to form the amidine, b) the nitrile with an alcohol, for. B. ethanol in the presence of HCl in 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 in the pyrazolone system, with X = CH ₂ , takes place, for. B. by reacting compounds of formula II

wherein R ¹ , R ² and R ⁴ each represent 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 III

implements.

In the compounds of formula III, R ^{3 is} a radical which cannot be alkylated according to claim 1, such as. B. is a phenyl radical substituted by 5-methyl- [1,2,4] oxadiazol-3-yl and wherein L is Cl, Br, I or a free or reactive functional OH group. L is preferably Cl, Br, I or a reactively modified OH group such as. B. an activated ester, an imidazolide or alkylsulfonyoxy with 1-6 carbon atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).

The pyrazolone ring system is constructed by known methods by reacting a suitable β-keto ester with hydrazine or a Hydrazine derivative.

It is also possible to convert a compound of the formula I into another compound of the formula I by one or more radicals R ¹ , R ² , R ³ and / or R ⁴ into one or more radicals R ¹ , R ² , R ³ , and / or R ⁴ converts, e.g. B. by acylating an amino group or reducing nitro groups (for example by hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanol) to amino groups.

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

You can also free amino groups in the usual way with an acid acylate chloride or anhydride or with an unsubstituted or sub alkylate substituted alkyl halide, advantageously in an inert solvent solvents such as dichloromethane or THF and / or in the presence of a Base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation men in particular acids, the physiologically acceptable Sal ze deliver. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorwas hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Amei sensic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascor bic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- Toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfur acid. Salts with physiologically unacceptable acids, e.g. B. picrates,  can for the isolation and / or purification of the compounds of For mel I can be used.

On the other hand, compounds of the formula I with bases (e.g. sodium or potassium hydroxide or carbonate) in the corresponding metal, ins special alkali metal or alkaline earth metal, or in the corresponding Ammonium salts are converted.

Also physiologically acceptable organic bases, such as. B. ethanol amine can be used.

Compounds of the formula I according to the invention can on the basis of their Mo lecular structure can be chiral and can accordingly be in different enantiomeric forms occur. You can therefore in racemic or in optically active form.

Since the pharmaceutical effectiveness of the Racemate or the Stereo can differentiate isomers of the compounds according to the invention, it may be desirable to use the enantiomers. In these In some cases, the end product or the intermediate products may already be in enantiomeric compounds, by chemical known to those skilled in the art or physical measures, separated or already as such the synthesis can be used.

In the case of racemic amines, the mixture is reacted formed with an optically active release agent diastereomers. As a separator agents are suitable for. B. optically active acids, such as the R and S forms of Tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, apples acid, lactic acid, suitable N-protected amino acids (e.g. N-Ben zoylproline or N-benzenesulfonylproline) or the various optically ak tive camphorsulfonic acids. A chromatographic is also advantageous Enantiomer separation using an optically active separating agent (e.g. Dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of Carbohydrates or chiral derivatized methacrylate fixed on silica gel polymers). Aqueous or alcoholic solvents are suitable as solvents Solvent mixtures such as B. hexane / isopropanol / acetonitrile e.g. B. in Ratio 82: 15: 3.  

The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts position of pharmaceutical preparations, especially on non-chemical ischemic way. Here you can together with at least one fe most liquid and / or semi-liquid carrier or auxiliary and counter possibly in combination with one or more other active ingredients be brought into a suitable dosage form.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of the formula and / or one of them physiologically acceptable salts.

These preparations can be used as medicinal products in human or veteri used in medicine. Organic or inorganic substances in question that are suitable for enteral (e.g. oral), parenteral or topical application and with the new compound not react, e.g. 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, coated tablets, Capsules, powder, granules, syrups, juices or drops, for rectal application application suppositories, for parenteral application solutions, preferred wise oily or aqueous solutions, also suspensions, emulsions or implants, for topical application of ointments, creams or powder. The new compounds can also be lyophilized and the Lyo obtained philisate z. B. can be used for the preparation of injectables. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, Emulsifiers, salts to influence the osmotic pressure, buffers substances, colors, flavors and / or several other active ingredients included, e.g. B. one or more vitamins.

The compounds of formula I and their physiologically acceptable Salts can help combat and prevent thromboemboli diseases such as thrombosis, myocardial infarction, arteriosclero  se, inflammation, apoplexy, angina pectoris, restenosis after angiopla stie and intermittent claudication.

The substances according to the invention are generally preferred as in doses between about 1 and 500 mg, in particular between 5 and 100 mg per dosage unit administered. The daily Thursday Sation is preferably between about 0.02 and 10 mg / kg body weight important. However, the specific dose for each patient depends on the ver various factors, such as the effectiveness of the put special connection, of age, body weight, general ge state of health, gender, on the diet, on the administration time point and route, from the rate of excretion, drug com combination and severity of the respective disease to which the therapy applies. Oral application is preferred.

All temperatures above and below are given in ° C. In the following examples, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, to a pH between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1.
Mass spectrometry (MS): EI (electron impact ionization) M ⁺
FAB (Fast Atom Bombardment) (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-oxo-pentanoic acid ethyl ester ("AA") is obtained as a colorless oil, FAB 381

A solution of 1.30 g "AA" and 0.62 ml hydrazinium hydroxide in 10 ml acetic acid is heated to boiling for 24 hours. After customary processing, 5-isopropyl-4- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) naphthalin-2-ylmethyl] -1,2-dihydro-pyrazol-3 is obtained -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-amidino naphthalene, diacetate, FAB 309.

Example 2

94 mg of cesium carbonate are added to 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 and the mixture is stirred at room temperature for 20 hours. 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 3- [4- (7-amidino-naphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] - is obtained therefrom by hydrogenation. benzamidine, diacetate, FAB 441

The connection is obtained analogously
4- [4- (7-Amidino-naphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-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-oxo pentanoic acid ethyl ester ("AC") as a colorless oil, FAB 317

Reaction with hydrazinium hydroxide gives 5-isopropyl-4- [3- (5-methyl- [1,2,4] oxadiazol-3-yl) -benzyl] -1,2-dihydro-pyrazol-3-one, FAB 299 ("AD")

The compound 3- [5-isopropyl-3-oxo 2,3-dihydro-1H-pyrazol-4-ylmethyl] benzamidine.

Analogously, you get by implementing "AD"
3- (3-bromomethylphenyl) -5-methyl- [1,2,4] oxadiazole,
3- (7-bromomethyl-naphthalen-2-yl) -5-methyl- [1,2,4] oxadiazole,
2- (tert-butylaminosulfonyl) -4'-bromomethyl-biphenyl
and after subsequent hydrogenation the compounds
3- [4- (3-Amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] benzamidine, triacetate, FAB 391;
7- [4- (3-Amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidino-naphthalene,
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-1H-pyrazol-2-ylmethyl] -2- by splitting off the tert-butyl group aminosulfonyl-biphenyl.

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

Example 4

Analogously to Example 1, reaction of 5-isopropyl-1,2- dihydro-pyrazol-3-one with 3- (7-bromomethyl-naphthalin-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-pyrazole- 3-one ("AB"), diacetate, FAB 309.

Example 5

Analogously to Example 1, starting from 3- (7-bromomethyl-naphthalene 2-yl) -5-methyl- [1,2,4] oxadiazole and 3-oxobutyric acid ethyl ester, conversion tion 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 3-oxo-butyric acid ethyl ester is replaced by 3-oxo-heptanoic acid ethyl ester so you get the connection analog 7- [4- (7-Amidino-naphth-2-ylmethyl) -5-butyl-3-oxo-2,3-dihydro-1H- pyrazol-2-ylmethyl] -2-amidino-naphthalene.

Example 6

Analogously to Example 1, starting from 2- (tert-butylaminosulfonyl) -4'-bromomethyl-biphenyl and ethylisobutrylacetate, reaction with hydrazine and subsequent reaction with 3- (3-bromomethyl-phenyl) -5-methyl- [1 , 2,4] oxadiazole, hydrogenation and elimination 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

Analogously to Examples 1 and 2, the following compounds are obtained
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, when hydrazine is replaced by phenylhydra zin the connection 7- [5-isopropyl-3-oxo-2-phenyl-2,3-dihydro-1H-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 Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection glass 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 soy lecithin and 1400 g cocoa butter, pour into molds and leave cold. Each suppository contains 20 mg of active ingredient.

Example C solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2 H ₂ O, 28.48 g of Na ₂ HPO ₄ .12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml double distilled water. It is adjusted to pH 6.8, made up to 1 l 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 formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.  

Example F Dragees

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example 6 Capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

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

Claims (10)

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 are H, Ar, Het, R ⁵ , where at least one of the two radicals is R ⁵ ,
R ⁵ by -C (= NH) -NH ₂ , which can also be simply substituted by -COA, Ar- [C (R ⁷ R ^{7 '} )] _n -CO-, COOA, OH or by a conventional amino protecting group, NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,
Substituted phenyl, naphthyl or biphenyl, which may optionally be mono- or disubstituted by A, Ar ', Het, OR ⁶ , NR ⁶ R ^6' , NO ₂ , ON, Hal, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ SO ₂ A, NR ⁶ SO ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , COR ⁷ , CO-Ar ', SO ₂ NR ⁶ R ^6' , S (O) _n Ar 'or S (O) _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 ,
A alkyl having 1-20 C atoms, in which one or two CH ₂ groups can be replaced by O or S atoms and / or by CH = CH groups and / or also 1-7 H atoms by F,
Ar unsubstituted or single, double or triple by A, Ar ', Het, OR ⁶ , NR ⁶ R ^6' , NO ₂ , CN, Hal, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ SO ₂ A, NR ⁶ SO ₂ Ar ', COOR ⁶ , CO-NR ⁶ R ^6' , CON ⁶ Ar ', COR ⁷ , COAr', SO ₂ NR ⁶ R ^{6 '} , S (O) _n Ar' or S (O) _n A substituted phenyl, naphthyl or biphenyl,
Ar 'unsubstituted or single, double or triple by A, OR ⁷ , NR ⁷ R ^7' , NO ₂ , CN, Hal, NR ⁷ COA, NR ⁷ SO ₂ A, COOR ⁷ , CO-NR ⁷ R ^{7 '} , COR ⁷ , SO ₂ NR ⁷ R ^{7 '} or S (O) _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, which is unsubstituted or mono-, di- or triple by A, OR ⁷ , NR ⁷ , NO ₂ , CN, Hal, NR ⁷ COA, NR ⁷ SO ₂ A, COOR ⁷ , CO-NR ⁷ R ^{7 '} , COR ⁷ , SO ₂ NR ⁷ R ^7' , S (O) _n A and / or carbonyl oxygen can be substituted ,
Hal F, Cl, Br or I,
n is 0, 1 or 2,
as well as their pharmaceutically acceptable salts and solvates. 2. Compounds according to claim 1

• a) 7- [5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyi] -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-1H-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) liberating them from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent, by
  • a) releases an amidino group from its oxadiazole derivative or oxaz olidinone derivative by hydrogenolysis or solvolysis,
  • b) 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

• a) in a compound of formula I converts one or more radicals R ¹ , R ² , R ³ and / or R ⁴ into one or more radicals R ¹ , R ² , R ³ and / or R ⁴ ,
  for example by
  • a) hydrolyzing an ester group to a carboxy group,
  • b) a nitro group is reduced,
  • c) acylating an amino group,
  • d) a cyano group in an amidino group and / or
• b) converting a base or acid of the formula I into one of its salts.

4. Process for the preparation of pharmaceutical preparations, thereby characterized in that a compound of formula I according to An saying 1 and / or one of their physiologically acceptable salts together with at least one solid, liquid or semi liquid carrier or auxiliary in a suitable dosage form brings. 5. Pharmaceutical preparation, characterized by a content on at least one compound of the formula I according to claim 1 and / or one of their physiologically acceptable salts. 6. Compounds of formula I according to claim 1 and their physiological harmless salts or solvates as active pharmaceutical ingredients. 7. Compounds of formula I according to claim 1 and their physiological harmless salts to combat thrombosis, myocar dialem infarct, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication. 8. Medicament of formula I according to claim 1 and their physiologically un questionable 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 production of egg drug. 10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the fight  for thrombosis, myocardial infarction, arteriosclerosis, ent Ignitions, apoplexy, angina pectoris, restenosis after angiopla stie and intermittent claudication.