SK12152001A3 - Pyrazole-3-on-derivative as factor xa inhibitors - 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

Pyrazol-3-one derivative as a factor Xa inhibitor, process for its preparation, use thereof and pharmaceutical composition containing it

Technique area

The invention relates to pyrazol-3-one derivatives of the general formula I

wherein R ^{@ 1} , R ^{@ 2} independently of one another are hydrogen, A, + cycloalkyl [C (R @ ⁷ R @ ⁷ ') n - or Ar - [C (R @ ⁷ R @ ⁷ ')] n -,

R ^3, R ⁴ independently of one another, H, Ar, Het, R ^5, wherein at least one of is R ^5,

R ^{5 is} -C (= NH) -NH 2, which is also optionally once substituted by -COA, Ar- [C (R ⁷ R ⁷ '] n -CO-, COOOA, OH or a conventional amino protecting group, or - NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl group optionally having one or two substituents r

- 2 entities from group A, Ar ', Het, OR ⁶ ,

NR ⁶ R ⁶ ', N02, CN, Hal, COA NR ^6, NR ⁶ COAr', NR ⁶ SO2A,

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 'and S (O) _n A,

R ⁶ R ⁶ 'independently of one another are hydrogen, A, CR ⁷ R ⁷ ' -Ar 'or CR ⁷ R ⁷ ' -Het,

R ⁷ , R ⁷ ', independently of one another, are hydrogen, A,

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

A is alkyl having 1 to 20 carbon atoms, in which one or two CH ₂ -groups are optionally replaced by O or S, and / or by -CH = CH / or one to seven hydrogen atoms may be replaced by F,

Ar is phenyl, naphthyl or biphenyl unsubstituted or substituted by one, two or three substituents selected from the group consisting of A, AT ', Het, OR ⁶ , NR ⁶ R ⁶ ', NO 2, CN, Hal, NR ⁶ COA, NR ⁶ COAr ' , NR ⁶ SO2A, NR ⁶ SO ² Ar ', COOR ⁶ , CO-NR ⁶ R ⁶ ', CO ⁶ Ar ', COR ⁷ , CO-Ar', SO ² NR ⁶ R ⁶ ', S (O) _n Ar' and S ( O) _n A,

Ar 'phenyl or naphthyl unsubstituted or substituted by one, two or three substituents selected from the group consisting of A, OR ⁷ , NR ⁷ R ⁷ ', NO 2, CN, Hal, NR ⁷ COA, NR ⁷ SO 2A, COOR ⁷ , CO-NR ⁷ R ⁷ ', COR ⁷ , SO ² NR ⁷ R ⁷ ' and S (O) nA,

Het a mononuclear or bi-core saturated or unsaturated or aromatic hetero group having from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, which is unsubstituted or has one, two or three substituents from the group consisting of.

- 3 A, OR ⁷ , NR ⁷ R ⁷ ', NO 2, CN, Hal, NR ⁷ COA, NR ⁷ SO 2A, COOR ⁷ ,

CO-NR ⁷ R ⁷ ', COR ⁷ , SO ² NR ⁷ R ⁷ ' and S (O) n A and / or oxo,

Hal is a fluorine, chlorine, bromine or iodine atom, n 0/1 or 2, and pharmaceutically acceptable salts and solvates thereof.

BACKGROUND OF THE INVENTION

Aromatic amidine derivatives having antithrombotic activity are known from European patent specification EP 0 540051 G1. Cyclic guanidines for the treatment of thromboembolic diseases are known, for example, from WO 97/08165. Aromatic heterocyclic compounds having Factor Xa inhibitory activity are known from WO 97/10022. Substituted N - [(aminoiminomethyl) phenylalkyl] azaheterocyclylamides as Factor Xa inhibitors are described in WO 96/40679.

SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds having valuable properties, in particular suitable for the manufacture of medicaments.

SUMMARY OF THE INVENTION

The present invention relates to the compounds of formula I as described above.

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

It has been found that the compounds of the formula I and their salts have, with good tolerability, very valuable pharmacological properties. In particular, they exhibit Factor Xa inhibiting properties and can therefore be used in the treatment and prevention of three boembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angioplasty restenosis and gastric pain in walking (Claudicatio intermitt).

The compounds of formula I may also be inhibitors of the clotting factors VIIa, IXa and thrombin in the blood clotting cascade.

The antithrombotic and anticoagulant activity of the compounds of the invention is derived from an inhibitory action on an activated clotting protease, referred to as factor Xa, or from inhibiting other activated serine proteases such as factor VIIa, factor IXa or thrombin.

Factor Xa is a protease involved in a complex blood coagulation process. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin cleaves fibrinogen into fibrin monomers which, once crosslinked, contribute elementally to thrombus formation. Activation of thrombin can lead to thromboembolic diseases. However, by inhibiting thrombin, the formation of fibrin that is involved in thrombus formation can be inhibited. Measurement of thrombin inhibition is possible as described by G.F. Cousins et al. (Circulation 94: 1705-1712, 1996).

Thus, inhibition of factor Xa prevents the formation of thrombin.

The compounds of formula I and their salts interfere with the inhibition of factor Xa in the blood coagulation process, thereby inhibiting the formation of thrombi.

Inhibition of factor Xa by the compounds of the invention and the measurement of anticoagulant and antithrombotic effects are possible by conventional in vitro and in vivo methods. A suitable method is described, for example, by J. Hauptmann et al. (Thrombosis and Haemostasis 63: 220-223 (1990)).

The inhibition of factor Xa can be measured, for example, by the method of T. Hara et al. (Thrombosis and Haemostasis 71, 1994, pp. 314-319).

Clotting Factor VIIa, upon binding to tissue factor, initiates an externally acting portion of the clotting cascade and contributes to the activation of Factor X to Factor Xa. Thus, inhibition of Factor VIIa prevents the formation of Factor Xa and consequently thrombus formation.

The inhibition of the clotting factor VIIa by the compounds of the invention and the measurement of antithrombotic and anticoagulant activity are carried out by known methods in vitro and in vivo. A conventional method for measuring factor VIIa inhibitory activity is described, for example, by H.F. Ronning et al. (Thrombosis Research 84: 73-81, 1996).

The clotting factor IXa is generated in the intrinsic clotting cascade and is also involved in the activation of factor X to factor Xa. Thus, inhibition of factor IXa may prevent the formation of factor Xa.

Inhibition of factor IXa by the compounds of the invention and measurement of antithrombotic and anticoagulant activity is accomplished by known methods in vitro and in vivo. A suitable measurement method is described, for example, by J. Chang et al. (Journal of Biological Chemistry 273, pp. 12089-12094, 1998).

The compounds of the formula I can be used as medicament active compounds in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angioplasty restenosis and calf pain muscles while walking (Claudicatio intermittens).

à F »

Thus, the present invention provides compounds of the general formula

I and their salts. According to the invention, the process for the preparation of the compounds of the formula I and their salts consists in:

(a) are released from their functional derivatives by treatment with solvolysis and hydrogenolysis agents so as to:

(i) that the amidino group is liberated from its oxadiazole or oxazolidinone derivative by hydrogenolysis or solvolysis; (ii) the conventional amino-protecting groups are replaced with hydrogen by solvolysis and hydrogenolysis agents, or the amino-protected group is released by conventional protecting groups;

(b) in a compound of formula (I), one or more R ³ , R ² , R ³ and / or R ⁴ groups is changed to one or more other R ¹ , R ² , R ³ and / or R ⁴ groups such that: for example

i) the ester group hydrolyzes to the carboxyl group, ii) the nitro group is reduced, iii) the amino group is acylated, iv) the cyano group is converted to the amidino group and / or

c) the base or acid of formula I is converted to a salt.

All groups that occur several times have independent meaning.

The groups R ^{@ 1} , R ^{@ 2} , R ^{@ 3} , R @ ⁴ , X and Y are each as defined in formula (I) unless otherwise stated.

The symbol A is always understood to mean an alkyl group unbranched (linear) or branched having 1 to 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbon atoms. Preferably A is methyl, further ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and 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, further preferably trifluoromethyl. More preferably, A is C 1 -C 6 alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

Cycloalkyl is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl group.

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

Ar is preferably phenyl, naphthyl or biphenyl unsubstituted or substituted by one or two substituents selected from the group consisting of A, Ar, Het, OR ⁶ , NR ⁶ R ⁶ ', NO 2, CN, Hal, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ SO 2A, NR ⁶ SO ² Ar', COOR ⁶ , CO-NR ⁶ R ⁶ ', CON ⁶ Ar', COR ⁷ , CO-Ar ', SO ² NR ⁶ R ⁶ ', S (O) _n Ar ' and S (O) _n A. Preferred biphenyl substituents are fluorine, SO ₂ NH ₂ or SO ₂ NHA.

Ar 'is preferably phenyl or naphthyl unsubstituted or substituted by one, two or three substituents selected from the group consisting of A, Het,

OR ⁶ , NR ⁶ R ⁶ ', NO 2, CN, Hal, NR ⁶ COA, NR ⁶ SO 2A, 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.

Ar is preferably unsubstituted phenyl, naphthyl or biphenyl, further preferably a phenyl or naphthyl group monosubstituted, disubstituted or trisubstituted by a group selected from, for example, methyl, ethyl, propyl, isopropyl, butyl, chloro, hydroxy, bromo, hydroxy, bromo, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-l-yl, piperidin-l-yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, tert-butylsulfonamido, tert-butylaminosulfonyl, dimethylsulfonamido, phenylsulfonamido, methoxycarbonyl, carboxyl, dimethylaminocarbonyl, phenyls nocarbonyl, acetyl, propionyl, benzoyl, methylsulfonyl and phenylsulfonyl groups.

Ar 'is preferably an unsubstituted phenyl or naphthyl group, further preferably a phenyl or naphthyl group monosubstituted, disubstituted or trisubstituted by a group selected from, for example, methyl, ethyl, propyl, isopropyl, butyl, fluorine, chlorine, chlorine, chlorine, hydroxy, chlorine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-l-yl, piperidin-l-yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, methoxycarbonyl, carboxyl, dimethylaminocarbonyl, phenylaminocarbonyl, acetyl, propionyl, benzoyl, methylsulfonyl and bitches a sulfonyl group.

Ar is particularly preferably, for example, phenyl, naphthyl, biphenyl o-, m- or p-tolyl, o-, er-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-methylminocarbonyl) 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-, male- 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'-sulfamoylbiphenyl-4-yl, 3-fluoro-2'-N-tert-butylsulfamoylbiphenyl-4-yl, 2'-sulfamoylbiphenyl-4 -yl, 2'-N-tert-butylsulfa moylbiphenyl-4-yl, o-, m- or p- (pyrrolidin-1-yl) phenyl, o-, m- or p- (piperidin-1-yl-phenyl), further preferably a 2,3-, 2-group; , 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-chlorophenyl, 2-amino-3-chlorophenyl, 2-amino-4-chlorophenyl, 2-anino 5-chlorophenyl,

2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylaminophenyl,

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 'is particularly preferably 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-, m10 or p-hydroxyphenyl, ο-, m- or p-nitrophenyl, o-, male or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylminocarbonyl) 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'-sulfamoylbiphenyl-4-yl, 3-fluoro-2'-N-tert-butylsulfamoylbiphenyl-4-yl, 2'-sulfamoylbiphenyl-4-yl, 2'-N-tert-butylsulfamoylbiphenyl-4-yl o, o-, m- or p- (pyrrolidin-1-yl) phenyl or o-, m- or p- (piperidin-1-yl) phenyl group.

The symbol Het preferably represents, for example, the group 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 a 1,2,3-triazole group -1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole-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-cinolinyl,

2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxap-11-vinyl, 2-, 3-, 5-, 6-, 7- or 8-2H- benzo [1,4] oxazinyl further 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 groups may also be partially or fully hydrogenated.

Thus, Het may also be, for example, 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-, 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-dioxane-2-4- or -5 -yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2- or -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-isoquinolinyl, 2-, 3-, 5-, 6-, 7- or 8-3,4- the dihydro-2H-benzo [1,4] oxazinyl group further preferably is 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- (2-oxomethylenedioxy) phenyl or also 3,4-dihydro-2H-1,5-benzodioxepin-6- or 7-yl, also 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl .

Het is unsubstituted or has one, two or three substituents selected from the group consisting of 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 ' and S (O) _n A and / or carbonyl oxygen.

Particularly preferably, Het is furyl, thienyl, thiazolyl, imidazolyl, [2,1,3] benzothiadiazolyl, oxazolyl, pyridyl, indolyl, piperidinyl or pyrrolidinyl.

The symbol R ¹ is preferably, for example, H, A, a cycloalkyl-CH ₂ - or _Ar-CH2 ~, particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 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, further preferably a trifluoromethyl group. More preferably, R ^{@ 1} is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl.

The symbol R ² is preferably, for example, H, A, a cycloalkyl-CH ₂ - or Ar-CH ₂ -, particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 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, further preferably a trifluoromethyl group . Very particularly preferably R ² is hydrogen.

about

R is preferably, for example, hydrogen, Ar, Het, -C (= NH) -NH ₂ , which is also optionally substituted with -COA, Ar-CH ₂ -CO-, COOA, OH or a conventional group. an amino protecting group, or -nh-c (= nh) -nh ₂ , -co-n = c (nh ₂ ) ₂ ,

substituted phenyl, naphthyl or biphenyl.

The symbol R ³ is preferably, for example, H, phenyl, NH ₂ SO ₂ - mono- substituted phenyl, naphthyl or biphenyl group, a -C (= NH) -NH _2, or

or

substituted phenyl, naphthyl or biphenyl.

R ⁴ is preferably, for example, hydrogen, Ar, Het, -C (= NH) -NH ₂ , which is also optionally once substituted by -COA, Ar-CH ₂ -CO-, COOA, OH or a conventional group amino protecting group, or -NH-C (= NH) -NH ₂ , -co-n = c (nh ₂ ) ₂ ,

or

substituted phenyl, naphthyl or biphenyl.

The symbol R ⁴ represents a particular example, H, phenyl, NH ₂ SO ₂ - mono- substituted phenyl, naphthyl or biphenyl group, a -C (= NH) -NH _2, or

or

substituted phenyl, naphthyl or biphenyl.

R ⁶ and R ⁶ 'independently of one another preferably represent, for example, a hydrogen atom, a methyl, ethyl, propyl, butyl or benzyl group, in particular a hydrogen atom, a methyl, ethyl, propyl or butyl group.

R @ ⁷ and R @ ⁷ 'independently of one another preferably represent, for example, a hydrogen atom, a methyl, ethyl, propyl group, very preferably a hydrogen atom.

One of X and Y is each independently preferably a group such as _{(CH2) n,} wherein n is preferably whole is preferably 0 or the first

The compounds of formula I may have one or more chiral centers and may therefore be in different stereoisomeric forms. Formula I includes all these forms.

Accordingly, the invention relates in particular to compounds of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula (I) are the following compounds of formulas (Ia) to (Ie), wherein not specifically indicated are as defined in formula (I), wherein in formula (Ia) R ¹ , R ² are independently hydrogen or A,

Ib R ³ , R ⁴ independently of one another hydrogen or Ar, or R ⁵ , wherein at least one of the symbols represents a group R ⁵ ,

R ^{5 is} -C (= NH) -NH ₂ , which is also optionally once substituted with -COA, Ar- (CH ₂ ) _n -CO-, COOA, OH or a conventional amino-protecting group, or -NH-C ( = NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

or

substituted phenyl, naphthyl or biphenyl,

Ic R ¹ group A,

R ² is H,

R ^3, R ⁴ independently of one another H or Ar, or R ^5, wherein at least one of is R ^5,

R ^{5 is} -C (= NH) -NH ₂ , which is also optionally once substituted by -COA, Ar- (CH ₂ ) _n -CO-, COOA, OH or a conventional amino protecting group, or -NH-C ( = NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ , {

or

substituted phenyl, naphthyl or biphenyl,

Id R ¹ group A,

R ² is H,

R ^3, R ⁴ independently of one another H or Ar, or R ^5, wherein at least one of is R ^5,

R ^{5 is} -C (= NH) -NH ₂ , which is also optionally once substituted with -COA, Ar- (CH ₂ ) _n -CO-, COOA, OH or a conventional amino-protecting group, or -NH-C ( = NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ , or

HN <

ABOUT

substituted phenyl, naphthyl or biphenyl,

A (C1-C6) alkyl,

X, Y are independently (CH ₂ ) _n ,

Ie R ^{1 is} group A,

R ² is H,

R ^3, R ⁴ independently of one another H or Ar, or R ^5, wherein at least one of is R ^5,

R ^{5 is} -C (= NH) -NH ₂ or

- - -J

CH, f rr * rr * r *

- 17 substituted phenyl, naphthyl or biphenyl,

Ar with a group SO ₂ NR R a substituted biphenyl group,

R ⁶ , R ⁶ 'independently of one another are hydrogen or A,

A (C1-C6) alkyl,

X, Y independently of one another (CH ₂ ) _n ·

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

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

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

The starting materials for solvolysis or hydrogenolysis are compounds which otherwise correspond to the above formulas, but instead have free amino or hydroxyl groups corresponding to protected amino or hydroxy groups, preferably compounds which have a protecting group instead of a hydrogen atom which is bonded to a nitrogen atom. amino, especially compounds of formula I which have an R'-N group instead of the HN group, wherein R 'is an amino protecting group and / or compounds which have a hydroxyl protecting group instead of a hydrogen atom in a hydroxyl group, e.g. -COOH have a -COOR group wherein R is a hydroxyl protecting group. Preferred starting materials are also oxadiazole derivatives which can be converted to the corresponding amidino compounds.

For example, the liberation of the amidino group from its oxadiazole derivatives is possible by cleavage of hydrogen in the presence of a catalyst (e.g., water-moistened Raney-nickel). Suitable solvents are the following solvents, in particular alcohols such as methanol, ethanol, organic acids such as acetic or propionic acid or mixtures thereof. The hydrogenolysis is generally carried out at a temperature of 0 to 100 ° C and at a pressure of 1 to 20 MPa, preferably at a temperature of 20 to 30 ° C and at a pressure of 0.1 to 1 MPa.

The introduction of the oxadiazole moiety is accomplished, for example, by reacting the cyano compound with hydroxylamine and reacting with phosgene, dialkyl carboxylate, chloroformic acid ester, Ν, Ν-carbonyldiimidazole or acetic anhydride.

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

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

Depending on the protecting group used, the release of the compounds of the formula I from their functional derivatives is successful, for example with strong acids, preferably trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids. such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are, for example, organic carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol. as well as water. Mixtures of these solvents may also be suitable. Trifluoroacetic acid is preferably used in excess without the addition of additional solvents, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. Reaction r * p r

The 20 cleavage temperature is expediently about 0 to about 50 ° C, preferably 15 to 30 ° C (room temperature).

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

Hydrogenolytically removable protecting groups (e.g. CBZ or benzyl or amidino groups from an oxadiazolobic derivative) can be cleaved off: for example by treatment with hydrogen in the presence of a catalyst (e.g. noble metal catalyst such as palladium, suitably supported, such as carbon). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C, at a pressure of about 1 to 20 MPa, preferably at a temperature of 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group succeeds well, for example on 5-10% Pd-C in methanol or using ammonium formate (instead of hydrogen) on Pd in methanol / DMF at 20-30 C. ^e.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, trifluoromethylbenzene, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethyl21 acetamide, N-methylpyrrolidone (NMP) dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulphide; organic carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; water or mixtures of these solvents.

_Biphenyl-2 to the NH ₂ -group is used preferably in the form of its tert-butyl derivative. The cleavage of the t-butyl group is carried out, for example, with trifluoroacetic acid with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1-10% by volume).

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

For the preparation of an amidine of the formula I (where, for example, Ar represents a C (= NH) -NH ₂ substituted phenyl group), ammonia can also be added to the nitrile. The addition is preferably carried out a number of steps by, in a manner known per se a) converting the nitrile with hydrogen sulfide to yield the thioamide, which is an alkylating agent such as methyl iodide is converted into the corresponding S-alkylimidothioester, which is then reacting with ammonia (NH ₃₎ to give the amidine; b) reacting the nitrile with an alcohol, for example ethanol, in the presence of hydrogen chloride to give the corresponding imidoester, which is then treated with ammonia; or c) reacting the nitrile with lithium bis- (trimethylsilyl) amide and then hydrolyzing the product.

Introduction of the -XR ³ group into the pyrazolone system with X = CH ₂ is possible, for example, by reaction of a compound of formula II

/ HR ² wherein R ¹ , R ² and R ⁴ are as defined in formula I and are non-alkylable and Y is as defined in formula I, with a compound of formula III r ³ -ch ₂ -l (III) where R is ^{3 is a} non-alkylable group as defined in formula I, for example a 5-methyl [1,2,4] oxadiazol-3-yl substituted phenyl group, and L represents a chlorine, bromine, iodine or ηϊηύ atom or a reactive functionally modified hydroxyl group.

Preferably L is a chlorine, bromine, iodine or reactive functionally modified hydroxyl group such as an activated, ester, imidazolide or alkylsulfonyloxy group (preferably methylsulfonyloxy) or arylsulfonyloxy group (preferably 6 to 10 carbon atoms) phenylsulfonyloxy or p-tolylsulfonyloxy).

Pyrazolone ring systems are built by known methods of reacting the appropriate β-ketoester with hydrazine or a hydrazine derivative.

In addition, it is possible to convert compounds of formula I to other compounds of formula I by changing one or more R ¹ , R ² , R ³ and / or R ⁴ groups to one or more other R ¹ , R ² groups , R ³ and / or R ⁴ for example by acylating the amino group or reducing the nitro group (for example, by hydrogenation in the presence of Raney nickel or palladium on carbon in an inert solvent such as methanol or ethanol) to the amino group.

Esters can be saponified, for example, using acetic acid or using NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 ^e C

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

The base of formula (I) may be converted into an appropriate acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and subsequently evaporating the solvent.

Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or non-polycarboxylic, sulfonic acids may be used. or sulfuric acids such as formic, acetic, propionic, pivalic, diethyl acetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, ethanesulfonic, methanesulfonic, methanesulfonic, -hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid, naphthalenedisulfonic acid and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I.

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

The compounds of the formula I can be chiral on the basis of their molecular structure and can therefore be in various enantiomeric forms. They may therefore be in racemic or optically active form.

In the case of racemic amines, diastereomers can be formed from the mixture by reaction with an optically active resolving agent.

Examples of such resolving agents are optically active acids such as the D and L forms of tartaric, diacetyltartaric, dibenzoyltartaric, mandelic, malic or lactic acid, suitably nitrogen-protected amino acids (e.g. N-benzoylproline or N-benzolsulfonylproline) or various optically active camphorsulfonic acids. Also preferred is chromatographic resolution of enantiomers by columns packed with optically active resolving agents (e.g. dinitrobenzoylphenylglycine, cellulose triacetate, or other hydrocarbon derivatives or silica-fixed chiral derivatized methacrylate polymers). Suitable eluents are, for example, hexane / isopropanol / acetonitrile, for example in a 82: 15: 3 by volume ratio.

The invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical compositions, in particular by a non-chemical route. For this purpose, they can be converted into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more other active substances.

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

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

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

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

The invention is illustrated by the following non-limiting examples. Temperatures are always given in degrees Celsius. In the following examples, the expression conventional processing means:

Optionally, water is added or, depending on the constitution of the final product, the pH is adjusted to 2-10, the reaction mixture is extracted with ethyl acetate or dichloromethane, separated, dried over the organic phase with sodium sulfate, evaporated and purified by silica gel chromatography ‘/ or crystallization. The Rf values are on silica gel, the mobile phase is an ethyl acetate / methanol system (9: 1 by volume).

Mass Spectrometry (MS): EI (electron impact ionization) M ⁺ FAB (fast atom bombardment) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To 4.0 g of 3- (7-bromomethylnaphthalen-2-yl) -5-methyl [1,2,4] oxadiazole and 2.1 g of ethyl isobutyl acetate in 50 ml of acetonitrile was added 4.3 g of cesium carbonate. The suspension was stirred at room temperature for 20 hours. The mixture was filtered, the solvent was removed and the residue was chromatographed on silica gel. Pentane acid (AA) 4-methyl-2- [7- (5-methyl- [1,2,4] oxadiazol-3-yl) naphthalen-2-ylmethyl] -3-oxopentanethyl ester was obtained as a colorless oil, FAB 381. .

A solution of 1.30 g (AA) and 0.62 ml of hydrazinium hydroxide in 10 ml of acetic acid is maintained at reflux for 24 hours. After usual work-up, 5-isopropyl-4- [7- (5-methyl- [1,2,4]] oxadiazol-3-yl-naphthalen-2-ylmethyl] -1,2-dihydropyrazol-3-one (AB) is obtained. ), FAB 349.

A solution of 60 mg AB in 5 ml methanol was mixed with 60 mg Raney nickel and 30 mg acetic acid and hydrogenated at room temperature for 18 hours. The catalyst was filtered off, the solvent was removed to give 7- [5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-4-ylmethyl] -2-amidinonaphthalenediacetate, FAB 309.

Example 2

A solution of 100 mg of AB and 68 mg of 3- (3-bromomethylphenyl) -5-methyl [1,2,4] oxadiazole in 10 ml of acetonitrile was combined with 94 mg of cesium carbonate and stirred at room temperature for 20 hours. After usual work-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-dihydropyrazol-3-one, FAB 521.

Analogously to Example 1, 3- [4- (7-amidinonaphthalin-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] benzamidine diacetate, FAB, is obtained from this product by hydrogenation. 441st

Similarly, it is obtained

4- [4- (7-amidinonaftalin-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-pyrazol-2-ylmethyl] benzamidine.

Similarly, it is obtained by reacting AB with 3- (7-bromomethylnaphthalin-2-yl- (5-methyl- [1,2,4]] oxadiazole) followed by hydrogenation of diacetate 7- [4- (7-amidinonaphth-2-ylmethyl) - 5-Isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidinonaphthalene, FAB 491.

Example 3

Analogously to Example 1, ethyl 4-methyl-2- [3- (5-methyl [1,2, 5-methyl- [1,2,4]] oxadiazol-3-yl) benzyl bromide was added to methyl isobutyl acetate. 4]] oxadiazol-3-yl) benzyl] -3-oxopentanoic acid (AC) as a colorless oil,

FAB 317.

(AC)

Treatment of this product with hydrazinium hydroxide gives 5-isopropyl-4- [3- (5-methyl- [1,2,4]] oxadiazol-3-yl) benzyl] -1,2-dihydropyrazol-3-one, FAB 299 (AD).

Hydrogenation of this product gave [3- (5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-4-ylmethyl) -benzamidine.

Similarly, they are obtained by reacting (AD) with 3- (3-bromomethylphenyl) -5-methyl-1,2,4] oxadiazole, with 3- (7-bromomethylnaphthalin-2-yl) 5-methyl- [1,2,4] oxadiazole, with 2- (tert-butylaminosulfonyl) -4'-bromomethylbiphenyl, followed by hydrogenation of 3- [4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazole- 2-ylmethyl] benzamidine, FAB 391;

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

4 '- [4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-tert-butylaminosulfonyl) biphenyl and from it cleavage of the tert-butyl group trifluoroacetate 4' - [4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-aminosulfonylbiphenyl, FAB 504.

Similarly, they are obtained

7- [4- (4-amidino-benzyl) -5-isopropyl-3-oxo-2,3-dihydro-lH-pyrazole

2-ylmethyl] -2-amidinonaphthalene a

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

Example 4

Analogously to Example 1, 5-isopropyl-1,2-dihydropyrazol-3-one is reacted with 3- (7-bromomethylnaphthalin-2-yl) -5-methyl- [1,2,4]] oxadiazole followed by diacetate hydrogenation 5-Isopropyl-2- [7-amidinonaphthalin-2-ylmethyl] -1,2-dihydropyrazol-3-one (AB), FAB 309.

Example 5

Analogously to Example 1, starting from 3- (7-bromomethylnaphthalen-2-yl) -5-methyl- [1,2,4]] oxadiazole as starting material and 3-oxo-ethyl butyrate by reaction with hydrazine followed by by reaction with 3- (7-bromomethylnaphthalen-2-yl) -531

methyl [1,2,4] oxadiazole and hydrogenation of 7- [4- (7-amidinonaphth-2-ylmethyl) -5-methyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] - 2-amidinonaphthalene.

When replacing 3-oxo-ethyl butyrate with 3-oxoethyl heptanoate, analogously 7- [4- (7-amidinonaphth-2-ylmethyl) -5-butyl-3-oxo-2,3-dihydro-1H- pyrazol-2-ylmethyl] -2-amidinonaphthalene.

Example 6

Analogously to Example 1, from 2- (tert-butylaminosulfonyl-4'-bromomethylbiphenyl as starting material) and ethyl isobutyl acetate by reaction with hydrazine followed by reaction with 3- (3-bromomethylphenyl) -5-methyl [1,2,4] oxadiazole. , hydrogenation and cleavage of tert-butyl group of 3- [4- (2-aminosulfonylbiphenyl-4'ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] benzamidine trifluoroacetate, FAB 504 .

Similarly, 7- [4- (2-aminosulfonylbiphenyl-4'ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-amidinaphthalene trifluoroacetate is obtained, FAB 554.

Example 7

In analogy to Examples 1 and 2, the following compounds were obtained:

7- (4-benzyl-5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl) -2-amidinonaphthalene; and

7- [2-benzyl-5-isopropyl-3-oxo-2,3-dihydro-lH-pyrazol-4-ylmethyl] -2-amidinonaphthalene.

Example 8

Analogously to Example 1, the hydrazine is replaced with phenylhydrazine

7- [5-isopropyl-3-oxo-2-phenyl-2,3-dihydro-lH-pyrazol-4-ylmethyl] -2-amidinonaphthalene.

The following examples illustrate pharmaceutical compositions:

Example A. Injection ampoules

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

Example B. suppositories

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

Example C. Solution

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

Example D. Ointment

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

Example E. Tablets

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

Example F. Dragees

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

EXAMPLE G. Capsules of kg of active ingredient of the formula I are filled into hard gelatin capsules in a known manner such that each capsule contains 20 mg of active ingredient.

Example H. Ampoules

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

Industrial usability

The pyrazol-3-one derivative and its pharmaceutically acceptable salts are useful as coagulation factor Xa inhibitors for the manufacture of pharmaceutical compositions for the treatment of thromboembolic diseases.

Claims (10)

PATENT CLAIMS CLAIMS 1. Compounds of formula (I) EMI3.0 wherein is R ^{@ 1} , R ^{@ 2} independently of one another are hydrogen, A, cycloalkyl [C (R @ ⁷ R @ ⁷ ')] - or Ar - [C (R @ ⁷ R @ ⁷ ']] -, R ^3, R ⁴ independently of one another, H, Ar, Het, R ^5, wherein at least one of is R ^5, R ^{5 is} -C (= NH) -NH ₂ , which is also optionally once substituted with -COA, Ar- [C (R ⁷ R ⁷ ') _n -CO-, COOA, OH, or a conventional amino-protecting group, or -NH-C (= NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ , or a substituted phenyl, naphthyl or biphenyl group optionally having one or two substituents from the group consisting of A, Ar ', Het , OR ⁶ , NR ⁶ R ⁶ ', NO 2, CN, Hal, NR ⁶ COA, NR ⁶ CO 2', NR ⁶ SO 2A, NR ⁶ SO ² Ar ', COOR ⁶ , CO-NR ⁶ R ⁶ ', COR ⁷ , CO- Ar 'SO2NR ⁶ R ⁶ ', S (O) _n Ar 'and S (O) _n A, rr R ŕ - 35 R ⁶ R ⁶ 'independently of one another hydrogen, A, CR ⁷ R ^7, -Ar' or CR ⁷ R ^7, -Het, R ⁷ , R ⁷ ', independently of one another, are hydrogen, A, X, Y independently of one another (CR ⁷ R ⁷ ') _n , A is alkyl having 1 to 20 carbon atoms, in which one or two CH ₂ -groups are optionally replaced by O or S, and / or by -CH = CH / or one to seven hydrogen atoms may be replaced by F, Ar is phenyl, naphthyl or biphenyl unsubstituted or substituted by one of two or three substituents selected from the group consisting of A, Ar ', Het, OR ⁶ , NR ⁶ R ⁶ ', NO 2, CN, Hal, NR ⁶ COA, NR ⁶ COAr ', NR ⁶ SO 2A, NR ⁶ SO ² Ar ', COOR ⁶ , CO-NR ⁶ R ⁶ ', CO ⁶ Ar ', COR ⁷ , CO-Ar', SO ² NR ⁶ R ⁶ ', S (O) _n Ar' and S (O ) _n A, Ar 'phenyl or naphthyl unsubstituted or substituted by one, two or three substituents from the group consisting of A, OR ⁷ , NR ⁷ R ⁷ ', NO ₂ , CN, Hal, NR ⁷ COA, NR ⁷ SO 2A, COOR ⁷ , CO-NR ⁷ R ⁷ ', COR ⁷ , SO ² NR ⁷ R ⁷ ' and S (O) _n A, Het a mononuclear or bi-core saturated or unsaturated or aromatic hetero group of 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur which is unsubstituted or has one, two or three substituents from the group A, OR ⁷ , NR ⁷ R ⁷ ' , NO ₂ , CN, Hal, NR ⁷ COA, NR ⁷ SO 2A, COOR ⁷ , CO-NR ⁷ R ⁷ ', COR ⁷ , SO ² NR ⁷ R ⁷ ' and S (O) _n A and / or oxo, Hal is fluorine, chlorine, bromine or iodine, n 0,1 or 2, and pharmaceutically acceptable salts and solvates thereof. Compounds according to claim 1 of the general formula I (a) 7- [5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] -2-aminononaphthalene; (b) 7- [4- (7-amidinonaphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-ΙΗ-pyrazol-2-ylmethyl] -2-amidinonaphthalene; (c) 3- [4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl] benzamidine; d) 3- [4- (7-amidinonaphth-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-aminononaphthalene and pharmaceutically acceptable salts and solvates thereof. A process for the preparation of the compounds according to claim 1 and their salts, characterized in that: (a) are released from their functional derivatives by treatment with solvolysis and hydrogenolysis agents so as to: (i) that the amidino group is liberated from its oxadiazole or oxazolidinone derivative by hydrogenolysis or solvolysis; I, one or more groups of R ¹ , R ² , R ³ and / or R ⁴ is changed to one or several other groups of R ¹ , R ² , R ³ and / or R ⁴ such that, for example, i) the ester group hydrolyzes to the carboxyl group, ii) the nitro group is reduced, iii) the amino group is acylated, iv) the cyano group is converted to the amidino group and / or c) the base or acid of formula I is converted to a salt. A process for the preparation of a pharmaceutical composition, characterized in that the compound according to claim 1 and / or a physiologically acceptable salt thereof is formulated in a suitable dosage form together with at least one solid liquid or semi-liquid carrier or excipient. Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound of the formula I according to claim 1 and / or a physiologically acceptable salt thereof. Compounds according to claim 1 of the formula I and their physiologically acceptable salts and solvates as active substances of medicaments. Compounds according to claim 1 of the formula I and their physiologically acceptable salts and solvates for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angioplasty restenosis and gastric walking pain. A medicament according to claim 1 and physiologically acceptable salts thereof as inhibitors of coagulation factor Xa. Use of the compounds according to claim 1, and / or their physiologically acceptable salts, for the manufacture of medicaments. Use of the compounds according to claim 1, and / or their physiologically acceptable salts, for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, angioplasty restenosis and gastric pain in walking.