KR20010102428A - Pyrazole-3-on-derivative as factor xa inhibitors - Google Patents

Abstract

The present invention is a novel compound of formula (I):

[Formula I]

(Wherein R ¹ , R ² , R ³ , R ⁴ , X and Y have the meaning given in claim 1)

It is about. The compound is an inhibitor of coagulation factor Xa and can be used for the prevention and / or treatment of thromboembolic diseases.

Description

Pyrazol-3-on-derived derivative as a factor XA inhibitor {PYRAZOLE-3-ON-DERIVATIVE AS FACTOR XA INHIBITORS}

The present invention relates to compounds of formula (I):

(Wherein

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

R ³ , R ⁴ are each independently H, Ar, Het, R ⁵ , wherein at least one of the two radicals is R ⁵ ,

R ⁵ is —COA, Ar— [C (R ⁷ R ^{7 ′} )] _n —CO—, COOA, OH or a common amino protecting group, —NH—C (═NH) —NH ₂ , —CO—N═C (NH ₂ ) ₂ ,

May be mono-substituted and optionally also 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 Phenyl, naphthyl or biphenyl substituted with -C (= NH) -NH ₂ ,

R ⁶ , R ^{6 '} are each independently H, A, CR ⁷ R ^7' -Ar 'or CR ⁷ R ^7' -Het,

R ⁷ and R ^{7 '} are each independently H or A,

X, Y are each independently (CR ⁷ R ^{7 '} ) _n ,

A has from 1 to ₂ carbon atoms in which one or two CH ₂ groups may be substituted by O or S atoms and / or by —CH═CH—groups, and / or 1 to 7 H atoms may be substituted by F Alkyl of 20,

Ar is unsubstituted or 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 'is unsubstituted or 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 phenyl or naphthyl, mono or trisubstituted with S (O) _n A,

Het is unsubstituted or 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 ′} , mononuclear or heteronuclear saturated, unsaturated or aromatic having 1 to 4 N, O and / or S atoms, which may be one, two or trisubstituted with S (O) _n A and / or carbonyl oxygen Heterocycle,

Hal is F, Cl, Br or I,

n is 0, 1 or 2)

And pharmaceutically resistant salts and solvates thereof.

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

It is an object of the present invention to find novel compounds having useful properties, in particular properties useful for the preparation of a medicament.

The compounds of formula (I) and salts thereof have been found to have very useful pharmacological properties and good resistance. They especially exhibit factor Xa-inhibiting properties and can therefore be used for the control and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina, restenosis after angioplasty and intermittent claudication.

The compounds of formula (I) according to the invention can also be inhibitors of factor VIIa, factor IXa and thrombin, which are the coagulation factors of the blood coagulation cascade.

Aromatic amidine derivatives with antithrombotic action are for example disclosed in EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic diseases are described, for example, in WO 97/08165. Aromatic heterocycles having factor Xa-inhibitory activity are disclosed, for example, in WO 96/10022. Substituted N-[(aminoiminomethyl) phenylalkyl] azaheterocyclylamide as a Factor Xa inhibitor is disclosed in WO 96/40679.

The antithrombotic and anticoagulant action of the compounds according to the invention is due to the inhibitory action on activated coagulation proteases known as factor Xa or the inhibition of other activated serine proteases such as factor VIIa, factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex process of blood coagulation. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin breaks down fibrinogen into fibrin monomers that cross-link and basically form thrombi. Thrombin activation can lead to thromboembolic disorders. However, inhibiting thrombin can inhibit the formation of fibrin associated with thrombus formation.

Inhibition of thrombin can be measured, for example, according to the method of GF Cousins et al., In Circulation 1996 , 94, 1705-1712.

Thus, inhibiting factor Xa can prevent thrombin from forming.

The compounds of formula (I) and salts thereof according to the invention participate in the blood coagulation process by inhibiting factor Xa, thus inhibiting thrombus formation.

Inhibition of factor Xa using the compounds according to the invention and the determination of anticoagulant and antithrombotic activity can be measured by conventional in vitro or in vivo methods. Suitable methods are disclosed, for example, in J. Hauptmann et al. In Thrombosis and Haemostatis 1990 , 63, 220-223.

Inhibition of factor Xa can be measured, for example, by the method of T. Hara et al., In Thromb. Haemostas. 1994 , 71, 314-319.

Coagulation factor VIIa binds to tissue factors and then initiates the exogenous portion of the coagulation cascade and activates factor X with factor Xa. Thus, inhibiting factor VIIa prevents the formation of factor Xa, which in turn prevents thrombin formation.

Inhibition and anti-aggregation and antithrombotic activity of Factor VIIa using the compounds according to the invention can usually be determined by in vitro or in vivo methods. Conventional methods for measuring factor VIIa inhibition are disclosed, for example, in HF Ronning et al., In Thrombosis Research 1996 , 84, 73-81.

Coagulation factor IXa is produced in an endogenous coagulation cascade and is involved in activating factor X with factor Xa. Thus, suppressing factor IXa prevents factor Xa from being formed in other ways.

Inhibition and anticoagulation and antithrombotic activity of Factor IXa using the compounds according to the invention can be measured by conventional in vitro or in vivo methods. Suitable methods are disclosed in J. Chang et al., In Journal of Biological Chemistry 1998 , 273, 12089-12094.

Compounds of formula (I) are particularly useful as pharmaceutically active compounds in human and animal medicines for the control and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication. Can be used.

The present invention relates to a compound of formula (I) and salts thereof and to a process for the preparation of compounds of formula (I) according to claim 1 and salts thereof.

a) i) hydrogenolysis or solvolysis to liberate the amidino group from an oxadiazole derivative or an oxazolidinone derivative of an amidino group,

ii) by treating with a solubilizing agent or a hydrogenolysis agent to substitute a conventional amino protecting group with hydrogen, or by releasing an amino group protected with a conventional protecting group,

Treatment with a solubilizer or a hydrogenolytic agent to liberate them from one of their functional derivatives, or

b) in compounds of formula (I), for example

i) hydrolyzing ester groups to carboxyl groups,

ii) reducing the nitro group,

iii) acylating amino groups,

iv) converting the cyano group to an amidino group,

Converting 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 , and / or

c) the conversion of a base or acid of formula (I) to one of its salts.

All radicals which appear several times are mutually independent in the meaning.

Above and below, the radicals and parameters R ¹ , R ² , R ³ , R ⁴ , X and Y have the meanings indicated in formula (I) unless stated otherwise.

A is alkyl, straight (linear) or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, also ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl or 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, more preferably, for example, trifluoromethyl. A is particularly preferably alkyl having 1 to 6 carbon atoms, with methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, tert-butyl, pentyl or hexyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Hal is preferably F, Cl or Br, and also I.

Ar is unsubstituted or 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, -Or trisubstituted, phenyl, naphthyl or biphenyl. Preferred substituents for biphenyl are fluorine, SO ₂ NH ₂ or SO ₂ NHA.

Ar 'is unsubstituted or 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 phenyl or naphthyl, mono-, di-, or trisubstituted with S (O) _n A.

Ar is preferably unsubstituted phenyl, naphthyl or biphenyl, more preferably methyl, ethyl, propyl, isopropyl, butyl, fluorine, chlorine, bromine, hydroxyl, methoxy, ethoxy , Propoxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidine -1-yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, tert-butylsulfonamido, tert-butylaminosulfonyl, dimethylsulfonamido, Phenyl, naphthyl which is mono-, di- or trisubstituted with phenylsulfonamido, methoxycarbonyl, carboxyl, dimethylaminocarbonyl, phenylaminocarbonyl, acetyl, propionyl, benzoyl, methylsulfonyl or phenylsulfonyl Or biphenyl.

Ar 'is preferably unsubstituted phenyl or naphthyl, more preferably methyl, ethyl, propyl, isopropyl, butyl, fluorine, chlorine, bromine, hydroxyl, methoxy, ethoxy, pro Foxy, butoxy, pentyloxy, hexyloxy, cyano, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl, piperidine-1 -Yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, methoxycarbonyl, carboxyl, dimethylaminocarbonyl, Phenylaminocarbonyl, acetyl, propionyl, benzoyl, methylsulfonyl or phenylsulfonyl, phenyl or naphthyl.

Ar is particularly preferably, for example, phenyl, naphthyl, biphenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl , o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylaminocarbonyl) phenyl, o-, m- Or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-di Ethylamino) 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'-sulfamoylbiphenyl-4-yl, 3-fluoro-2'-N-tert-butylsulfamoylbiphenyl -4-yl, 2'-sulfamoylbiphenyl-4-yl, 2'-N-tert-butylsulfamoylbiphenyl-4-yl, o-, m- or p- (pyrrolidine-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-bro Phenyl, 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 preferably, for example, phenyl, naphthyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o- , m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p- (N-methylaminocarbonyl) phenyl, o-, m- or p- Acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p- (N, N-dimethylamino) phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m- or p- (N-ethylamino) phenyl, o-, m- or p- (N, N-diethylamino) Phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido ) Phenyl, 3-fluoro-2'-sulfamoylbiphenyl-4-yl, 3-fluoro-2'-N-tert-butylsulfamoylbiphenyl-4-yl, 2'-sulfamo Ylbiphenyl-4-yl, 2'-N-tert-butylsulfamoylbiphenyl-4-yl, o-, m- or p- (pyrrolidin-1-yl) phenyl, o-, m- Or p- (piperidin-1-yl) phenyl.

Het is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrroyl, 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, more preferably 1,2,3-tria Zol-1-,-4- or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxa Diazol-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-benz Soxazolyl, 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-quina Sleepinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1,4] oxazinyl, more preferably 1,3 -Benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazole -5- days.

Heterocyclic radicals may also be partially or wholly hydrogenated.

Thus, Het is also, 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-pyrroyl, 2,5-dihydro-1-, -2-, -3-,-4- or -5-pyrroyl, 1-, 2 Or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5- Pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4 -Tetrahydro-1-,-2-,-3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-,-3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-,-4- or -5-yl, hexa Hydro-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-benz [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) phenyl, 2,3-dihydrobenzofuran-5- Or 6-yl, 2,3- (2-oxomethylenedioxy) phenyl or alternatively 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, also preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

Het is unsubstituted or 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 Mono-, di-, or trisubstituted with NR ⁷ R ^{7 ′} , S (O) _n A and / or carbonyloxygen.

Het is particularly preferably, for example, furyl, thienyl, thiazolyl, imidazolyl, [2,1,3] -benzothiadiazolyl, oxazolyl, pyridyl, indolyl, piperidinyl or pipet. It is Ralidinyl.

R ¹ is preferably, for example, H, A, cycloalkyl, -CH ₂ - or Ar-CH ₂ -, particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary -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-methylphenyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1- Ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, more preferably, for example, trifluoromethyl. Particular preference is given to H, methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl.

R ² is preferably, for example, H, A, cycloalkyl, -CH ₂ - or Ar-CH ₂ -, particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary -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-methylphenyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1- Ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, more preferably, for example, trifluoromethyl. H is particularly preferred.

R ³ is preferably, for example, H, Ar, Het, or -COA, Ar-CH ₂ -CO-, COOA, OH or a common amino protecting group, -NH-C (-NH) -NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

Phenyl, naphthyl or biphenyl substituted with -C (= NH) -NH ₂ which may be monosubstituted by:

R ³ is particularly preferably, for example, H, phenyl or phenyl, naphthyl or biphenyl monosubstituted with NH ₂ SO _2- ,

Or -C (= NH) -NH ₂

Phenyl, naphthyl or biphenyl substituted by

R ⁴ is preferably, for example, H, Ar, Het or —COA, Ar—CH ₂ —CO—, COOA, OH or a common amino protecting group, —NH—C (═NH) —NH ₂ , -CO-N = C (NH ₂ ) ₂ ,

Phenyl, naphthyl or biphenyl substituted with -C (= NH) -NH ₂ which may be monosubstituted by:

R ⁴ is particularly preferably, for example, H, phenyl or phenyl, naphthyl or biphenyl monosubstituted with NH ₂ SO _2- ,

Or -C (= NH) -NH ₂

Substituted with phenyl, naphthyl or biphenyl.

R ⁶ and R ^{6 '} are each independently of one another, for example, H, methyl, ethyl, propyl, butyl or benzyl, particularly preferably H, methyl, ethyl, propyl or butyl.

R ⁷ and R ^{7 '} are each independently of one another, for example, preferably H, methyl, ethyl or propyl, particularly preferably H.

It is preferable that X and Y are each independently of one another, for example, (CH ₂ ) _n , where n is particularly preferably 0 or 1.

Compounds of formula (I) may have one or more chiral centers, and therefore, various stereoisomeric forms exist. Formula I includes all of these forms.

The present invention therefore relates in particular to compounds of formula (I) in which at least one of said radicals has one of the above preferred meanings. Some of the preferred groups of compounds may be represented by the following formulas Ia to Ie corresponding to formula I, wherein radicals not described in detail have the meaning in formula I,

In Ia, R ¹ , R ² are each independently H or A;

In Ib, R ³ , R ⁴ are each independently H, Ar or R ⁵ , wherein two

At least one of the radicals is R ⁵ ,

R ⁵ is —COA, Ar— (CH ₂ ) _n —CO—, COOA, OH or a common amino protecting group,

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

Phenyl, naphthyl substituted with -C (= NH) -NH ₂ , which may be monosubstituted with

Biphenyl,

In Ic R ¹ is A,

R ² is H,

R ³ , R ⁴ are each independently H, Ar or R ⁵ , wherein

At least one of the radicals is R ⁵ ,

R ⁵ is —COA, Ar— (CH ₂ ) _n —CO—, COOA, OH or a common amino protecting group,

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

Phenyl, naphthyl substituted with -C (= NH) -NH ₂ , which may be monosubstituted with

Biphenyl,

In Id R ¹ is A,

R ² is H,

R ³ , R ⁴ are each independently H, Ar or R ⁵ , wherein

At least one of the radicals is R ⁵ ,

R ⁵ is —COA, Ar— (CH ₂ ) _n —CO—, COOA, OH or a common amino protecting group,

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

Phenyl, naphthyl substituted with -C (= NH) -NH ₂ , which may be monosubstituted with

Biphenyl,

A is alkyl having 1 to 6 carbon atoms,

X and Y are each independently (CH ₂ ) _n ,

In Ie, R ¹ is A,

R ² is H,

R ³ , R ⁴ are each independently H, Ar or R ⁵ , wherein

At least one of the radicals is R ⁵ ,

R ⁵ is —CO—N═C (NH ₂ ) ₂ , or

Phenyl, naphthyl or biphenyl substituted by

Ar is biphenyl monosubstituted with SO ₂ NR ⁶ R ^{6 ′} ,

R ⁶ , R ^{6 '} are each independently H or A,

A is alkyl having 1 to 6 carbon atoms,

X and Y are each independently (CH ₂ ) _n .

Compounds of formula (I) and starting materials for preparing them are described in, for example, standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart. It is prepared using the same known method, that is, under reaction conditions suitable and known for the above reaction. In this case, modification methods known per se and not mentioned in more detail herein may also be used.

If necessary, the starting material may be formed in situ so that the reaction may be continued immediately without separation in the reaction mixture to give the compound of formula (I).

The compounds of formula (I) are preferably obtained by treating the compounds of formula (I) from one or more functional derivatives of the compounds of formula (I) by treatment with a solubilizer or a hydrogenolysis agent.

Preferred starting materials for solvolysis or hydrogenolysis are those which correspond to formula (I) but which have corresponding protective amino and / or hydroxyl groups in place of one or more free amino and / or hydroxyl groups, preferably A substance having an amino protecting group instead of an H atom bonded to an N atom, in particular a substance having an R'-N group in which R 'is an amino protecting group instead of an HN group, and / or having a hydroxyl protecting group instead of an H atom of a hydroxyl group , For example corresponding to formula (I), but having a —COOR ″ group in which R ″ is a hydroxyl protecting group instead of a —COOH group.

Preferred starting materials are also oxadiazole derivatives which can be converted into the corresponding amidino compounds.

Amidino groups can be liberated from their oxadiazole derivatives, for example, by treatment with hydrogen in the presence of a catalyst (eg, wet Raney nickel). Suitable solvents are shown below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof. In general, the hydrogenolysis is carried out at a temperature of about 0 to 100 °, a pressure of about 1 to 200 bar, preferably 20 to 30 ° (room temperature) and 1 to 10 bar.

Oxadiazole groups are introduced, for example, by reacting a cyano compound with hydroxylamine and by reacting with phosgene, dialkyl carbonate, chloroformic acid ester, N, N'-carbonyldiimidazole or acetic anhydride.

Also, multiple -identical or different-protected amino and / or hydroxyl groups can be present in the starting material molecule. If the protecting groups present are different, in many cases they can be selectively removed.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (shielding) an amino group from chemical reactions, but which can be easily removed after the desired chemical reaction has been carried out at another position in the molecule. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, alkoxymethyl or aralkyl groups. The amino protecting groups are removed at the end of the desired reaction (or order of reaction), so their properties and size are not important, but those having 1 to 20 carbon atoms, particularly those having 1 to 8 carbon atoms, are preferred. In the context of the method of the present invention, the expression "acyl group" is used in its broadest sense. These include acyl groups derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, in particular alkoxycarbonyl groups, aryloxycarbonyl groups and especially aralkylcarbonyl groups. Examples of such acyl groups include alkanoyl such as acetyl, propionyl or butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodineethoxycarbonyl; Aralkyloxycarbonyls such as CBZ (“carbobenzoxoxy”), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, with CBZ, Fmoc, benzyl and acetyl also being preferred.

Depending on the type of protecting group used, for example, strong acids, advantageously TFA or perchloric acid, or also other strong inorganic acids such as hydrochloric acid, sulfuric acid, or sulfonic or trichloro, such as benzenesulfonic acid or p-toluenesulfonic acid Strong organic carboxylic acids such as acetic acid can be used to liberate compounds of formula (I) from their functional derivatives. It may also be carried out in the presence of additional inert solvents, but this is not necessary. Examples of suitable inert solvents are carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also organics such as alcohols such as methanol, ethanol, isopropanol Solvent and also water. Also suitable are mixtures of the above solvents. TFA is preferably used in excess without further addition of other solvents, and perchloric acid is preferably used in the form of a mixture of 9: 1 of acetic acid and 70% perchloric acid. The reaction temperature for decomposition is conveniently from about 0 to about 50 ° C, preferably at 15 to 30 ° C (room temperature).

The BOC, OBut and Mtr groups can be decomposed, for example, using about 3 to 5N HCl in dioxane or preferably using TFA in dichloromethane at 15 to 30 ° C., and the FMOC group is DMF at 15 to 30 ° C. It can be decomposed using about 5 to 50% solution of dimethylamine, diethylamine or piperidine in water.

Protecting groups that can be removed by hydrogenolysis (eg, free of amidino groups from CBZ, benzyl, or oxadiazole derivatives) are catalysts (eg, noble metal catalysts such as palladium; advantageously carbon such as Can be removed by treatment with hydrogen in the presence of a substrate). Suitable solvents for this are as described above, but alcohols such as methanol or ethanol and amides such as DMF are particularly preferred. Hydrolysis is generally carried out at a temperature of about 0 to 100 ° C. and a pressure of about 1 to 200 bar, preferably 20 to 30 ° C. and 1 to 10 bar. Hydrolysis of CBZ groups can easily occur using ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF, for example at 20-30 °, or on 5-10% Pd / C in methanol. .

Suitable inert solvents include, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, trifluoromethylbenzene, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), or ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of these solvents.

Biphenyl-SO ₂ NH ₂ groups are preferably used in the form of their tert-butyl derivatives. The tert-butyl group is removed using, for example, TFA with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1 to 10% by volume).

The cyano group is reacted with, for example, hydroxylamine, and then converted to an amidino group by reducing N-hydroxyamidine to hydrogen in the presence of a catalyst such as, for example, Pd / C.

Ammonia may also be added to the nitrile to prepare amidine of formula I (eg, phenyl monosubstituted with Ar═C (═NH) —NH ₂ ). a) converting the nitrile to thioamide using H ₂ S and converting it to the corresponding S-alkylimidothio ester using an alkylating agent such as CH ₃ I, a portion of which is reacted with NH ₃ to give amidine Or b) converting the nitrile to the corresponding imido ester in the presence of HCl using an alcohol such as ethanol and treating it with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide, It is preferable that the addition is carried out in multiple stages by a known method of hydrolysis.

The radical -XR ³ , wherein X = CH ₂ , is a compound of Formula II:

(Wherein R ¹ , R ² and R ⁴ are each non-alkylated radicals according to claim 1 and Y also has the meaning indicated in claim 1)

And compounds of formula III:

R ³ -CH ₂ -L

Is introduced into the pyrazolone system.

In the compounds of formula III, R ³ is a radical which cannot be alkylated according to claim 1, for example, a phenyl radical substituted with 5-methyl [1,2,4] oxadiazol-3-yl, and L is Cl , Br, I or free or functionally modified reactive OH groups. L is preferably Cl, Br, I or, for example, activated esters, imidazolides or alkylsulfonyloxy having 1 to 6 carbon atoms (preferably methylsulfonyloxy) or 6 to 10 carbon atoms Modified reactive OH groups such as phosphorus arylsulfonyloxy (preferably phenylsulfonyloxy or p-tolylsulfonyloxy).

The pyrazolone ring system is synthesized according to known methods by the reaction of suitable β-keto esters with hydrazine or hydrazine derivatives.

Furthermore, by converting 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, acylating amino groups or nitro groups The compound of formula (I) can be converted to another compound of formula (I) by reduction with (for example hydrogenation over Ranickel or Pd-carbon in an inert solvent such as methanol or ethanol).

The ester can be hydrolyzed at a temperature of about 0-100 ° using, for example, acetic acid or NaOH or KOH in water, water-THF or water-dioxane.

In addition, the free amino group is conveniently dissolved in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at a temperature of -60 to + 30 ° It can be alkylated or acylated by conventional methods using acid chlorides or anhydrides.

Bases of formula (I) can be converted to the related acid addition salts by the use of an acid, for example by reacting the same amount of base and acid in an inert solvent such as ethanol and then evaporating. Particularly suitable acids for use in this reaction include acids which produce physiologically acceptable salts. Thus, inorganic acids that can be used include hydrochloric acid such as sulfuric acid, nitric acid, hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid, and also usable organic acids, especially aliphatic, alicyclic, aromatic aliphatic, aromatic Or an organic acid such as monocyclic or polybasic carboxylic acid, sulfonic acid or sulfuric acid, formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid. , Tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono Sulfonic acid, naphthalenedisulfonic acid or laurylsulfuric acid. Salts with physiologically unacceptable acids, such as picrates, can be used to isolate and / or purify the compound of formula (I).

On the other hand, bases (eg sodium or potassium hydroxides or carbonates) can be used to convert the compounds of formula (I) to the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or corresponding ammonium salts. Physiologically acceptable organic bases (eg ethanolamine) can also be used.

The compounds of formula (I) according to the invention may be chiral due to their molecular structure, and therefore various enantiomeric forms may exist. Thus, they may exist in racemate or optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use enantiomers. In such cases, the final product or even intermediates may be separated into enantiomers or even used in synthesis as known by those skilled in the art in a chemical or physical manner.

In the case of racemic amines, they are reacted with an optically active splitting agent to form diastereomers from the compound. Suitable splitting agents are, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitably N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfur) of the R and S forms. Optically active acids such as ponylproline) or several optically active camphorsulfonic acids. It is also advantageous to chromatographically decompose the enantiomers using optically active splitting agents (eg, dinitrobenzoylphenylglycine, cellulose triacetate, or other derivatives of carbohydrates or chiral derived methacrylate polymers immobilized on silica gel). . Suitable eluents for this purpose are water-soluble or alcoholic solvent mixtures such as, for example, hexane / isopropanol / acetonitrile in a ratio of 82: 15: 3.

The present invention relates in particular to the use of the compounds of formula (I) and / or physiologically acceptable salts thereof for the preparation of pharmaceutical preparations by non-chemical methods. In this regard, they may be combined with one or more solid, liquid and / or semi-liquid vehicles or excipients, where appropriate, with one or more other active compounds to form a suitable dosage form.

The invention also relates to pharmaceutical preparations comprising at least one compound of formula (I) and / or physiologically acceptable salts thereof.

These formulations can be used as medicaments in human or veterinary medicine. Suitable vehicles are organic or inorganic substances which are suitable for enteral (eg oral) or parenteral administration or topical application and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, Carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, lactose or starch, magnesium stearate, talc, and waceline. Tablets, pills, tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, suppositories are used for rectal administration, liquids, preferably oily or aqueous solutions, also suspensions for parenteral administration. , Emulsions or implants are used, and ointments, creams or powders are used for topical application. In addition, the novel compounds of the present invention can be lyophilized and the resulting lyophilisate can be used, for example, in the preparation of injectable preparations. Such formulations may be sterilized and / or lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, flavoring agents and / or various additional active compounds, for example It may contain one or more vitamins.

The compounds of formula (I) and their physiologically acceptable salts can be used for the control and prevention of thromboembolic diseases such as thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina, restenosis after angioplasty and intermittent claudication.

In general, the substances according to the invention may preferably be administered at about 1 to 500 mg, in particular 5 to 100 mg, per dosage unit. The daily dosage is preferably about 0.02 to 10 mg / kg body weight. However, the specific dosage for each patient may vary depending on various factors, such as the efficacy, age, weight, general health, sex, diet, time of administration and route of administration, rate of excretion, combination of drugs and treatment of the specific compound used. It depends on the severity of the particular disease. Oral administration is preferred.

Above and below, all temperatures are expressed in degrees Celsius. In the following examples, " normal reaction finish " is required, if necessary, water is added, and if necessary, the pH of the mixture is adjusted to 2 to 10 depending on the composition of the final product, extracted with ethyl acetate or dichloromethane, and the organic phase separated. Off, dried over sodium sulfate and evaporated, and the residue purified by chromatography and / or crystallization on silica gel. Rf value on silica gel; Eluent: ethyl acetate / methanol 9: 1

Mass spectroscopy (MS): EI (electron impact ionization) M ⁺

Fast Atomic Impact (FAB) (M + H) ⁺

Example 1

4.3 g of cesium carbonate, 4.0 g of 3- (7-bromomethylnaphthalen-2-yl) -5-methyl [1,2,4] oxadiazole and 2.1 g of ethyl isobutyryl acetate are 50 ml of aceto. It was added to the solution dissolved in nitrile. This suspension was stirred at rt for 20 h. The mixture was filtered, the solvent was removed and the residue was chromatographed on a silica gel column. Ethyl 4-methyl-2- [7- (5-methyl [1,2,4] oxadiazol-3-yl) naphthalen-2-ylmethyl] -3-oxopentanate ("AA") as a colorless oil , FAB 381 was obtained.

A solution of 1.30 g of "AA" and 0.62 ml of hydrazinium hydroxide in 10 ml of acetic acid was heated for 24 hours. After usual reaction, 5-isopropyl-4- [7- (5-methyl [1,2,4] oxadiazol-3-yl) naphthalen-2-ylmethyl] -1,2-dihydropyra Zol-3-one ("AB"), FAB 349 was obtained.

A solution of 60 mg of "AB" in 5 ml of methanol was treated with 60 mg of Raney nickel and 30 mg of acetic acid and hydrogenated at room temperature for 18 hours. Filter off the catalyst, remove the solvent,

7- [5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-4-ylmethyl] -2-amidinonaphthalene, diacetate and FAB 309 were obtained.

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 treated with 94 mg of cesium carbonate and at room temperature Stir for 20 hours. After usual reaction 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 and FAB 521 were obtained.

Similar to Example 1, the following compounds were obtained therefrom by hydrogenation

3- [4- (7-amidinononft-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] benzamidine, Diacetate, FAB 441 was obtained.

Similarly the following compound

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

Similarly, "AB" is reacted with 3- (7-bromomethylnaphthalen-2-yl) -5-methyl [1,2,4] oxadiazole and then hydrogenated to yield

7- [4- (7-amidinonaphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2-amimi Dinonaphthalene, diacetate and FAB 491 were obtained.

Example 3

Similar to Example 1, compound ethyl 4-methyl-2, which is a colorless oil by reacting 3- (5-methyl [1,2,4] oxadiazol-3-yl) benzyl bromide with methyl isobutyryl acetate -[3- (5-methyl [1,2,4] oxadiazol-3-yl) benzyl] -3-oxopentanoate ("AC"), FAB 317 was obtained.

Reacted with hydrazinium hydroxide to thereby give 5-isopropyl-4- [3- (5-methyl [1,2,4] oxadiazol-3-yl) benzyl] -1,2-dihydropyrazole- 3-one, FAB 299 (“AD”) was obtained.

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

Similarly, with "AD"

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

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

2- (tert-butylaminosulfonyl) -4'-bromomethylbiphenyl is reacted, and then hydrogenated to

3- [4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] benzamidine, triacetate, FAB 391;

7- [4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2-amidinonaphthalene,

4 '-[4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2- (tert-butylamino Sulfonyl) biphenyl was obtained,

Tertiary-butyl group was removed,

4 '-[4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2-aminosulfonylbiphenyl Got it.

Similarly, the following compounds

7- [4- (4-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2-amidinonaphthalene was obtained.

Example 4

Similar to Example 1, 5-isopropyl-1,2-dihydropyrazol-3-one and 3- (7-bromomethylnaphthalen-2-yl) -5-methyl [1,2,4] Oxadiazole is reacted and then hydrogenated

5-isopropyl-2- [7-amidinonaphthalen-2-ylmethyl] -1,2-dihydropyrazol-3-one ("AB"), diacetate and FAB 309 were obtained.

Example 5

Similar to Example 1, starting with 3- (7-bromomethylnaphthalen-2-yl) -5-methyl [1,2,4] oxadiazole and ethyl 3-oxobutyrate, reacted with hydrazine, Then reacted with 3- (7-bromomethylnaphthalen-2-yl) -5-methyl [1,2,4] oxadiazole and hydrogenated to yield

7- [4- (7-amidinonaphth-2-ylmethyl) -5-methyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2-amidino Naphthalene was obtained.

When ethyl 3-oxobutyrate is replaced with ethyl 3-oxoheptanoate, the compounds

7- [4- (7-amidinonaphth-2-ylmethyl) -5-butyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2-amidino Naphthalene was obtained.

Example 6

Similar to Example 1, starting with 2- (tert-butylaminosulfonyl) -4'-bromomethylbiphenyl and ethyl isobutyryl acetate, reacted with hydrazine and then 3- (3-bromo Methylphenyl) -5-methyl [1,2,4] oxadiazole, reacted with hydrogen, and removed tert-butyl group

3- [4- (2-aminosulfonylbiphenyl-4'-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] benzami Dean, trifluoroacetate and FAB 504 were obtained.

Similarly, the following compounds

7- [4- (2-aminosulfonylbiphenyl-4'-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl-2- Amidinonaphthalene, trifluoroacetate, and FAB 554 were obtained.

Example 7

Similar to Examples 1 and 2, the following compounds

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

7- [2-benzyl-5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-4-ylmethyl] -2-amidinonaphthalene was obtained.

Example 8

Similar to Example 1, hydrazine was replaced with phenylhydrazine to yield the following compounds

7- [5-isopropyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazol-4-ylmethyl] -2-amidinonaphthalene was obtained.

The following examples relate to pharmaceutical formulations:

Example A: Vials for Injection

A solution of 100 g of the active compound of formula (I) and 5 g of sodium diphosphate was adjusted to pH 6.5 with 2 N hydrochloric acid in 3 l of secondary distilled water, then sterile filtered, filled into an injection vial, lyophilized under sterile conditions, Sealed by sterile method. Injectable vials containing 5 mg of the active compound were obtained.

Example B: Suppositories

A mixture of 20 g of active compound of formula I was melted together with 100 g of soya lecithin and 1400 g of cocoa butter, then poured into a mold and cooled. Suppositories containing 20 mg of the active compound were obtained.

Example C: Liquid

A solution was prepared by dissolving 1 g of the active compound of Formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ 0, and 0.1 g of benzalkonium chloride in 940 mL of secondary distilled water. This solution was adjusted to pH 6.8, filled to 1 l and sterilized by radiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of the active compound of formula (I) were mixed with 99.5 g of waseline under aseptic conditions.

Example E: Tablets

A tablet was prepared by compressing a mixture of 1 kg of active compound of formula (I), 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate in a conventional manner such that each tablet contains 10 mg of active compound.

Example F: Tablets

Similar to Example E, the tablets were compressed and then coated in a conventional manner using a coating consisting of sucrose, potato starch, talc, tragacanth and colorants.

Example G: Capsule

Hard gelatine capsules were filled with 2 kg of the active compound of formula (I) in a conventional manner such that each capsule contained 20 mg of the active compound to prepare a capsule.

Example H: Ampoules

A solution in which 1 kg of the active compound of formula I was dissolved in 60 l of secondary distilled water was sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed by sterile method. An ampoule containing 10 mg of the active compound was obtained.

Claims (10)

Compound of formula (I) [Formula I] (Wherein R ¹ , R ² are each independently H, A, cycloalkyl- [C (R ⁷ R ^{7 '} )] _n -or Ar- [C (R ⁷ R ^7' )] _n- , R ³ , R ⁴ are each independently H, Ar, Het, R ⁵ , wherein at least one of the two radicals is R ⁵ , R ⁵ is —COA, Ar— [C (R ⁷ R ^{7 ′} )] _n —CO—, COOA, OH or a common amino protecting group, —NH—C (═NH) —NH ₂ , —CO—N═C (NH ₂ ) ₂ , May be mono-substituted and optionally also 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 Phenyl, naphthyl or biphenyl substituted with -C (= NH) -NH ₂ , R ⁶ , R ^{6 '} are each independently H, A, CR ⁷ R ^7' -Ar 'or CR ⁷ R ^7' -Het, R ⁷ and R ^{7 '} are each independently H or A, X, Y are each independently (CR ⁷ R ^{7 '} ) _n , A has 1 to ₂ carbon atoms in which one or two CH ₂ groups can be substituted by O or S atoms and / or by -CH = CH- groups, and / or 1 to 7 H atoms can be substituted by F Alkyl of 20, Ar is unsubstituted or 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 'is unsubstituted or 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 phenyl or naphthyl, mono or trisubstituted with S (O) _n A, Het is unsubstituted or 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 ′} , mononuclear or heteronuclear saturated, unsaturated or aromatic having 1 to 4 N, O and / or S atoms, which may be one, two or trisubstituted with S (O) _n A and / or carbonyl oxygen Heterocycle, Hal is F, Cl, Br or I, n is 0, 1 or 2) And pharmaceutically resistant salts and solvates thereof. Compounds according to claim 1 a) 7- [5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2-amidinonaphthalene; b) 7- [4- (7-amidinonaphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] -2 -Amidinonaphthalene; c) 3- [4- (3-amidinobenzyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] benzamidine; d) 3- [4- (7-amidinonaphth-2-ylmethyl) -5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-2-ylmethyl] benzami Dean; e) 7- [5-isopropyl-3-oxo-2,3-dihydro-1 H -pyrazol-4-ylmethyl] -2-amidinonaphthalene And pharmaceutically resistant salts and solvates thereof. a) i) hydrogenolysis or solvolysis to liberate the amidino group from an oxadiazole derivative or an oxazolidinone derivative of an amidino group, ii) by treating with a solubilizing agent or a hydrogenolysis agent to substitute a conventional amino protecting group with hydrogen, or by releasing an amino group protected with a conventional protecting group, Treatment with a solubilizer or a hydrogenolytic agent to liberate them from one of their functional derivatives, or b) in compounds of formula (I), for example i) hydrolyzing ester groups to carboxyl groups, ii) reducing the nitro group, iii) acylating amino groups, iv) converting the cyano group to an amidino group, Converting 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 , and / or c) A process for the preparation of a compound of formula (I) and a salt thereof according to claim 1, characterized in that the base or acid of formula (I) is converted to one of its salts. A process for the preparation of a pharmaceutical preparation, characterized in that one of the compounds of formula (I) and / or physiologically acceptable salts thereof according to claim 1 is formulated with one or more solid, liquid or semi-liquid vehicles or excipients. A pharmaceutical formulation characterized by containing at least one of the compounds of formula (I) according to claim 1 and / or physiologically acceptable salts thereof. A compound of formula (I) and a physiologically acceptable salt or solvate thereof according to claim 1 as a pharmaceutically active compound. A compound of formula (I) and a physiologically acceptable salt thereof according to claim 1 for control of thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication. A medicament of formula (I) according to claim 1 as an inhibitor of coagulation factor Xa and a physiologically acceptable salt thereof. Use of a compound of formula (I) and / or a physiologically acceptable salt thereof according to claim 1 for the manufacture of a medicament. Use of a compound of formula (I) and / or a physiologically acceptable salt thereof according to claim 1 in the treatment of thrombosis, myocardial infarction, atherosclerosis, inflammation, stroke, angina pectoris, restenosis after angioplasty and intermittent claudication.