DE10234057A1 - New carboxamides, their production and their use as medicines - Google Patents

Abstract

The present invention relates to new carboxamides of the general formula DOLLAR F1 in which R · 1 · to R · 5 · are defined as in claim 1, their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, and their preparation and their use as a medicine. The compounds of the general formula I above have valuable pharmacological properties, in particular an antithrombotic activity and a factor Xa-inhibiting activity.

Description

deren Tautomere, deren Enantiomere, deren Diastereomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträglichen Salze mit anorganischen oder organischen Säuren oder Basen, welche wertvolle Eigenschaften aufweisen.The present invention relates to new carboxamides of the general formula

their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases, which have valuable properties.

The compounds of the general above Formula I and their tautomers, their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiological compatible Salts with inorganic or organic acids or bases, and their Stereoisomers have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa inhibitory effect.

Subject of the present application are thus the new compounds of the above general formula I, their preparation, the pharmacologically active compounds containing medicines, their manufacture and use.

in denen im heterocyclischen Teil jeweils ein Wasserstoffatom durch eine Aminomethyl- oder Aminocarbonylgruppe ersetzt sein kann,
R² ein Fluor-, Chlor- oder Bromatom, eine C₂_₃-Alkenylgruppe oder
eine C_1-3-Alkoxy- oder C_1-3-Alkylgruppe, in der die Wasserstoffatome ganz oder teilweise durch Fluoratome ersetzt sein können,
R³ eine Hydroxy- oder Aminogruppe,
R⁴ eine Phenyl- oder Heteroarylgruppe, die gegebenenfalls durch eine Hydroxy-, C_1-4-Alkyloxy-, Benzyloxy-, Hydroxycarbonyl-C_1-3-alkoxy-, C_1-3-Alkyloxy-carbonyl-C_1-3-alkyloxy-, Aminocarbonyl-C_1-3-alkyloxy-, C_1-3-Alkylaminocarbonyl-C_1-3-alkyloxy-, Di-(C_1-3-alkyl)-aminocarbonyl-C_1-3-alkyloxy-, Carboxy-, C_1-3-Alkyloxy-carbonylgruppe substituiert ist,
eine 1-H-Pyridonyl- oder 1-(C_1-3-Alkyl)-pyridonylgruppe,
eine 4- bis 7-gliedrige Cycolalkyleniminogruppe oder
eine 4- bis 7-gliedrige Cycloalkylgruppe, in der eine oder zwei Methylengruppen durch eine -NH- oder -N(C_1-3-Alkyl)- Gruppe ersetzt sind und in der eine oder zwei der -NH- oder -N(C_1-3-Alkyl)- Gruppe benachbarte Methylengruppen jeweils durch eine Carbonylgruppe ersetzt sein können mit der Maßgabe, daß eine wie oben definierte Cycloalkylgruppe, in der zwei -NH- oder -N(C_1-3-Alkyl)- Gruppen durch genau eine -CH₂- Gruppe voneinander getrennt sind, ausgeschlossen sind, und
R⁵ eine Gruppe der Formel -CH₂-NHR⁶, in der
R⁶ ein Wasserstoffatom, eine C_1-10-Alkoxy-carbonyl-, 2,2,2-Trichlorethoxycarbonyl-, Phenyloxycarbonyl- oder Benzyloxycarbonylgruppe darstellt, oder eine Gruppe der Formel -C(=NH)-NH₂, in der ein Wasserstoffatom durch eine C_1-10-Alkoxy-carbonyl-, 2,2,2-Trichlorethoxycarbonyl-, Phenyloxycarbonyl-, Benzyloxycarbonyl-, Phenylcarbonyl-, Hydroxy-, C_1-5-Alkyloxy-, Benzyloxy- oder Phenyloxygruppe ersetzt sein kann,
wobei, soweit nicht anderes erwähnt wurde, unter dem Ausdruck eine Heteroarylgruppe eine im Kohlenstoffgerüst gegebenenfalls durch eine C_1-3-Alkyl-, Carboxy-, C_1-3-Alkoxy-carbonyl- oder C_1-3-Alkoxy-carbonylaminogruppe substituierte monocyclische 5- oder 6-gliedrige Heteroarylgruppe zu verstehen ist, wobei
die 6-gliedrige Heteroarylgruppe ein, zwei oder drei Stickstoffatome und
die 5-gliedrige Heteroarylgruppe eine gegebenenfalls durch eine C_1-3-Alkyloder Phenyl-C_1-3-alkylgruppe substituierte Iminogruppe, ein Sauerstoff- oder Schwefelatom oder
eine gegebenenfalls durch eine C_1-3-Alkyl-, Amino-C_1-3-alkyl-, C_1-3-Alkylamino-C_1-3-alkyl-, Di-(C_1-3-alkyl)-amino-C_1-3-alkyl- oder Phenyl-C_1-3-alkylgruppe substituierte Iminogruppe oder ein Sauerstoff- oder Schwefelatom und zusätzlich ein Stickstoffatom oder
eine gegebenenfalls durch eine C_1-3-Alkyl- oder Phenyl-C_1-3-alkylgruppe substituierte Iminogruppe oder ein Sauerstoff- oder Schwefelatom und zusätzlich zwei Stickstoffatome enthält,
eine gegebenenfalls durch eine C_1-3-Alkyl- oder Phenyl-C_1-3-alkylgruppe substituierte Iminogruppe und drei Stickstoffatome enthält,
und außerdem an die vorstehend erwähnten monocyclischen heterocyclischen Gruppen über zwei benachbarte Kohlenstoffatome ein Phenylring ankondensiert sein kann und die Bindung über ein Stickstoffatom oder über ein Kohlenstoffatom des heterocyclischen Teils oder eines ankondensierten Phenylrings erfolgt,
und wobei die oben erwähnten Alkyl- und Alkoxygruppen lineare und verzweigte Alkyl- und Alkoxygruppen einschließen, in denen zusätzlich ein bis 3 Wasserstoffatome durch Fluoratome ersetzt sein können.In the general formula above mean
R ^{1 is} a C _3-7 cycloalkyl carbonyl group, wherein
the methylene group in the 3- or 4-position in a C _5-7 cycloalkylcarbonyl group can be replaced by an -NH group in which
the hydrogen atom of the -NH group can be replaced by a C _1-3 alkyl or C _1-3 alkylcarbonyl group,
a C _1-6 alkylcarbonyl group optionally substituted by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) amino group in the alkyl part,
a group of the formula R _f R _g N-CH ₂ ) _m - (R _h ) N-CO-, in which R _f , R _g and R _h each independently represent a hydrogen atom or a C _1-3 alkyl group and m one of the numbers 2, 3 or 4 mean
a phenylcarbonyl, naphthylcarbonyl or heteroarylcarbonyl group,
wherein the phenyl, naphthyl or heteroaryl part by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl, amino C _1-3 alkyl, C _1-3 alkylamino-C _1-3 alkyl, di (C _1-3 alkyl) aminoC _1-3 alkyl or C _1-3 alkoxy group may be substituted,
a C _1-3 alkyl group substituted by a phenyl or heteroaryl group,
wherein the phenyl or heteroaryl substituent by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 -alkyl-, di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl or C _1-3 -alkoxy group may be substituted,
a 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group,
optionally by an amino-C _1-3 -alkyl-, C ₁ _ ₃ -alkylamino-C _1-3 -alkyl-, di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-, Aminocarbonyl, C _1-3 alkylamino carbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted 4- to 7-membered cycloalkyleneiminocarbonyl or cycloalkyleneiminosulfonyl group or a group of the formula

in which one hydrogen atom in the heterocyclic part can be replaced by one aminomethyl or aminocarbonyl group,
R ^{2 is} a fluorine, chlorine or bromine atom, a C ₂ _ ₃ alkenyl group or
a C _1-3 alkoxy or C _1-3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms,
R ^{3 is} a hydroxyl or amino group,
R ^{4 is} a phenyl or heteroaryl group which may be replaced by a hydroxy, C _1-4 alkyloxy, benzyloxy, hydroxycarbonyl C _1-3 alkoxy, C _1-3 alkyloxy carbonyl C _1-3 - alkyloxy, aminocarbonylC _1-3 alkyloxy, C _1-3 alkylaminocarbonylC _1-3 alkyloxy, di (C _1-3 alkyl) aminocarbonylC _1-3 alkyloxy, carboxy -, C _1-3 alkyloxy-carbonyl group is substituted,
a 1-H-pyridonyl or 1- (C _1-3 alkyl) pyridonyl group,
a 4- to 7-membered cycolalkyleneimino group or
a 4- to 7-membered cycloalkyl group in which one or two methylene groups have been replaced by a -NH- or -N (C _1-3 -alkyl) group and in which one or two of the -NH- or -N (C _1-3 alkyl) - group adjacent methylene groups can each be replaced by a carbonyl group with the proviso that a cycloalkyl group as defined above, in the two -NH or -N (C _1-3 alkyl) - groups by exactly one -CH ₂ - group are separated from each other, are excluded, and
R ^{5 is} a group of the formula -CH ₂ -NHR ⁶ , in which
R ^{6 represents} a hydrogen atom, a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl or benzyloxycarbonyl group, or a group of the formula -C (= NH) -NH ₂ , in which a hydrogen atom can be replaced by a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, phenylcarbonyl, hydroxyl, C _1-5 alkyloxy, benzyloxy or phenyloxy group,
where, unless stated otherwise, the expression "heteroaryl" means a monocyclic group optionally substituted in the carbon skeleton by a C _1-3 -alkyl, carboxy, C _1-3 -alkoxy-carbonyl or C _1-3 -alkoxy-carbonylamino group 5- or 6-membered heteroaryl group is to be understood, wherein
the 6-membered heteroaryl group has one, two or three nitrogen atoms and
the 5-membered heteroaryl group is an imino group which is optionally substituted by a C _1-3 -alkyl or phenyl-C _1-3 -alkyl group, an oxygen or sulfur atom or
one optionally by a C _1-3 alkyl, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, di (C _1-3 alkyl) amino C _1-3 alkyl or phenyl-C _1-3 alkyl group substituted imino group or an oxygen or sulfur atom and in addition a nitrogen atom or
contains an imino group optionally substituted by a C _1-3 alkyl or phenyl C _1-3 alkyl group or an oxygen or sulfur atom and additionally two nitrogen atoms,
contains an imino group optionally substituted by a C _1-3 alkyl or phenyl C _1-3 alkyl group and three nitrogen atoms,
and a phenyl ring may also be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bond takes place via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring,
and wherein the above-mentioned alkyl and alkoxy groups include linear and branched alkyl and alkoxy groups in which one to three hydrogen atoms may additionally be replaced by fluorine atoms.

Those compounds of the general formula (I) in which R ¹ to R ⁴ are defined as mentioned at the outset and R ^{5 is} substituted on the nitrogen atom by a C _1-10 -alkoxycarbonyl-, 2,2,2-trichloroethoxycarbonyl-, phenyloxycarbonyl- or benzyloxycarbonyl group substituted aminomethyl group or an amidino group substituted by a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, phenylcarbonyl, hydroxy, C _1-5 alkyloxy, benzyloxy or phenyloxy group represents prodrugs for those compounds of the general formula (I) in which R ^{5 represents} an aminomethyl or amidino group.

in denen im heterocyclischen Teil jeweils ein Wasserstoffatom durch eine Aminomethyl- oder Aminocarbonylgruppe ersetzt sein kann, bedeutet,
wobei die oben erwähnten Alkyl- und Alkoxygruppen lineare und verzweigte Alkyl- und Alkoxygruppen einschließen, in denen zusätzlich ein bis 3 Wasserstoffatome durch Fluoratome ersetzt sein können,
deren Tautomere, Enantiomere, deren Diastereomere, deren Gemische und deren Salze.Preferred compounds of the above general formula I are those in which
R ² , R ³ , R ⁴ and R ⁵ are defined as mentioned above and
R ^{1 is} a 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group,
one optionally by an amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 alkyl, di (C _1-3 alkyl) amino C _1-3 alkyl, aminocarbonyl -, C _1-3 alkylamino carbonyl or di (C _1-3 alkyl) aminocarbonyl group substituted 4- to 7-membered cycloalkyleneiminocarbonyl group or
a group of the formula

in which one hydrogen atom in the heterocyclic part can be replaced by one aminomethyl or aminocarbonyl group,
wherein the above-mentioned alkyl and alkoxy groups include linear and branched alkyl and alkoxy groups in which one to three hydrogen atoms can additionally be replaced by fluorine atoms,
their tautomers, enantiomers, their diastereomers, their mixtures and their salts.

Those compounds of the above general formula I in which
R ¹ , R ² , R ³ and R ⁵ are defined as mentioned above and
R ^{4 is} a phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl or isoxazolyl group, which may be replaced by a hydroxy, C _1-4 alkyloxy, Benzyloxy-, hydroxycarbonyl-C _1-3 -alkoxy-, C _1-3 -alkyloxy-carbonyl-C _1-3 -alkyloxy-, aminocarbonyl-C _1-3 -alkyloxy-, C _1-3 -alkylaminocarbonyl-C _{1- 3} -alkyloxy-, di- (C _1-3 -alkyl) -aminocarbonyl-C _1-3 -alkyloxy-, carboxy-, C _1-3 -alkyloxycarbonyl group means,
wherein the above-mentioned alkyl and alkoxy groups include linear and branched alkyl and alkoxy groups in which one to three hydrogen atoms can additionally be replaced by fluorine atoms,
their tautomers, enantiomers, their diastereomers, their mixtures and their salts.

For example, the following preferred compounds of general formula I are mentioned:
(1) 2- (5-amidino-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide,
(2) 2- (5-Amidino-2-hydroxyphenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] -3- (pyridin-3-yl) propionamide and
(3) 2- (5-aminomethyl-2-hydroxyphenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] -3-phenyl-propionamide,
in which the amidino group can additionally be substituted by a hydroxy, C _1-5 alkyloxy, C _1-10 alkoxycarbonyl or phenylcarbonyl group, and their salts.

in der R¹ und R² wie eingangs erwähnt definiert sind, mit einer Carbonsäure oder mit einem reaktionsfähigen Carbonsäurederivat der allgemeinen Formel

in der R³ und R⁴ wie eingangs erwähnt definiert sind, wobei die Reste R³ und R⁴ gegebenenfalls vor der Umsetzung durch geeignete Schutzgruppe geschützt werden, welche nach der Umsetzung wieder abgespalten werden,
R⁵ eine Cyanogruppe, eine geschützte Aminomethylgruppe oder eine durch eine Carbamatgruppe geschützte Amindinogruppe darstellt und
Z¹ eine Hydroxygruppe oder eine nukleofuge Abgangsgruppe wie beispielsweise eine C_1-6-Alkoxy-carbonyloxy-, C_1-6-Alkyl-carbonyloxy- oder 2,6-Dichlorphenylcarbonyloxygruppe oder ein Chlor- oder Bromatom bedeutet, und anschließende Überführung der so erhaltenen Cyanoverbindung in eine gegebenenfalls mit den eingangs erwähnten Gruppen substituierte Amidino- oder Aminomethylverbindung.According to the invention, the compounds of general formula 1 are obtained by processes known per se, for example by the following processes:
a) Acylation of a compound of the general formula

in which R ¹ and R ² are defined as mentioned at the outset, with a carboxylic acid or with a reactive carboxylic acid derivative of the general formula

in which R ³ and R ⁴ are defined as mentioned at the outset, the radicals R ³ and R ^{4 being} optionally protected from the reaction by a suitable protective group, which are split off again after the reaction,
R ^{5 represents} a cyano group, a protected aminomethyl group or an amindino group protected by a carbamate group and
Z ^{1 represents} a hydroxyl group or a nucleofugic leaving group such as, for example, a C _1-6 alkoxycarbonyloxy, C _1-6 alkylcarbonyloxy or 2,6-dichlorophenylcarbonyloxy group or a chlorine or bromine atom, and subsequent conversion of the thus obtained Cyano compound in an amidino or aminomethyl compound optionally substituted with the groups mentioned at the outset.

The acylation is convenient with an appropriate halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, Dioxane, benzene, toluene, acetonitrile, dimethylformamide or sulfolane optionally in the presence of an inorganic or organic Base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C, carried out.

However, the acylation can also be carried out with the free acid or an ester, if appropriate in the presence of an acid-activating agent or of a water-removing agent, for example in the presence of chlora isobutyl formate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, triethylamine, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimidol (N) -hydroxy-benzotriazole (N) -benzohydroxy-benzodiazole (N) -dicyclo-hydroxodiimidol (N) -benzydroxy-benzodiimidol (N) -dicyclo-benzodiimidol (N) -benzydroxy-benzodiimidol (N) -benzydroxy-1-hydroxodiimidol / n-benzodiimidol / n-benzodiimidol / n-benzodiimidol (N) -dicyclo-benzodi-hydroxyl-tri-benzotriazole (N) -1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate / N-methylmorpholine, propanephosphonic acid cyclo-anhydride / N-methylmorpholine, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride , at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.

Other amide coupling processes are described, for example, in P.D.Bailey, I.D. Collier, K.M. Morgan in comprehensive Functional Group Intervconversions Vol.5, 257ff. Pergamon, 1995 described.

The subsequent conversion of the cyano group into a Amidino group is carried out as described in process b).

in der
R¹ bis R⁴ wie eingangs erwähnt definiert sind und
Z² eine Alkoxy-, Aralkoxy-, Alkylthio- oder Aralkylthiogruppe darstellt, mit einem Amin der allgemeinen Formel H – R⁷NR⁸ (V), in der
R⁷ ein Wasserstoffatom und
R⁸ ein Wasserstoffatom oder eine Hydroxy, C_1-5-Alkyloxy-, Benzyloxy- oder Phenyloxygruppe bedeuten, oder mit dessen Salzen.b) To prepare a compound of general formula I in which R _{5 is} optionally substituted by a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, phenylcarbonyl, hydroxy, C _1-5 alkyloxy, benzyloxy or phenyloxy group substituted amidino group:
Reaction of a compound of the general formula optionally formed in the reaction mixture

in the
R ¹ to R ⁴ are defined as mentioned at the beginning and
Z ^{2 represents} an alkoxy, aralkoxy, alkylthio or aralkylthio group, with an amine of the general formula H - R ⁷ NR ⁸ (V), in the
R ^{7 is} a hydrogen atom and
R ^{8 represents} a hydrogen atom or a hydroxy, C _1-5 alkyloxy, benzyloxy or phenyloxy group, or with its salts.

The implementation will be convenient in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane Temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, with an amine of the general Formula V or with an appropriate acid addition salt such as Ammonium carbonate or ammonium acetate performed.

A compound of the general formula IV receives one, for example, by reacting a corresponding cyano compound with an appropriate alcohol such as methanol, ethanol, n-propanol, Isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting an appropriate amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, Tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, preferably however at 20 ° C, or a corresponding nitrile with hydrogen sulfide expediently in a solvent such as pyridine or dimethylformamide and in the presence of a base such as Triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.

in der
R¹ bis R⁴ wie eingangs erwähnt definiert sind, und gegebenenfalls anschließende Umsetzung der so erhaltenen Aminomethylverbindung mit einer Verbindung der Formel R⁹ – Z³ (VII), in der R⁹ eine C_1-10-Alkoxy-carbonyl-, 2,2,2-Trichlorethoxycarbonyl-, Phenyloxycarbonyl- oder Benzyloxycarbonylgruppe und Z³ eine Austrittsgruppe wie ein Halogenatom oder eine Sulfonyloxygruppe darstellt, z.B. ein Chlor-, Brom- oder Iodatom oder eine Trifluormethylsulfonyloxygruppe.c) For the preparation of a compound of the general formula I in which R _{5 represents} an aminomethyl group optionally substituted on the nitrogen atom by a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl or benzyloxycarbonyl group:
Catalytic hydrogenation of a compound of the general formula

in the
R ¹ to R ⁴ are defined as mentioned at the outset, and optionally subsequent reaction of the aminomethyl compound thus obtained with a compound of the formula R ⁹ - Z ³ (VII), in which R ^{9 represents} a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl or benzyloxycarbonyl group and Z ^{3 represents} a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy group.

The catalytic hydrogenation will with hydrogen in the presence of a catalyst such as palladium / carbon, Platinum in a solvent such as methanol, ethanol, ethyl acetate, Dimethylformamide, dimethylformamide / acetone or glacial acetic acid if necessary with the addition of an acid like hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, or for example with Raney nickel, preferably in methanolic ammonia solution.

Any subsequent acylation can be carried out as described in method a).

If, according to the invention, a compound of the general formula I is obtained which contains an amino or imino group, this can then be converted with a corresponding acyl derivative into a corresponding acyl compound of the general formula I and / or
a compound of the general formula I which contains an esterified carboxy group, this can be converted into a corresponding carboxylic acid of the general formula I by hydrolysis and / or
a compound of the general formula I which contains a carboxy group, this can then be converted into an appropriate ester by esterification.

The subsequent acylation is expediently carried out with an appropriate halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C. However, this can also be carried out with the free acid, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'- Dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, preferably, however, at -20 ° C Temperatures between -10 and 160 ° C are carried out. The acylation can, for example, introduce the C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl or phenylcarbonyl group.

The subsequent hydrolysis is convenient either in the presence of an acid like hydrochloric acid, Sulfuric acid, Phosphoric acid, Acetic acid, trichloroacetic trifluoroacetic or mixtures thereof or in the presence of a base such as lithium hydroxide, Sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol, water / isopropanol, Methanol, ethanol, water / tetrahydrofuran or water / dioxane and the subsequent one Decarboxylation in the presence of an acid as described above at temperatures between –10 and 120 ° C, e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture.

The subsequent esterification is advantageously carried out with an appropriate alcohol in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in In the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclo hexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole, triphenylphosphine / carbon tetrachloride or triphenylphosphine / azodicarboxylic acid, diethyl ethylamine or di-diethyl ethylamine, optionally in a diethyl diethylamine or diethyl ethylamine in a diethyl diethylamine, or a diethyl diethylamine amine, or a diethyl diethylamine amine in a diethyl diethylamine amine or a diethyl ethylamine amine, or a diethyl ethylamine amine, or a diethyl ethylamine amine in a diethyl diethylamine amine, or in a diethyl diethylamine amine, or a diethyl diethylamine amine in a diethyl diethylamine amine, or in a diethyl diethylamine amine, or in a diethyl diethylamine amine, diethyl ethylamine, or in a diethyl diethylamine aminate, n-ethyl or , N-Dimethylaminopyridine expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, or with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone optionally in the presence of a reaction accelerator such as Sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent at the same time, or optionally in the presence of silver carbonate or silver oxide b Temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.

In the above Implementations can optionally present reactive groups such as hydroxyl, carboxy, Amino, alkylamino or imino groups during the reaction by conventional protective groups protected which are split off after the implementation.

For example, comes as a protective residue for one Hydroxyl group the methoxy, benzyloxy, trimethylsilyl, acetyl, Benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group, as protective remains for a carboxyl group the trimethylsilyl, methyl, ethyl, tert-butyl, Benzyl or tetrahydropyranyl group and as a protective radical for an amino, Alkylamino or imino group, acetyl, trifluoroacetyl, benzoyl, Ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, Methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group additionally the phthalyl group into consideration.

Further protecting groups and their splitting off are in T.W. Greene, P.G.M. Wuts, Protective Groups in Synthesis, Wiley, 1991.

The subsequent subsequent splitting, if applicable of a protective residue used is, for example, hydrolytic in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or Dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether cleavage, e.g. in present of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

The cleavage of a benzyl, methoxybenzyl or benzyloxycarbonyl radical, for example, takes place hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, Dimethylformamide, dimethylformamide / acetone or glacial acetic acid if necessary with the addition of an acid like hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

The cleavage of a methoxybenzyl group can also in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C, but preferably at room temperature.

The cleavage of a methoxy group expediently takes place in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between –35 and -25 ° C.

The cleavage of a 2,4-dimethoxybenzyl radical however, it is preferably carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of a tert-butyl or tert-butyloxycarbonyl radical is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid optionally using a solvent such as methylene chloride, Dioxane or ether.

The cleavage of a phthalyl radical is preferably carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane Temperatures between 20 and 50 ° C.

The cleavage of an allyloxycarbonyl radical is carried out by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) chloride in a solvent like watery Ethanol and optionally in the presence of a base such as 1,4-diazabicyclo [2.2.2] octane at temperatures between 20 and 70 ° C.

The used as raw materials Compounds of the general formulas II to VI, some of which are known from the literature are receives one according to methods known from the literature, furthermore their production described in the examples.

in der
R³ wie eingangs erwähnt definiert ist, wobei R³ gegebenenfalls vor der Umsetzung durch geeignete Schutzgruppe geschützt wird, welche nach der Umsetzung wieder abgespalten wird,
R⁵ eine Cyanogruppe darstellt und
R¹⁰OCO eine gegebenenfalls geschützte Carboxygruppe darstellt, wobei R¹⁰ Wasserstoff oder einen geeigneten Schutzrest bedeutet wie beispielsweise eine C_1-6-Alkylgruppe,
in Benzylstellung deprotoniert und anschließend durch Umsetzung mit einer Verbindung der allgemeinen Formel R⁴-CH₂-Z⁴ (IX), in der R⁴ wie eingangs erwähnt definiert ist und Z⁴ eine nucleofuge Abgangsgruppe wie beispielsweise ein Chlor-, Brom- oder Iodatom oder eine p-Tolylsulfonyl-, Methylsulfonyl- oder Trifluormethylsulfonylgruppe bedeutet,
alkyliert. Die Deprotonierung erfolgt mittels geeigneter Basen wie beispielsweise Natriumhydrid, Kaliumtert.butylat oder Lithiumdiisopropylamin in Lösungsmitteln wie etwa DMF, Tetrahydrofuran, Dimethylsulfoxid, Ether oder deren Gemische bei Temperaturen zwischen -10 und 20°C, bevorzugt bei 5 bis 15°C.For example, a compound of general formula III can be prepared by using a compound of general formula

in the
R ³ is defined as mentioned at the beginning, R ³ possibly being protected from the reaction by a suitable protective group which is split off again after the reaction,
R ^{5 represents} a cyano group and
R ¹⁰ OCO represents an optionally protected carboxy group, where R ¹⁰ denotes hydrogen or a suitable protective radical such as, for example, a C _1-6 alkyl group,
deprotonated in the benzyl position and then by reaction with a compound of the general formula R ⁴ -CH ₂ -Z ⁴ (IX), in which R ⁴ is defined as mentioned at the outset and Z ⁴ denotes a nucleofugic leaving group such as, for example, a chlorine, bromine or iodine atom or a p-tolylsulfonyl, methylsulfonyl or trifluoromethylsulfonyl group,
alkylated. Deprotonation is carried out using suitable bases such as sodium hydride, potassium tert-butoxide or lithium diisopropylamine in solvents such as DMF, tetrahydrofuran, dimethyl sulfoxide, ether or their mixtures at temperatures between -10 and 20 ° C, preferably at 5 to 15 ° C.

The production of carboxylic acid derivatives the general formula III are in methods of organic chemistry (Houben-Weyl), Volume E5, carboxylic acids and carboxylic acid derivatives, 4th edition, published by Thieme, Stuttgart 1985.

Furthermore, the compounds obtained of the general formula I in its enantiomers and / or diastereomers be separated.

For example, the Compounds of general formula I obtained, which in racemates occur, according to methods known per se (see Allinger N. L. and Eliel E. L. in "Topics in stereochemistry ", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and Compounds of general formula I with at least 2 asymmetrical Carbon atoms due to their physico-chemical differences according to methods known per se, e.g. by chromatography and / or fractional crystallization, separate into their diastereomers, which, if they occur in racemic form, then like mentioned above can be separated into the enantiomers.

The enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optical active solvent or by reaction with a, with the racemic compound salts or derivatives such as Esters or amides forming optically active Substance, especially acids and their activated derivatives or alcohols, and separating the diastereomeric salt mixture or derivative obtained in this way, e.g. due to different solubilities, whereby from the pure diastereomeric salts or derivatives the free antipodes can be released by the action of suitable agents. Especially common, optically active acids are e.g. the D and L forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or China acid. The optically active alcohol is, for example, (+) - or (-) - menthol and as an optically active acyl radical in amides, for example the (+) - or (-) - menthyloxycarbonyl radical in Consideration.

Furthermore, the compounds obtained of the formula I in their salts, in particular for pharmaceutical use in their physiologically tolerable Salts with inorganic or organic acids. Come as acids therefor for example hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic into consideration.

In addition, the so obtained new compounds of formula I, if this is a carboxy group included, if desired subsequently in their salts with inorganic or organic bases, in particular for the pharmaceutical application in their physiologically acceptable Salts, transfer. As bases come here, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, Ethanolamine, diethanolamine and triethanolamine.

As already mentioned at the beginning, point the compounds of general formula 1 and their tautomers, their enantiomers, their diastereomers and their physiologically acceptable Salts valuable pharmacological properties, in particular an antithrombotic effect, which is preferably due to one factor Xa influencing effect is based, for example, on a factor Xa-inhibitory effect and on an inhibitory effect on related serine proteases such as B. thrombin, trypsin, urokinase, factor VIIa, factor IXa, Factor XIa and factor XIIa.

For example, the connection
(A) 2- (5-Amidino-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] -3- (pyridin-3-yl) -propionamide- dihydrochloride
examined for their effect on the inhibition of factor Xa as follows:

methodology

Enzyme kinetic measurement with a chromogenic substrate. The amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (based on the solvent control) is determined at different test substance concentrations and from this the IC _{50 is} calculated as the concentration which inhibits the factor Xa used by 50%.

material

Tris (hydroxymethyl) aminomethane buffer (100 mmol) and sodium chloride (150 mmol), pH 8.0
Factor Xa (Roche), specific activity: 10 U / 0.5 ml, final concentration: 0.175 U / ml per reaction mixture
Chromozym X (Roche) substrate, final concentration: 200 μmol / l per reaction mixture
Test substance: final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 μmol / l

execution

10 μl of a 23.5-fold more concentrated starting solution the test substance or solvent (Control), 175 ul Tris (hydroxymethyl) aminomethane buffer and 25 ul Factor Xa working solution of 1.65 U / ml are incubated at 37 ° C for 10 minutes. After adding 25 ul chromozyme X-use solution (1.88 μmol / l) the sample in the photometer (SpectraMax 250) at 405 nm for 150 seconds at 37 ° C measured.

evaluation

• 1. Determination of the maximum increase (deltaOD / minutes) over 3 measuring points.
• 2. Determination of the% inhibition based on the solvent control.
• 3. Create a dose-response curve (% inhibition vs substance concentration).
• 4. Determination of the IC ₅₀ by interpolation of the X value (substance concentration) of the dose-response curve with Y = 50% inhibition.

The following table contains the values found: substance Inhibition of factor Xa (IC ₅₀ in μM) (A) 0,007

The compounds produced according to the invention are generally well tolerated.

Due to their pharmacological properties, the new compounds and their physiologically acceptable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the prevention and treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases, as well as prevention and treatment of pulmonary embolism, disseminated intravascular coagulation, prophylaxis and treatment of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts. In addition, the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT (C) A, for the prophylaxis and treatment of ischemic incidents in patients of all forms coronary heart disease, to prevent metastasis and tumor growth and of inflammatory processes, for example in the treatment of pulmonary fibrosis, for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin-dependent tissue adhesions and / or scar tissue formation, and for promoting wound healing processes. The new compounds and their physiologically tolerable salts can be used therapeutically in combination with acetylsalicylic acid, with platelet aggregation inhibitors such as fibrinogen receptor antagonists (eg abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogs (for example, their recombinant analogs C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticlopidine), with P ₂ T receptor antagonists (e.g. Cangrelor) or with combined thromboxes receptor antagonists / synthetase inhibitors (e.g. Terbogrel).

To achieve a corresponding The required dose is expediently effective when administered intravenously 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg, and oral Administration 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, each 1 up to 4 times a day. For this can be produced according to the invention Compounds of formula I, optionally in combination with others Active substances, together with one or more inert usual excipients and / or diluents, e.g. with cornstarch, Milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, Polyvinyl pyrrolidone, citric acid, Tartaric acid, Water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, Propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in usual pharmaceutical preparations such as tablets, coated tablets, capsules, powders, Suspensions or suppositories incorporated.

The following examples are intended the invention closer explain, without, however, limiting their scope:

example 1

2- (5-amidino-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) phenyl-3-phenyl-propionamide hydrochloride

a. 4-Nitro-2-trifluoromethyl-benzonitrile

30.9 g (0.15 mol) of 2-amino-5-nitro-benzotrifluoride are concentrated in 335 ml of water and 66.5 ml. Suspended sulfuric acid. At 0 ° C will be a solution added dropwise from 10.7 g (0.156 mol) of sodium nitrite in 40 ml of water and after the addition has ended, stirred for a further 20 minutes. The undissolved material is suctioned off, you get the Diazonium salt.

45 g (0.18 mol) of copper sulfate × 5 H ₂ O are dissolved in 500 ml of water, then 52.5 g (0.8 mol) of potassium cyanide are added with gentle ice cooling and the mixture is stirred for 20 minutes. A solution of 225 g (2.1 mol) of sodium carbonate in 450 ml of water is then added, and the diazonium salt solution is added dropwise at 0.degree. After the reaction has warmed to room temperature, the mixture is stirred for a further 2 hours at 45 ° C. and then extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate (9/1 to 8/2).
Yield: 6.9 g (18% of theory)
R _f value: 0.5 (silica gel; petroleum ether / ethyl acetate = 8: 2)

b. 4-Nitro-2-trifluoromethyl-benzoic acid

2.1 g (10 mmol) of 4-nitro-2-trifluoromethyl-benzonitrile are dissolved in 20 ml of 55% sulfuric acid and stirred at 165 ° C for 2 hours. It is then cooled, adjusted to pH 8-9 with sodium hydroxide solution and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is chromatographed on silica gel, eluting with dichloromethane / methanol 50: 1.
Yield: 1.0 g (45% of theory)
Rf value: 0.1 (silica gel; dichloromethane / ethanol = 9: 1)

c. 3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -nitrobenzene

3.9 g (16.5 mmol) of 4-nitro-2-trifluoromethyl-benzoic acid are dissolved in 75 ml of dimethylformamide and after adding 5.9 g (18 mmol) of O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate, 2.0 ml (18.5 mmol) of N-methylmorpholine and 1.5 ml (18 mmol) of pyrrolidine were stirred for 16 hours at room temperature. The The reaction product is stirred into ice water / 1 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are dried and evaporated. The residue is crystallized from ether / petroleum ether.
Yield: 4.1 g (80% of theory)
Rf value: 0.6 (silica gel; dichloromethane / ethanol = 9: 1)

d. 3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl-aniline

2.6 g (7.4 mmol) of 3-trifluoromethyl-4- (pyrrolidin-1-y1-carbonyl) nitrobenzene are dissolved in 50 ml of ethyl acetate and 50 ml of methanol and, after adding 1 g of palladium on activated carbon (10%), at room temperature Hydrogen hydrogenates. The catalyst is then filtered off and evaporated. The residue is recrystallized from ethyl acetate.
Yield: 1.6 g (87% of theory)
R _f value: 0.45 (silica gel; dichloromethane / ethanol = 9: 1)

e. 2- (2-benzyloxy-5-cyano-phenyl) -3-phenyl-propionic acid methyl ester

1.0 g (3.5 mmol) of (2-benzyloxy-5-cyano-phenyl) -acetic acid methyl ester are suspended in 25 ml of tetrahydrofuran and 120 mg (4.7 mmol) of sodium hydride are added in portions at 10 ° C. After 45 minutes, 0.5 ml (4.6 mmol) of benzyl bromide are added dropwise and the mixture is stirred at room temperature for 16 hours. The tetrahydrofuran is distilled off, the residue is distributed in ethyl acetate / water, the organic phase is washed with sodium bicarbonate solution, dried and evaporated.
Yield: 1.5 g (97% of theory)
R _f value: 0.52 (silica gel; petroleum ether / ethyl acetate = 7: 3)

f. 2- (2-benzyloxy-5-cyano-phenyl) -3-phenyl-propionic acid

1.5 g (4 mmol) of methyl 2- (2-benzyloxy-5-cyano-phenyl) -3-phenyl-propionate are dissolved in 25 ml of methanol and, after addition of 10 ml of 1 M sodium hydroxide solution, stirred at 60 ° C. for 3 h. The methanol is distilled off, the residue is taken up in water and extracted with ether. The aqueous phase is adjusted to pH 6 with glacial acetic acid and the precipitated product is filtered off with suction.
Yield: 1.0 g (69% of theory)
Melting point: 170-171 ° C

G. 2- (2-benzyloxy-5-cyano-phenyl-3-phenyl-propionic acid

1.00 g (2.8 mmol) of 2- (2-benzyloxy-5-cyano-phenyl) -3-phenyl-propionic acid are dissolved in 10 ml of dichloromethane and after the addition of 0.6 ml (8.4 mmol) of thionyl chloride and 0.1 ml of dimethylformamide for 1.5 hours at reflux heated. The reaction mixture is then evaporated and reacted further without purification.
Yield: 1.05 g (100% of theory)

H. 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-trifluoromethyl-4-pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide

A solution of 413 mg (1.1 mmol) of 2- (2-benzyloxy-5-cyano-phenyl) -3-phenyl-propionic acid chloride in 30 ml of tetrahydrofuran is mixed with 258 mg (1 mmol) of 3-trifluoromethyl-4- (pyrrolidin-1 -yl-carbonyl) -aniline added. Then 0.3 ml (3 mmol) of triethylamine are added dropwise. After 14 hours at room temperature, it is poured onto 100 ml of ice water and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid, dried and evaporated. The residue is chromatographed on silica gel, eluting with petroleum ether / ethyl acetate 1: 1.
Yield: 0.50 g (84% of theory)
Rf value: 0.35 (silica gel; petroleum ether / ethyl acetate = 2: 1)

i. 2- (2-benzyloxy-5-amidino-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl-phenyl] -3-phenyl-propionamide hydrochloride

500 mg (0.8 mmol) of 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-trifluoromethyl-4-pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide are dissolved in 30 ml saturated ethanolic hydrochloric acid dissolved and stirred at room temperature for 17 hours. The solvent is distilled off and the residue is dissolved in 20 ml of absolute ethanol and mixed with 1.2 g (12.5 mmol) of ammonium carbonate. After 22 hours, the mixture is evaporated to dryness. Ethanol is added to the residue, the insoluble inorganic salts are filtered off with suction, ether is added to the filtrate and the precipitated product is filtered off with suction.
Yield: 0.45 g (83% of theory)
Rf value: 0.26 (silica gel; petroleum ether / ethyl acetate = 1: 1)
C ₃₅ H ₃₃ F ₃ N ₄ O ₃ × HCl (614.67 / 651.134)
Mass Spectrum:
(M + H) ⁺ = 615
(M + Cl) ^- = 649/51 (chlorine isotopes)

k. 2- (5-amidino-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) phenyl-3-phenyl-propionamide hydrochloride

Prepared analogously to Example 1d from 2- (2-benzyloxy-5-carbamimidoyl-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3-phenyl-propionamide and palladium on activated carbon in methanol.
Yield: 80% of theory
R _f value: 0.66 (reversed phase RP 8; 5% sodium chloride solution / methanol = 1: 3)
C ₂₈ H ₂₇ F ₃ N ₄ O ₃ × HCl (524.54 / 561.009)
Mass Spectrum:
(M + H) ⁺ = 525
(MH) ^- = 523
(M + Cl) ^- = 559/61 (chlorine isotopes)

Example 2 2- (5-Amidino-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3- (pyridin-3-yl) -propionamide- dihydrochloride

Prepared analogously to Example 1k from 2- (5-amidino-2-benzyloxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3- (pyridin-3-yl) -propionamide dihydrochloride and palladium on activated carbon in methanol.
Yield: 66% of theory,
R _f value: 0.42 (reversed phase RP 8; 5% sodium chloride solution / methanol = 2: 3)
C ₂₇ H ₂₉ N ₅ O ₃ × 2 HCl (471.55 / 544.48)
Mass spectrum: (M + H) ⁺ = 472

Example 3

2- (5-aminomethyl-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyll-3-phenyl-propionamide

a. 2- (5-aminomethyl-2-benzyloxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3-phenyl-propionamide

580 mg (0.97 mmol) of 2- (2-benzyloxy-5-cyano-phenyl) -N- [3-trifluoromethyl-4-pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide (e.g. 1 h ) are dissolved in 40 ml of methanolic ammonia and hydrogenated with hydrogen after adding 400 mg of Raney nickel for 5 hours at room temperature. The catalyst is filtered off and the solution is evaporated.
Yield: 580 mg (100% of theory)
R _f value: 0.2 (silica gel; dichloromethane / methanol = 4: 1)

b. 2- (5-aminomethyl-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3-phenyl-propionamide

Prepared analogously to Example 1 k from 2- (5-aminomethyl-2-benzyloxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] -3-phenyl-propionamide and palladium Activated carbon in methanol.
Yield: 75% of theory,
R _f value: 0.75 (silica gel; dichloromethane / ethanol / ammonia = 4: 1: 0.1)
C ₂₈ H ₂₈ F ₃ N ₃ O ₃ (511.549)
Mass Spectrum:
(M + H) ⁺ = 512
(MH) ^- = 510

Example 4

Dry ampoule with 75 mg of active ingredient per 10 ml

Composition: active substance 75.0 mg mannitol 50.0 mg Water for injections ad 10.0 ml

manufacturing

Active ingredient and mannitol are in Water dissolved. After bottling is freeze-dried. The resolution to ready-to-use solution done with water for Injections.

Example 5

Dry ampoule with 35 mg of active ingredient per 2 ml

Composition: active substance 35.0 mg mannitol 100.0 mg Water for injections ad 2.0 ml

manufacturing

Active ingredient and mannitol are in Water dissolved. After bottling is freeze-dried.

The resolution for ready to use solution done with water for Injections.

Example 6

Tablet with 50 mg of active ingredient

Composition: (1) Active ingredient 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinyl pyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg

manufacturing

(1), (2) and (3) are mixed and with an aqueous solution of (4) granulated. (5) is added to the dried granulate. Out This mixture tablets are pressed, biplane with bilateral Facet and one-sided partial notch. Tablet diameter: 9 mm.

Example 7

Tablet with 350 mg of active ingredient

Composition: (1) Active ingredient 350.0 mg (2) milk sugar 136.0 mg (3) corn starch 80.0 mg (4) polyvinyl pyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg

manufacturing

(1), (2) and (3) are mixed and with an aqueous solution of (4) granulated. (5) is added to the dried granulate. Out This mixture tablets are pressed, biplane with bilateral Facet and one-sided partial notch. Tablet diameter: 12 mm.

Example 8

Capsules with 50 mg of active ingredient

Composition: (1) Active ingredient 50.0 mg (2) Dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg

manufacturing

(1) is triturated with (3). This The mixture of (2) and (4) is triturated with intensive mixing added.

This powder mixture is on a Capsule filling machine in hard gelatin capsules Bottled size 3.

Example 9

Capsules with 350 mg of active ingredient

Composition: (1) Active ingredient 350.0 mg (2) Dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg

manufacturing

(1) is triturated with (3). This The mixture of (2) and (4) is triturated with intensive mixing added.

This powder mixture is dispensed on a capsule filling machine in size 0 hard gelatin capsules filled.

Example 10

Suppositories with 100 mg of active ingredient

1 suppository contains: active substance 100.0 mg Polyethylene glycol (MG 1500) 600.0 mg Polyethylene glycol (MG 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg 2000.0 mg

manufacturing

The polyethylene glycol is put together melted with polyethylene sorbitan monostearate. At 40 ° C milled active substance dispersed homogeneously in the melt. It will to 38 ° C chilled and in slightly pre-chilled Poured out suppository molds.

Claims (9)

Compounds of the general formula

in R ^{1 is} a C _3-7 cycloalkylcarbonyl group, the methylene group in the 3- or 4-position in a C _5-7 cycloalkylcarbonyl group can be replaced by an -NH group in which the hydrogen atom of the NH group can be replaced by a C _1-3 alkyl or C _1-3 alkylcarbonyl group, one terminally in the alkyl part optionally by an amino, C _1-3 alkylamino or di (C _1-3 alkyl) ) -amino group substituted C _1-6 alkylcarbonyl group, a group of the formula R _f R _g N- (CH ₂ ) _m - (R _h ) N-CO-, in which Rf, Rg and Rh are each independently a hydrogen atom or a C _1-3 alkyl group and m is one of the numbers 2, 3 or 4, a phenylcarbonyl, naphthylcarbonyl or heteroarylcarbonyl group, the phenyl, naphthyl or heteroaryl part being represented by a fluorine, chlorine or bromine atom, by a trifluoromethyl , C _1-3 -alkyl-, amino-C _1-3 -alkyl-, C _1-3 -alkylamino-C _1-3 -alkyl-, di- (C _1-3 -alkyl) -amino-C _{1- 3} alkyl or C _1-3 alkoxy group may be substituted , a C _1-3 alkyl group substituted by a phenyl or heteroaryl group, the phenyl or heteroaryl substituent being substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C _1-3 alkyl, amino C _{1- 3} -alkyl-, C _1-3 -alkylamino-C _1-3 -alkyl-, di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl- or C _1-3 -alkoxy group can be substituted , a 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group, optionally by an amino-C _1-3 -alkyl-, C _1-3 -alkylamino-C _1-3 -alkyl-, di- (C _{1 -3-} alkyl) -amino-C _1-3 -alkyl-, aminocarbonyl-, C _1-3 -alkylamino-carbonyl or di- (C _1-3 -alkyl) -aminocarbonyl group substituted 4- to 7-membered cycloalkyleneiminocarbonyl- or cycloalkyleneiminosulfonyl group or a group of the formula

in which in the heterocyclic part a hydrogen atom can be replaced by an aminomethyl or aminocarbonyl group, R ^{2 is} a fluorine, chlorine or bromine atom, a C ₂ _ ₃ alkenyl group or a C _1-3 alkoxy or C _1-3 Alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, R ^{3 is} a hydroxyl or amino group, R ^{4 is} a phenyl or heteroaryl group, which may be replaced by a hydroxy, C _1-4 alkyloxy, benzyloxy, Hydroxycarbonyl-C _1-3 -akoxy-, C _1-3 -alkyloxy-carbonyl-C _1-3 -alkyloxy-, aminocarbonyl-C _1-3 -alkyloxy-, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyloxy -, Di- (C _1-3 alkyl) aminocarbonyl-C _1-3 alkyloxy, carboxy, C _1-3 alkyloxy carbonyl group, a 1-H-pyridonyl or 1- (C _{1 -3-} alkyl) -pyridonyl group, a 4- to 7-membered cycloalkyleneimino group or a 4- to 7-membered cycloalkyl group in which one or two methylene groups are represented by a -NH- or -N (C _1-3 -alkyl) group are replaced and in the one or two methylene groups adjacent to the -NH- or -N (C _1-3 -alkyl) group can each be replaced by a carbonyl group with the proviso that a cycloalkyl group as defined above, in which two -NH- or -N ( C _1-3 alkyl) groups are separated from one another by exactly one -CH ₂ group, and R ^{5 is} a group of the formula -CH ₂ -NHR ⁶ , in which R ^{6 is} a hydrogen atom, a C _1-10 -Alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl or benzyloxycarbonyl group, or a group of the formula -C (= NH) -NH ₂ , in which a hydrogen atom through a C _1-10 alkoxy-carbonyl -, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, phenylcarbonyl, hydroxy, C _1-5 alkyloxy, benzyloxy or phenyloxy group can be replaced, where, unless stated otherwise, under the expression a heteroaryl group, optionally in the carbon skeleton, by a C _1-3 alkyl, carboxy, C _1-3 alkoxy carbonyl or C _1-3 alkoxy-carbonylamino group substituted monocyclic 5- or 6-membered heteroaryl group is to be understood, the 6-membered heteroaryl group having one, two or three nitrogen atoms and the 5-membered heteroaryl group, one optionally substituted by a C _1-3 alkyl or Phenyl-C _1-3 alkyl group substituted imino group, an oxygen or sulfur atom or one optionally substituted by a C _1-3 alkyl, amino C _1-3 alkyl, C _1-3 alkylamino C _1-3 -alkyl-, di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl or phenyl-C _1-3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally a nitrogen atom or one optionally by one C _1-3 alkyl or phenyl C _1-3 alkyl group substituted imino group or an oxygen or sulfur atom and additionally contains two nitrogen atoms, one optionally by a C _1-3 alkyl or phenyl C _1-3 alkyl group contains substituted imino group and three nitrogen atoms, and also to the vorst The monocyclic heterocyclic groups mentioned above may have a phenyl ring fused on to two adjacent carbon atoms and the bond may be via a nitrogen atom or via a carbon atom of the heterocyclic part or a fused-on phenyl ring, and the alkyl and alkoxy groups mentioned above include linear and branched alkyl and alkoxy groups , in which one to three hydrogen atoms can additionally be replaced by fluorine atoms, their tautomers, enantiomers, their diastereomers, their mixtures and their salts. Compounds of general formula I according to claim 1, in which R ² , R ³ , R ⁴ and R ^{5 are} as defined in claim 1 and R ^{1 is} a 2,5-dihydro-1H-pyrrol-1-ylcarbonyl group, one optionally by a Amino-C ₁ _ ₃ -alkyl-, C _1-3 -alkylamino-C _1-3 -alkyl-, di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-, aminocarbonyl-, C _1-3- alkylamino-carbonyl or di- (C _1-3 -alkyl) -aminocarbonyl group substituted 4- to 7-membered cycloalkyleneiminocarbonyl group or a group of the formula

in which in the heterocyclic part in each case one hydrogen atom can be replaced by an aminomethyl or aminocarbonyl group means, the abovementioned alkyl and alkoxy groups including linear and branched alkyl and alkoxy groups in which one to three hydrogen atoms can additionally be replaced by fluorine atoms, their tautomers , Enantiomers, their diastereomers, their mixtures and their salts. Compounds of the general formula 1 according to Claim 1, in which R ¹ , R ² , R ³ and R ^{5 are} as defined in Claim 2 and R ^{4 is} phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyridinyl, Pyrazinyl, pyridazinyl, pyrimidinyl, thiazolyl or isoxazolyl group, which may be replaced by a hydroxy, C _1-4 alkyloxy, benzyloxy, hydroxycarbonyl C _1-3 alkoxy, C _1-3 alkyl oxy carbonyl-C _1-3 -alkyloxy-, aminocarbonyl-C _1-3 -alkyloxy-, C _1-3 -alkylaminocarbonyl-C _1-3 -alkyloxy-, di- (C _1-3 -alkyl) -aminocarbonyl-C _{1 -3-} alkyloxy, carboxy, C ₁ _ ₃ alkyloxycarbonyl group means, where the above-mentioned alkyl and alkoxy groups include linear and branched alkyl and alkoxy groups, in which one to three hydrogen atoms can additionally be replaced by fluorine atoms, their tautomers , Enantiomers, their diastereomers, their mixtures and their salts. The following compounds of the general formula I according to claim 1: (1) 2- (5-amidino-2-hydroxyphenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) phenyl] -3- phenyl-propionamide, (2) 2- (5-amidino-2-hydroxyphenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-ylcarbonyl) phenyl] -3- (pyridin-3-yl ) -propionamide, (3) 2- (5-aminomethyl-2-hydroxy-phenyl) -N- [3-trifluoromethyl-4- (pyrrolidin-1-yl-carbonyl) -phenyl] -3-phenyl-propionamide, in which the amidino group can additionally be substituted by a hydroxy, C _1-5 alkyloxy, C _1-10 alkoxycarbonyl or phenylcarbonyl group, and their salts. Physiologically acceptable Salts of the compounds according to claims 1 to 4th Medicament containing a compound according to at least one of claims 1 to 4 or a salt according to claim 5 in addition to optionally one or more inert carriers and / or diluents. Use of a compound according to at least one of claims 1 to 4 or a salt according to claim 5 for the manufacture of a medicament with an antithrombotic Effect. A method of manufacturing a medicament according to claim 7, characterized in that on non-chemical Ways a connection according to at least one of claims 1 to 4 or a salt according to claim 5 into one or more inert carriers and / or diluents is incorporated. Process for the preparation of the compounds according to Claims 1 to 6, characterized in that a) for the preparation of a compound of the formula I, a compound of the general formula

in which R ¹ and R ^{2 are} as defined in claims 1 to 4, with a carboxylic acid or with a reaction capable carboxylic acid derivative of the general formula

in which R ³ and R ^{4 are} as defined in claims 1 to 4, the radicals R ³ and R ⁴ optionally being protected from the reaction by a suitable protective group which are split off again after the reaction, R ^{5 is} a cyano group, a protected one Represents aminomethyl group or an amindino group protected by a carbamate group and Z ^{1 represents} a hydroxyl group or a nucleofugic leaving group such as, for example, a C _1-6 alkoxycarbonyloxy, C _1-6 alkylcarbonyloxy or 2,6-dichlorophenylcarbonyloxy group or a chloro or bromine, acylated and the cyano compound thus obtained is subsequently converted into an amidino or aminomethyl compound which is optionally substituted by the groups mentioned in claims 1 to 4 or b) for the preparation of a compound of the general formula I in which R _{5 is} optionally substituted by a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, phenylcarb represents onyl, hydroxy, C _1-5 alkyloxy, benzyloxy or phenyloxy group substituted amidino group, a compound of the general formula optionally formed in the reaction mixture

in which R ¹ to R ^{4 are} as defined in claims 1 to 4 and Z ^{2 represents} an alkoxy, aralkoxy, alkylthio or aralkylthio group, with an amine of the general formula H - R ⁷ NR ⁸ (V), in which R ^{7 represents} a hydrogen atom and R ^{8 represents} a hydrogen atom or a hydroxy, C _1-5 alkyloxy, benzyloxy or phenyloxy group, or is reacted with its salts or c) to prepare a compound of the general formula I, in which R ₅ is an optionally substituted on the nitrogen atom by a C _1-1 0-alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl or phenyloxycarbonyl substituted aminomethyl group, a compound of general formula

in which R ¹ to R ^{4 are} as defined in claims 1 to 4, catalytically hydrogenated and the aminomethyl compound thus obtained, if appropriate subsequently subsequently with a compound of the formula R ⁹ - Z ³ (VII), in which R ^{9 represents} a C _1-10 alkoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenyloxycarbonyl or benzyloxycarbonyl group and Z ^{3 represents} a leaving group, and if desired subsequently a compound of the general formula I thus obtained, which contains an amino or imino group, is converted into a corresponding acyl compound of the general formula I by means of a corresponding acyl derivative and / or a compound of the general formula I thus obtained, which contains an esterified carboxy group, is converted into a corresponding carboxylic acid of the general formula I by means of hydrolysis is and / or a compound of the general formula I thus obtained, which contains a carboxy group, is converted into an appropriate ester by esterification and / or a protective radical used during the reactions to protect reactive groups is split off and / or a compound of the thus obtained general formula I in their stereoisomers is separated and / or a compound of the general formula I thus obtained is converted into its salts, in particular for pharmaceutical use into its physiologically tolerable salts with an inorganic or organic acid or base.