EP1480948A1

EP1480948A1 - Semicarbazide derivatives and their use as antithrombotics

Info

Publication number: EP1480948A1
Application number: EP03704559A
Authority: EP
Inventors: Werner Mederski; Bertram Cezanne; Christos Tsaklakidis; Dieter Dorsch; Christopher Barnes; Johannes Gleitz
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2002-03-04
Filing date: 2003-02-06
Publication date: 2004-12-01
Also published as: JP2005519114A; BR0308136A; US20050119316A1; MXPA04008479A; AR038621A1; PL371214A1; CA2478528A1; WO2003074479A1; RU2004129594A; AU2003206852A1; KR20040095256A; CN1639115A; ZA200407903B

Abstract

The invention relates to the novel compounds of formula (I), wherein R, R1, R2 and R3 are defined as in claim 1. The novel compounds are inhibitors of coagulation factor Xa and are used in the prophylaxis and/or therapy of thromboembolic diseases and in the treatment of tumors.

Description

SEMICARBAZIDE DERIVATIVES AND THEIR USE AS ANTITHROMBOTICS

The invention relates to compounds of the formula

where RC (= NH) -NH ₂ , which is also simply by OH, OCOOA, OCOO (CH ₂ ) nN (A) ₂ , OCOO (CH ₂ ) m-Het, COO (CH ₂ ) nN (A) _2l COO ( CH ₂ ) m-Het, CO-C (A) ₂ -R ⁴ , COOA, COSA, COOAr, COOAr ', CH ₂ NH ₂₎

R ¹ X, Ar or Ar ',

R ^{2 is} simply phenyl substituted by S (0) _p A, S (0) _p NHA, CF ₃ , COOA or CH ₂ NHA, R ³ H or shark,

Ar unsubstituted or single, double or triple by A, OH, OA, NH ₂ , NHA, NA ₂ , N0 ₂ , CF ₃ , CN, shark, COA, NHCOA, COOA, CONH ₂ , CONHA, CONA ₂ , S (0) _p A, S (0) _p NH ₂ , S (0) _p NHA,

S (0) _p NA ₂ substituted phenyi, Ar '- (CH ₂ ) _n -Ar, AH, unbranched, branched or cyclic alkyl with 1-20 C-

Atoms, X unbranched or branched alkyl having 1-20 C atoms, in which one or two CH ₂ groups can be replaced by O or S atoms and / or also 1-7 H atoms by F, or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and / or S atoms, which can be unsubstituted or mono- or disubstituted by A, Hai F. CI. Br or 1, 2 1, 2, 3, 4, 5 or 6, m 1, 2, 3, 4, 5 or 6, p 0, 1 or 2, and their pharmaceutically usable derivatives, solvates and stereoisomers, including theirs Mixtures in all proportions.

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

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they show factor Xa inhibitory properties and can therefore be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis,

Inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication can be used. The compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade.

Aromatic amidine derivatives with antithrombotic activity are e.g. from EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO 00/71511, WO

00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO 00/71515 or WO 00/71516. Cyclic guanidines for the treatment of thromboembolic diseases are e.g. described in WO 97/08165.

Aromatic heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022. Substituted N - [(aminoiminomethyl) phenylalkyl] azaheterocyclylamides as factor Xa inhibitors are in WO

96/40679.

Regioisomeric compounds of the derivatives according to the invention are described in DE 10040783.8 (compounds of the formula 7 in synthesis scheme 1).

The antithrombptic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory action against the activated coagulation protease, known under the name factor Xa, or to the inhibition of other activated serine proteases such as factor VIII, factor IXa or thrombin.

Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of

Prothrombin in thrombin. Thrombin cleaves fibrinogen into fibrin monomers which, after cross-linking, make an elementary contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic

Lead diseases. An inhibition of thrombin can, however, in the

Inhibit thrombus formation involved fibrin formation. The inhibition of thrombin can be measured, for example, by the method of GF Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent thrombin from being formed.

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

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

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

The coagulation factor VIa initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of the factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus the subsequent formation of thrombin. The inhibition of the factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be carried out according to customary in vitro or in vivo methods.

Methods are determined. A common method of measuring the

Inhibition of factor VIIa is e.g. by H. F. Ronning et al. in

Thrombosis Research 1996, 84, 73-81. Coagulation factor IXa is generated in the intrinsic coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed.

The inhibition of factor IXa by the invention

Compounds and the measurement of anticoagulant and antithrombotic activity can be carried out according to the usual in vitro or in vivo

Methods are determined. A suitable method is e.g. by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.

The compounds according to the invention can furthermore be used for the treatment of tumors, tumor diseases and / or tumor metastases.

A relationship between the tissue factor TF / factor Vlla and the

Development of various cancers was by T.Taniguchi and

N.R. Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic Cancer), 57-59.

The publications listed below describe an anti-tumor effect of TF-VII and factor Xa inhibitors in various

Tumor types: K.M. Donnelly et al. in thromb. Haemost. 1998; 79: 1041-1047;

E.G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999);

B. M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998);

M. E. Bromberg et al. in thromb. Haemost. 1999; 82: 88-92

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, claudication intermittent, venous thrombosis, pulmonary embolism, arterial

Thrombosis, myocardial ischemia, unstable angina and thrombosis-based stroke.

The compounds of the invention are also used for treatment or

Prophylaxis of atherosclerotic diseases such as coronary arterial

Disease, cerebral arterial disease or peripheral arterial

Disease used.

The compounds are also used in combination with other thrombolytics for myocardial infarction, and also for prophylaxis

Reocclusion after thrombolysis, percutaneous transluminal angioplasty

(PTCA) and coronary artery bypass surgery.

The compounds according to the invention are also used for the prevention of rethrombosis in microsurgery, furthermore as

Anticoagulants related to artificial organs or in the

Hemodialysis.

The compounds are also used in the cleaning of

Catheters and medical devices in patients in vivo, or as

Anticoagulants for the preservation of blood, plasma and others

Blood products in vitro. The compounds of the invention are also used in diseases in which the

Blood coagulation contributes significantly to the course of the disease or is a source of secondary pathology, such as cancer including metastasis, inflammatory diseases including

Arthritis and diabetes.

The compounds of the invention are also used to treat migraines (F. Morales-Asin et al., Headache, 40, 2000, 45-47).

In the treatment of the diseases described, the compounds according to the invention are also used in combination with other thrombolytically active compounds, such as, for example, with the "Tissue plasminogen activator" t-PA, modified t-PA, streptokinase or urokinase. The compounds according to the invention are administered with the other substances mentioned either simultaneously or before or after.

The simultaneous administration with aspirin is particularly preferred

To prevent recurrence of thrombus formation.

The compounds according to the invention are also used in

Combination with platelet glycoprotein receptor (llb / llla) - antagonists that inhibit platelet aggregation.

The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claims 1-9 and their pharmaceutically usable

Derivatives, solvates and stereoisomers, characterized in that

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

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

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

b) converting a residue R into another residue R by

i) converting a cyano group to an amidino group, ii) reducing an amide group to an aminoalkyl group, iii) reducing a cyano group to an aminoalkyl group, and / or converts a base or acid of the formula I into one of its salts.

The invention also relates to the optically active forms

(Stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds. Under Solvate's

Compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed due to their mutual attraction. Solvates are e.g. Mono- or dihydrates or

Alcoholates.

Pharmaceutically usable derivatives are e.g. the salts of the compounds according to the invention and also so-called prodrug compounds.

Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention. This also includes biodegradable polymer derivatives of the compounds according to the invention, as described, for. B. in Int. J. Pharm. 115. 61-67 (1995).

The invention also relates to mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers e.g. in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.

For all residues that occur more than once, e.g. A, that is

Meanings are independent of each other. Above and below, the radicals or parameters R, R ¹ , R ² , R ^{3 have} the meanings given in the formula I, unless expressly stated otherwise.

5

X represents alkyl, is unbranched (linear), branched or cyclic, and has

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20

C-atoms. X is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2-

10 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

A _C - trifluoromethyl.

X very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclopentyl , Cyclohexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl. 0 Cyclic alkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A means alkyl, is unbranched (linear), branched or cyclic, and has 5 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19 or 20

C-atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, 0 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 very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, Alkylene preferably means methylene, ethylene, propylene, butylene,

Pentylene or hexylene, furthermore branched alkylene.

-COA (acyl) preferably means acetyl, propionyl, but also butyryl,

Pentanoyl, hexanoyl or e.g. Benzoyl.

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

The invention also relates in particular to those by -COA,

-COOA, -OH or -C (= NH) -NH ₂ - compounds of the formula I substituted by a conventional amino protecting group

R preferably denotes amidino, which can also be substituted by OH or CH ₂ NH ₂ . R ¹ preferably denotes phenyl, benzyl or alkyl having 1, 2, 3, 4, 5, 6 or 7 carbon atoms,

R ² preferably denotes a phenyl radical which is simply substituted by alkylsulfonyl [S (0) ₂ A] or aminosulfonyl [S (0) ₂ NHA], the substituents S0 ₂ CH ₃ or S0 ₂ NH ₂ being particularly preferred. R ³ is preferably H or F.

Ar means e.g. unsubstituted phenyl, further preferably e.g. by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, sulfonamido, methylsulfonamido , Ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl or phenyl mono-, di- or tri-substituted by aminocarbonyl. Ar very particularly preferably means unsubstituted phenyl.

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

5-yl, 1, 3,4-thiadiazol-2- or -5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-

Thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1- , 2-, 4- or 5-benzimidazolyl, 1-, 3-,

4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-,

5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- Quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo [1, 4] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl , 2,1, 3-benzothiaediazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

The heterocyclic radicals can also be partially or completely hydrogenated.

Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2 - or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 4 -Dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6 -pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or - 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxane -2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2 , 3,4-tetrahydro-1 -, - 2 -, - 3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6- , 7- or 8- 3,4-dihydro-2H-benzo [1, 4] oxazinyl, further be 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-oxo-methylenedioxy) phenyl or also 3,4- Dihydro-2H-1,5-benzodioxepin-6- or -7-yl, further preferably 2,3-dihydro-benzofuranyl or 2,3-dihydro-2-oxo-furanyl.

Het preferably means a mononuclear saturated or unsaturated heterocycle having 1 to 2 N and / or O atoms, which can be unsubstituted or mono- or disubstituted by A.

Het very particularly preferably denotes pyridyl, pyrimidinyl, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl or oxazolidin-3-yl.

The compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. Formula I encompasses all of these forms.

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

in la R Amidino, which can also be substituted by OH or

Represents CH ₂ NH ₂ ;

in Ib R ¹ phenyl, benzyl or alkyl with 1, 2, 3, 4, 5, 6 or 7 C-

Atoms means;

in Ic R ^{3 is} H or F; in Id R ² denotes a phenyl radical which is simply substituted by alkylsulfonyl or aminosulfonyl;

in le R ² denotes a phenyl radical which is simply substituted by methylsulfonyl or aminosulfonyl;

as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

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

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

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

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but which correspond to one or more free amino and / or hydroxyl groups Protected amino and / or hydroxyl groups contain, preferably those which, instead of an H atom which is connected to an N atom, carry an amino protective group, in particular those which instead of one

HN group carry an R'-N group, in which R 'represents an amino protecting group 5 and / or those which carry a hydroxyl protecting group instead of the H atom of a hydroxyl group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group.

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

The release of the amidino group from its oxadiazole derivative can e.g. A C can be split off by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel). Suitable solvents are those specified below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof. The hydrogenolysis is generally carried out at 0 temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar. 5 The introduction of the oxadiazole group succeeds e.g. by reaction of the cyan compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformate, N, N'-carbonyldiimidazole or acetic anhydride. 0

Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively. 5 The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction at other locations on the

5

Molecule has been carried out. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size is im

10 others not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses aliphatic, araliphatic, aromatic or hetero-

Λ π cyclic carboxylic acids or sulfonic acids derived acyl groups and especially alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOG (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, 5 Fmoc, benzyl and acetyl.

The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or

Acyl groups, also alkyl groups. The nature and size of the hydroxyl 5 protecting groups is not critical since they are chemical

Reaction or sequence of reactions are removed again; are preferred T EP03 / 01177

- 16 -

Groups with 1-20, especially 1-10 carbon atoms. Examples of hydroxy protecting groups include Benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-

Toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

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

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

Protective groups which can be removed hydrogenolytically (for example CBZ, benzyl or the liberation of the amidino group from their oxadiazole derivative) can, for. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal). Suitable solvents are the above, especially z. B. alcohols such as methanol or

Ethanol or amides such as DMF. Hydrogenolysis is usually done with

Temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. A

Hydrogenolysis of the CBZ group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride,

Trifluoromethylbenzene, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid;

Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of the solvents mentioned.

The conversion of a cyano group into an amidino group takes place by reaction with e.g. Hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. Pd / C.

A nitrile can also be used to prepare an amidine of the formula I

Add ammonia. The addition is preferably carried out in several stages by, in a manner known per se, a) the nitrile with H ₂ S in a thioamide converts, which is converted with an alkylating agent, for example CH ₃ I, into the corresponding S-alkyl imidothioester, which in turn reacts with NH ₃ to give the amidine, b) the nitrile with an alcohol, for example ethanol in the presence of HCl, in the corresponding imido ester 5 converted and treated with ammonia (Pinner synthesis), or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and then hydrolyzing the product.

10 esters can e.g. with acetic acid or with NaOH or KOH in water,

Water THF or water dioxane can be saponified at temperatures between 0 and 100 °.

A ₅ Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, or reacted with CH ₃ -C (= NH) -OEt, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine 0 at temperatures between -60 and + 30 °.

A base of the formula I can be converted with an acid into the associated acid addition salt, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, inorganic acids can be used, for example Q sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon, sulfonic or sulfuric acids, for example 5 formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid,

Ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-

Toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used to isolate and / or purify the compounds of the

Formula I can be used.

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

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

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

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, Malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Chromatographic separation of enantiomers using an optically active separating agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or others) is also advantageous

Derivatives of carbohydrates or chiral derivatized methacrylate polymers fixed on silica gel). Aqueous or alcoholic solvent mixtures such as e.g. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.

The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.

The invention further relates to medicaments containing at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.

These preparations can be used in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, coated tablets,

Capsules, powder, granules, syrups, juices or drops, for rectal Use suppositories, for parenteral application solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application ointments, creams or powder or as a nasal spray. The new compounds can also be lyophilized and the lyophilizates obtained, for example for the preparation of

Injectables are used. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives,

Stabilizing and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring,

Contain flavor and / or several other active ingredients, e.g. one or more vitamins.

The compounds of the formula I and their physiologically acceptable salts can be used to combat and prevent thrombo-embolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication, migraine, tumors, tumor diseases and / or tumor metastases can be used.

The substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily

Dosage is preferably between about 0.02 and 10 mg / kg body weight. However, the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred. The invention also relates to a set (kit) consisting of separate packs of

(a) an effective amount of a compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and

(b) an effective amount of another drug.

The set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set can contain, for example, separate ampoules, each containing an effective amount of a compound of the _. Formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and an effective amount of a further medicament in solution or in lyophilized form.

The invention furthermore relates to the use of compounds of the formula I and / or their pharmaceutically usable derivatives,

Solvates and stereoisomers, including their mixtures in all

Conditions, for the manufacture of a medicament for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, migraine,

Tumors, tumor diseases and / or tumor metastases, in combination with at least one other drug ingredient.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, and the mixture is dried and dried organic phase EP03 / 01177

- 23 -

over sodium sulfate, evaporated and purified by chromatography

Silica gel and / or by crystallization. Rf values on silica gel; Eluent:

Ethyl acetate / methanol 9: 1.

Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺ ESI (Electrospray lonization) (M + H) ⁺ (unless otherwise stated)

example 1

Production of

1- (3-N-Hvdroxyamidinophenvπ-4- (3-fluoro-2'-methylsulfonylbiphenyl-4-vπ-

1-phenylsemicarbazide 8 1- (3-amidinophenvπ-4- (3-fluoro-2'-methylsulfonylbiphenyl-4-yl) -1-phenylsemicarbazide 9

1- (3-aminomethylphenyl) -4- (3-fluoro-2'-methylsulfonvibiphenyl-4-vπ-1-phenylsemicarbazide 10 according to synthesis scheme 1

Reaction conditions for synthesis scheme 1:

Stage 1. 20.0 g (75.384 mmol) of 3-fluoro-2'-methanesulfonyl-biphenyl-4-ylamine 2 are dissolved in 300 ml of THF and 9.149 ml (75.384 mmol) of trichloromethylchloroformate are added dropwise with stirring at RT. The reaction mixture is then heated under reflux for 3 h. The desired isocyanate 3 is thus obtained. 10.037 g (75.384 mmol) of 3-hydrazino-benzonitrile 1 are added to this reaction mixture and the mixture is heated under reflux for 4 h. The mixture is then worked up in the customary manner and 28.3 g (88.4%) 4 are obtained as white crystals; MS (EI) = 424.

Step 2. 9.2 g (21, 674 mmol) 4 are dissolved in 40.0 mL DCM, with 4.33 g

(23.842 mmol) copper (II) acetate and 1,924 mL (23.842 mmol) pyridine mixed and grown at RT for 18 h. The mixture is worked up in the customary manner and 9.0 g (98.2%) 5 are thus obtained as yellow crystals; MS (EI) = 422.

Step 3. 4.7 g (11.13 mmol) 5 are dissolved in 100 mL THF, cooled to -70 ° C. and 13.351 mL (13.351 mmol) phenyl magnesium bromide (1 M in THF) are added dropwise under a nitrogen atmosphere and with stirring. After a further 5 h at -70 ° C., the mixture is allowed to come to RT overnight and then worked up as usual. This gives 660 mg (11.9%) 6 and 1.3 g (23.3%) of regioisomer 7; MS (EI) = 500.

Level 4. [= Hydroxyamidine]. 600 mg (1, 199 mmol) 6 are dissolved in 30.0 mL EtOH, 0.665 ml (4.796 mmol) triethylamine and 0.333 g (4.796 mmol) hydroxylammonium chloride are added and the mixture is heated under reflux for 4 h. After the usual work-up, 420 mg (65.6%) of white crystals 8 are obtained; MS (EI) = 533.

Level 5. [= Amidinj. 300 mg (0.562 mmol) 8 are hydrogenated in 10 mL methanol / THF (1: 1), 0.5 mL glacial acetic acid with 0.3 g Raney nickel (water-moist) with 12.6 mL hydrogen at RT. After the usual work-up, 170 mg (52.4%) of crystals 9 are obtained; MS (ESI) = 518.

Stage 6. [= Benzylaminj. 410 mg (0.819 mmol) 6 are hydrogenated in 5 mL 10% methanolic ammonia solution over 0.2 g Raney nickel (water-moist). After working up, the crude product is dissolved in 2 ml of methanol and 5 ml of HCl in diethyl ether (c = 2 mol / L) are added. After the usual work-up, 310 mg of crystals 10 are obtained; MS (ESI) = 505. Synthesis scheme 1

Level 2

Step 4: a] R = -C = NH-0H (NH ₂ ) 8 Step 5: b] R = -C = NH ₂ -NH ₂ 9 Step 6: c] R = -CH ₂ NH ₂ 10 Alternative synthesis scheme

NC

analogous to Mackman et al.

J. Med. Chem. 2001, 44 _> 3856

analogous to synthesis scheme 1

Example 2

The following compounds are obtained analogously to Example 1

1 - (3-aminomethylphenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1 - phenylsemicarbazide,

1- (3-N-hydroxyamidinophenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1- phenylsemicarbazide,

1 - (3-amidinophenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1 - phenylsemicarbazide,

1 - (3-aminomethylphenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1 - phenylsemicarbazide, 1- (3-N-hydroxyamidinophenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1- phenylsemicarbazide,

, 1 - (3-amidinophenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1 - phenylsemicarbazide,

1 - (3-aminomethylphenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1 - benzylsemicarbazide,

1- (3-N-hydroxyamidinophenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1-benzylsemicarbazide,

1 - (3-amidinophenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1 - benzylsemicarbazide,

1 - (3-aminomethylphenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1 - propylsemicarbazide,

1- (3-N-hydroxyamidinophenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1-propylsemicarbazide,

1- (3-amidinophenyl) -4- (2'-aminosulfonylbiphenyl-4-yl) -1-propylsemicarbazide,

1 - (3-aminomethylphenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1 - benzylsemicarbazide, 1 - (3-N-hydroxyamidinophenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1 ■ benzylsemicarbazid,

1 - (3-amidinophenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1 - benzylsemicarbazide,

1- (3-aminomethylphenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1-propylsemicarbazide,

1- (3-N-hydroxyamidinophenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1-propylsemicarbazide,

1 - (3-Amidinophenyl) -4- (2'-methylsulfonylbiphenyl-4-yl) -1 - propylsemicarbazide. Pharmacological data

Affinity for receptors Table 1

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

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

Example B: Suppositories

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

Example C: solution

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

Example D: ointment

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

Example E: tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

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

Example G: capsules

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

Example H: ampoules

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

Claims

claims

Compounds of the formula

where RC (= NH) -NH ₂ , which is also simply by OH, OCOOA, OCOO (CH ₂ ) _n N (A) ₂ , OCOO (CH ₂ ) _m -Het, COO (CH ₂ ) _n N (A) ₂ , COO (CH ₂ ) _m -Het, CO-C (A) ₂ -R ⁴ , COOA, COSA, COOAr, COOAr 'can be substituted, CH ₂ NH ₂ ,

R ¹ unbranched or branched alkyl having 1-20 C atoms, in which one or two CH ₂ groups can be replaced by O or S atoms and / or 1-7 H atoms by F,

Ar or Ar ",

R ^{2 is} simply phenyl substituted by S (0) _p A, S (0) _p NHA, CF ₃ , COOA or CH ₂ NHA,

R ^d H or shark,

O Ar unsubstituted or single, double or triple by A, OH, OA, NH ₂ , NHA, NA ₂ , N0 ₂ , CF ₃ , CN, shark, COA, NHCOA, COOA, CONH ₂ , CONHA, CONA ₂ , S (0) _p A, S (0) _p NH ₂ , S (0) _p NHA, S (0) _p NA ₂ substituted phenyl, Ar '- (CH ₂ ) _n -Ar,

A H, unbranched, branched or cyclic alkyl with 1-20

C-atoms,

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

Atoms which can be unsubstituted or substituted once or twice by A,

Shark F, Cl, Br or I, n is 1, 2, 3, 4, 5 or 6, m is 1, 2, 3, 4, 5 or 6, p is 0, 1 or 2, and their pharmaceutically usable derivatives, solvates and

Stereoisomers, including their mixtures in all

Conditions.

Compounds according to Claim 1, in which R is amidino, which may also be substituted by OH or

CH ₂ NH ₂ means, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all

Conditions.

Compounds according to claim 1, wherein

R ¹ phenyl, benzyl or alkyl with 1, 2, 3, 4, 5, 6 or 7 C-

Atoms means as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

Compounds according to one or more of claims 1-3, wherein

R ³ denotes H or F, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all

Conditions.

Compounds according to one or more of claims 1-4, wherein R ^{2 is} a phenyl radical substituted simply by alkylsulfonyl or aminosulfonyl, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.

Compounds according to one or more of claims 1-5, wherein

R ² denotes a phenyl radical which is simply substituted by methylsulfonyl or aminosulfonyl, and also their pharmaceutically usable derivatives, solvates and

Stereoisomers, including their mixtures in all proportions.

Compounds according to claim 1 selected from the group 1- (3-N-hydroxyamidinophenyl) -4- (3-fluoro-2'-methylsulfonylbiphenyl-4-yl) -1-phenylsemicarbazide,

1- (3-amidinophenyl) -4- (3-fluoro-2'-methylsulfonylbiphenyl-4-yl) -1-phenylsemicarbazide,

1- (3-aminomethylphenyl) -4- (3-fluoro-2'-methylsulfonylbiphenyl-4-yl) -

1 -phenylsemicarbazide,

as well as their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all

Conditions.

Process for the preparation of compounds of formula I according to claims 1-7 and their pharmaceutically usable derivatives,

Solvates and stereoisomers, characterized in that a) they are made from one of their functional derivatives by treatment with a solvolysing and / or hydrogenolysing agent

Set freedom by

b) converts a radical R ¹ , R ² and / or Y into another radical R ¹ , R ² and / or Y by

i) converting a cyano group to an amidino group, ii) an amide group is reduced to an aminoalkyl group, iii) a cyano group is reduced to an aminoalkyl group,

and / or converts a base or acid of the formula I into one of its salts.

9. Compounds of formula I according to one or more of claims 1 to 7 as inhibitors of the coagulation factor Xa.

10

10. Compounds of formula I according to one or more of claims 1 to 7 as inhibitors of the coagulation factor Vlla.

A ₅ 11. Medicament containing at least one compound of the formula I according to one or more of claims 1 to 7 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries. 0

12. Medicament containing at least one compound of formula I according to one or more of claims 1 to 7 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, 5 including their mixtures in all proportions, and at least one further active pharmaceutical ingredient.

13. Use of compounds according to claims 1 to 7 Q and / or their physiologically acceptable salts and solvates for

Production of a medicament for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, migraine, tumors, tumor diseases and / or 5

Do mormetastases. Set consisting of separate packs of

(a) an effective amount of a compound of formula I according to one or more of claims 1 to 7 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and

(b) an effective amount of another drug ingredient.

Use of compounds of the formula I according to one or more of claims 1 to 7 and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, Apoplexy,

Angina pectoris, restenosis after angioplasty, intermittent claudication, migraines, tumors, tumor diseases and / or

Tumor metastases, in combination with at least one other drug ingredient.