EP1709017A1

EP1709017A1 - Urea derivatives

Info

Publication number: EP1709017A1
Application number: EP05700739A
Authority: EP
Inventors: Werner Mederski; Christos Tsaklakidis; Dieter Dorsch; Bertram Cezanne; Johannes Gleitz
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2004-01-30
Filing date: 2005-01-07
Publication date: 2006-10-11
Also published as: WO2005073201A1; US20070161623A1; CN1914184A; JP2007519645A; BRPI0507165A; KR20060128984A; AR047514A1; CA2554911A1; DE102004004731A1; AU2005209362A1; ZA200607219B

Abstract

Novel compounds of formula (I), wherein X-Y-D-E, R<1>, R<2> and R<3> have the meanings as cited in patent claim 1, are inhibitors of the coagulation factor Xa and can be used for preventing and/or treating thromboembolic diseases and for treating tumors.

Description

urea derivatives

The invention relates to compounds of the formula

R ³

where XYDE CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, N ⁺ (-0 ^~ ) = CH-CH = CH, CH = N ⁺ (-0 ^" ) -CH = CH, CH = CH-N ⁺ (-0 ^" ) = CH, CH = CH-CH = N ⁺ (-0 ^" ), NH-CO-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH, CH = CH-NH-CO, where the H- Atoms of the -CH groups by shark, A, OH, OA, A-COO-, Ph- (CH ₂ ) _n -COO-, cycloalkyl- (CH ₂ ) _n -COO-, A-CONH-, A-CONA -, Ph-CONA-, N ₃ , NH ₂ , N0 ₂ , CN, COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ , O-allyl, O-propargyl and / or O-benzyl may be substituted,

Ph unsubstituted or phenyl substituted once, twice or three times by A, OA, OH or shark,

R ¹ shark, -C≡CH, -C ≡ € -A, OH or OA, R ² H, shark or A,

R ^{J is} 2-oxo-1H-pyridin-1-yl, 2-oxo-1H-pyrazin-1-yl, 2-oxo-piperidin-1-yl, unsubstituted or mono- or disubstituted by A, OH and / or OA , 2-oxopyrrolidin-1-yl, 2-oxo- [1,3] oxazinan-3-yl, 3-oxomorpholin-4-yl, 2-oxo- tetrahydro-pyrimidin-1-yl, 3-oxo-2H-pyridazin-2-yl, 4-oxo-1 H-pyridin-1-yl, 2-oxo-imidazolidin-1-yl, 2,6-dioxopiperidine1 yl,

2-oxopiperazin-1-yl, 2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2- caprolactam-1-yl

(= 2-oxo-azepan-1-yl), 2-azabicyclo [2.2.2] octan-3-one-2-yl,

5,6-Dihydro-1H-pyrimidin-2-oxo-1-yl, 4H- [1,4] oxazin-4-yl, 2-imino-pipehdin-1-yl, 2-imino-pyrrolidin-1-yl , 3-imino-morpholin-4-yl, 2-imino-imidazolidin-1-yl or 2-imino-1H-pyrazin-1-yl,

A with unbranched, branched or cyclic alkyl

1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine,

Hai F. CI, Br or I, n 0, 1, 2 or 3, and their pharmaceutically usable derivatives, solvates, salts and

Stereoisomers, including their 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. 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 heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022.

Carboxamide derivatives are known from WO 02/48099 and WO 02/57236, pyrrolidine derivatives are described in WO 02/100830. Further heterocyclic derivatives are known from WO 03/045912.

Substituted benzothiophene anthranilamides are factor Xa inhibitors of Y.-L. Chou et al. in Bioorg. Med. Chem. Lett. 13 (2003) 507-511 and by W.D. Shrader et al. in Med. Chem. Lett. 11 (2001) 1801-1804.

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

Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin to 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 fibrin formation involved in thrombus 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 carried out according to customary in vitro or in vivo

Methods are determined. 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 determined by customary in vitro or in vivo methods. A common method for measuring factor VIIIa inhibition 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 involved. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed. The inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in vitro or in vivo methods. A suitable method is described, for example, 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 types of cancer 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

Treatment and prevention of thromboembolic disorders such as

Thrombosis, myocardial infarction, arteriosclerosis, inflammation,

Apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, 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 in myocardial infarction, furthermore for prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coronary bypass surgery. The compounds according to the invention are also used for the prevention of rethrombosis in microsurgery, and also as 5 anticoagulants in connection with artificial organs or in hemodialysis.

The compounds are also used in the cleaning of catheters and medical aids in patients in vivo, or as anticoagulants for the preservation of blood, plasma and other blood products in vitro. The compounds according to the invention are also used in diseases in which blood coagulation makes a decisive contribution to the course of the disease or is a source of secondary pathology, such as e.g. cancer 5 including metastasis, inflammatory diseases including arthritis and diabetes.

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

The invention also relates to the use of compounds of the formula I and their pharmaceutically usable derivatives, solvates, salts and 5

Stereoisomers, including their mixtures in all proportions, for the manufacture of a medicament for the prevention and treatment of thromboembolic diseases and / or thromboses as a result of surgery, genetic diseases with increased

Suitability for thrombosis, diseases of the arterial and venous

Vascular system, heart failure, atrial fibrillation, thrombophilia,

Tinnitus and / or sepsis.

Such uses are preferred, the surgical interventions being selected from the group

Chest surgery, abdominal surgery, orthopedic surgery, hip and knee replacement, CABG (Coronary Artery Bypass

Grafting), artificial heart valve replacement, operations when using a

Heart-lung machine, vascular surgery, organ transplantation and

Use of central venous catheters.

The use of anticoagulants in tinnitus therapy has been described by R. Mora et al. in International Tinnitus Journal (2003), 9 (2), 109-111.

The invention also relates to the use of the compounds of the formula I for the manufacture of a medicament for the prevention and treatment of thromboembolic disorders and / or thromboses in adults and children.

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 e.g. 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.

Simultaneous administration with aspirin is particularly preferred in order to prevent recurrence of thrombus formation. The compounds according to the invention are also used in combination with platelet glycoprotein receptor (llb / llla) antagonists which 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, salts and stereoisomers, characterized in that a) a compound of formula II

in which XYDE and R ^{1 have} the meanings given in claim 1, are reacted with a chloroformate derivative to give an intermediate carbamate derivative,

which then with a compound of formula III

R ³ wherein

R ² and R ^{3 have} the meanings given in claim 1,

is implemented

or

b) a compound of formula IV

R ³

wherein XYDE, R ² and R ^{3 have} the meanings given in claim 1,

with a compound of formula V

wherein R ^{1 has} the meaning given in claim 1,

implements,

or c) converting a radical XYDE into another radical XYDE by oxidizing the radical XYDE and / or converting 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. Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed on account of 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 as well as so-called

Prodrug compounds.

Prodrug derivatives are understood with z. B. alkyl or acyl groups,

Sugars or oligopeptides modified compounds of formula I, which in the organism quickly to the effective invention

Connections are split.

This also includes biodegradable polymer derivatives of the compounds according to the invention. 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 radicals that occur more than once, such as A, the meanings are independent of one another. Above and below, the radicals or parameters XYDE, R ¹ , R ² and R ^{3 have} the meanings given in the formula I, unless expressly stated otherwise.

A means alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,

5, 6, 7, 8, 9 or 10 carbon atoms. A is preferably methyl, furthermore

Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-,

2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, more preferably e.g. Trifluoromethyl. A also means cycloalkyl. Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A therefore also preferably denotes cyclopentylmethyl, cyclohexylmethyl, 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, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl.

OA preferably means methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy or tert-butoxy.

X-Y-D-E preferably means CH = CH-CH = CH, N = CH-CH = CH, CH = N-

CH = CH, CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N,

N ⁺ (-0 ^' ) = CH-CH = CH, CH = N ⁺ (-0 ^" ) -CH = CH, CH = CH-N ⁺ (-0 CH,

CH = CH-CH = N ⁺ (-0 ^" ), NH-CO-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH,

CH = CH-NH-CO, in which the H atoms of the -CH groups can be substituted by shark, A, OH and / or OA.

XYDE means in particular CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH , CH = N-CH = N, N ⁺ (-0 ^" ) = CH-CH = CH, CH = N ⁺ (-0 CH = CH, CH = CH-N ⁺ (-0 CH,

CH = CH-CH = N ⁺ (-0 ^" ), in which the H atoms of the -CH groups by shark (preferably F or Cl),

A (preferably methyl), OH and / or OA can be substituted. 5

R ¹ is preferably shark or -C = CH, especially shark

(preferably F or Cl).

R ^{2 represents} H, shark (preferably F or Cl) or A (preferably 10 methyl).

R ³ preferably denotes 2-oxo-1 H-pyridin-1-yl, 2-oxo-1r7-pyrazin-1-yl, 2-

Oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo- [1,3] oxazinan-3-yl, 3-oxomorpholin-4-yl, 2-oxo-tetrahydropyrimidine -1 -yl, 3-oxo-2 / - / - pyridazin-2-yl, ^ _c 4-oxo-l - -pyridin-1-yl, 2-oxo-imidazolidin-1-yl or 2-oxo-piperazine -1-yl, particularly preferably 2-oxo-1 / - -pyhdin-1-yl or 3-oxo-morpholin-4-yl.

The compounds of formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms. 0 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 abovementioned

25 radicals has one of the preferred meanings given above.

Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals which are not specified are those in the formula I.

3Q have given meaning, however

in la R ^{1 means} shark or -C ≡CH;

in Ib R means shark;

35 in Ic XYDE CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, N ⁺ (-0 CH-CH = CH, CH = N ⁺ (-0 ^" ) -CH = CH, CH = CH-N ⁺ (-0 ^" ) = CH, CH = CH-CH = N ⁺ (-0 ^" ), NH-CO-CH = CH,

CH = CH-CO-NH, CO-NH-CH = CH or CH = CH-NH-CO, in which the H atoms of the -CH groups can be substituted by shark, A, OH and / or OA;

in Id XYDE CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH .

CH = N-CH = N, N ⁺ (-0 CH-CH = CH, CH = N ⁺ (-0 ^" ) -CH = CH, CH = CH-N ⁺ (-0 ^" ) = CH, CH = CH -CH = N ⁺ (-0 ^' ) or NH-CO-CH = CH, in which the H atoms of the -CH groups are represented by shark, A,

OH and / or OA may be substituted;

in le R ³ 2-oxo-1 H-pyridin-1-yl, 2-oxo-1 H-pyrazin-1-yl, 2-oxopiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo [1,3] oxazinan-3-yl, 3-oxomorpholin-4-yl, 2-oxotetrahydro-pyrimidin-1-yl, 3-oxo-2H-pyridazin-2-yl, 4 - oxo-1 r7-ρyridin-1 -yl, 2-oxo-imidazolidin-1 -yl or 2-

Oxo-piperazin-1-yl, means;

in If R ^{3 is} 2-oxo-1 H-pyridin-1-yl or 3-oxo-morpholin-4-yl; in Ig XYDE CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, N ⁺ (-0 ^" ) = CH-CH = CH, CH = N ⁺ (-0> CH = CH,

CH = CH-N ⁺ (-0 CH or CH = CH-CH = N ⁺ (-0 ^" ), in which the H atoms of the -CH groups can be substituted by shark, OH and / or OA, R ¹ shark .

R ² H, shark or A,

R ³ 2-oxo-1 H-pyridin-1-yl, 2-oxo-1 H-pyrazin-1-yl, 2-

Oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo [1,3] oxazinan-3-yl, 3-oxomorpholin-4-yl, 2-oxotetrahydropyrimidine -1 -yl, 3-Oxo-2H-pyridazin-2-yl, 4-Oxo-l / - / - pyridin-1-yl, 2-Oxo-imidazolidin-1-yl or 2-Oxo-piperazin-1 - yl, A with unbranched, branched or cyclic alkyl

1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine, mean Hai F. CI, Br or I;

in Ih X-Y-D-E CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, N ⁺ (-0 ^" ) = CH-CH = CH,

CH = N ⁺ (-0 CH = CH,

CH = CH-N ⁺ (-0 ^" ) = CH or CH = CH-CH = N ⁺ (-0-), in which the H atoms of the -CH groups can be substituted by shark, OH and / or OA, R ¹ shark,

R ² H, shark or A, R ³ 2-oxo-l H-pyridin-1 -yl or 3-oxo-morpholin-4-yl,

A alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms.

Shark F, Cl, Br or I mean;

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

Compounds of formula I can preferably be obtained by treating compounds of formula II with a chloroformate derivative, e.g. 4-nitrophenyl chloroformate is converted into an intermediate carbamate, and this is then reacted with a compound of the formula III.

The reaction is usually carried out in an inert solvent

Presence of an acid-binding agent, preferably an alkali or

Alkaline earth metal hydroxides, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium. Also the

Addition of an organic base such as triethylamine, dimethylaniline, N, N'-

Dimethylene diamine, pyridine or quinoline is suitable. Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 °, particularly preferably between 60 and 90 °.

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, 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 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 starting compounds of the formulas II are generally new, those of the formula III are generally known.

Compounds of the formula I can furthermore be obtained by reacting compounds of the formula IV with compounds of the formula V. The reaction is usually carried out in an inert solvent

Presence of an acid-binding agent, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline can also be favorable. Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about 0 ° and 150 °, normally between 20 ° and 130 ^ °

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

Dichloroethane. Carbon tetrachloride, 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 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 starting compounds of the formulas IV are generally new, those of the formula V are generally known.

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.

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, namely under reaction conditions which 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.

The invention also relates to the intermediate compounds of the formula 11-1

wherein XYDE CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, NH-CO-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH or CH = CH-NH-CO, in which the H atoms of the -CH groups by Shark, A, OH, OA, A-COO-, Ph- (CH ₂ ) _n -COO-, Cycloalkyl- (CH ₂ ) _n -COO-, A-CONH-, A-CONA-, Ph-CONA-, N ₃ , NH ₂ , N0 ₂ , CN, COOH, COOA, CONH ₂ ,

CONHA, CON (A) ₂ , O-allyl, O-propargyl and / or O-benzyl may be substituted,

R ¹ shark, -C ≡CH, -C ≡CA, OH or OA,

A with unbranched, branched or cyclic alkyl

1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine,

Shark F, Cl, Br or I, n 0, 1, 2 or 3, and their salts.

The intermediate compounds of the formula 11-1 are preferred

X-Y-D-E CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CH-

N = CH, CH = CH-CH = N, N = CH-N = CH or

CH = N-CH = N, wherein the H atoms of the -CH groups by shark, OH and / or

OA can be substituted, R ¹ shark, A with unbranched, branched or cyclic alkyl

1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine,

Shark F, Cl, Br or I, and their salts.

The intermediate compounds of the formula 11-1 are particularly preferred

X-Y-D-E CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH or

CH = N-CH = N, wherein the H atoms of the -CH groups by shark, OH and / or

OA can be substituted, R ¹ shark,

A alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms.

Shark F, Cl, Br or I, and their salts.

Pharmaceutical salts and other forms The compounds according to the invention mentioned can be used in their final non-salt form. On the other hand, the present invention also encompasses the use of these compounds in the form of their pharmaceutically acceptable salts which can be derived from various organic and inorganic acids and bases by methods which are known in the art. Most of the pharmaceutically acceptable salt forms of the compounds of formula I are prepared conventionally. If the compound of the formula I contains a carboxylic acid group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide;

Alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; Alkali metal alcoholates, e.g. Potassium ethanolate and sodium propanolate; as well as various organic bases such as piperidine, diethanolamine and

N-methyl-glutamine. The aluminum salts of the compounds of formula I also count. For certain compounds of formula I, acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, e.g. Hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate , Succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of the formula I include the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate, camphor sulfonate, caprylate, chloride, chlorobenzoate , Cyclopentane propionate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate,

Hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, monophosphate sulfate, methylbenphosphate, monobenzate Nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but this is not a limitation.

Furthermore, the base salts of the compounds according to the invention include aluminum, ammonium, calcium, copper, iron (III), Iron (ll), lithium, magnesium, manganese (III), manganese (ll), potassium,

Sodium and zinc salts, but this should not be a limitation.

Preferred among the salts mentioned above are ammonium; the

Alkali metal salts sodium and potassium, as well as the alkaline earth metal salts

Calcium and magnesium. To salts of the compounds of formula I, which differ from pharmaceutically acceptable organic non-toxic

Deriving bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, e.g.

Arginine, betaine, caffeine, chlorprocaine, choline, N.N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, Glucosamine, histidine,

Hydrabamine, iso-propylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins, procain, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris (hydroxymethyl) methylamine ( Tromethamine), but this should not be a limitation.

Compounds of the present invention which contain basic nitrogen-containing groups can be prepared using agents such as (C ₁ -C 4) alkyl halides, for example methyl, ethyl, isopropyl and tert-butyl chloride, bromide and iodide; Di (-C ₄ ) A! Alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C ₁₀ -C 11 -alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl (C 1 -C ₄ ) alkyl halides, for example benzyl chloride and phenethyl bromide, quaternize. With such salts Both water- and oil-soluble compounds according to the invention can be prepared.

The above-mentioned pharmaceutical salts which are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, Meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but this is not intended to be a limitation.

The acid addition salts of basic compounds of formula I are prepared in that the free base form with a sufficient

The amount of the desired acid is brought into contact, which leads to the usual

Way the salt represents. The free base can be obtained by contacting the salt form with a base and isolating the free base to conventional ones

Regenerate wisely. The free base forms differ in a sense from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; in the context of the invention, however, the salts otherwise correspond to their respective free base forms.

As mentioned, the pharmaceutically acceptable base addition salts of the compounds of the formula I are formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N.N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base addition salts of acidic compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base, whereby the salt is prepared in the usual way. The free acid can be regenerated in a conventional manner by contacting the salt form with an acid and isolating the free acid. The free acid forms differ in a sense from their corresponding salt forms in terms of certain physical properties such as solubility in polar solvents; in the context of the invention, however, the salts otherwise correspond to their respective free acid forms. If a compound according to the invention contains more than one group which can form such pharmaceutically acceptable salts, this includes

Invention also multiple salts. To typical multiple salt forms

5 include, for example, bitartrate, diacetate, difumarate, dimeglumine,

Diphosphate, disodium and trihydrochloride, but this is not intended to be a limitation.

10 In view of what has been said above, it can be seen that the term "pharmaceutically acceptable salt" in the present context is to be understood as an active ingredient which contains a compound of the formula I in the form of one of its salts, in particular if this salt form

Λ _c imparts improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient which has been used previously. The pharmaceutically acceptable salt form of the active ingredient can only give this active ingredient a desired pharmacokinetic property which it did not previously have, and can even have a positive influence on the pharmacodynamics of this active ingredient with regard to its therapeutic effectiveness in the body. 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. 0

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 intermediate products can be converted into 5 enantiomeric compounds by chemical agents known to the person skilled in the art or physical measures, separated or already 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 e.g. 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 (e.g. N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Chromatographic separation of enantiomers using an optically active separating agent (e.g. dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chiral derivatized methacrylate polymers fixed on silica gel) is also advantageous. 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 a medicament (pharmaceutical preparation), in particular in a non-chemical way. 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.

Pharmaceutical formulations can be presented in the form of dose units containing a predetermined amount of active ingredient per dose unit. be enough. Such a unit can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the compound treated

Disease condition, route of administration and age, weight and

Condition of the patient, or pharmaceutical formulations can be in

Form of dose units that contain a predetermined amount of active ingredient per

Dose unit included. Preferred dosage unit formulations are those containing a daily dose or partial dose as indicated above, or a corresponding fraction thereof

Active ingredient included. Furthermore, such pharmaceutical

Prepare formulations using one of the methods well known in the pharmaceutical art.

Pharmaceutical formulations can be administered for administration by any suitable route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal). Ways to customize. Such formulations can be produced using all methods known in the pharmaceutical field, for example by bringing the active ingredient together with the carrier (s) or auxiliary (s).

Pharmaceutical formulations adapted for oral administration can be used as separate units, such as capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam dishes; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. For example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water and others. Powders are made by crushing the compound to a suitable fine size and using a similarly crushed pharmaceutical

Carrier, e.g. an edible carbohydrate such as

Starch or mannitol is mixed. A flavor, preservative, dispersant and color may also be present.

Capsules are made by making a powder mixture as described above and filling shaped gelatin shells with it. Lubricants such as e.g. finely divided silica, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form can be added to the powder mixture before the filling process. A disintegrant or solubilizer, e.g. Agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medication after taking the capsule.

In addition, if desired or necessary, suitable binding agents, lubricants and disintegrants, and also dyes, can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners from corn, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, etc. Among those used in these dosage forms Lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and others. The disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and others. The tablets are formulated by, for example, producing, granulating or mixing a powder mixture is pressed dry, a lubricant and a disintegrant are added and the whole thing is compressed into tablets. A powder mixture is produced by the compound, which has been comminuted in a suitable manner, with a diluent or a base, as described above, and optionally with a binder, such as, for example, carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a solution-reducing agent, such as, for example, paraffin Absorption accelerators, such as a quaternary salt and / or an absorbent, such as bentonite,

Kaolin or dicalcium phosphate is mixed. The powder mixture can be granulated by mixing it with a binder such as e.g. Syrup, starch paste, Acadia slime or solutions made of cellulose or polymer materials are wetted and pressed through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine, resulting in irregularly shaped lumps which are broken up into granules. The granules can be greased by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry compression steps. A transparent or opaque protective layer consisting of a shellac seal, a layer of sugar or polymer material and a gloss layer of wax may be present. Dyes can be added to these coatings in order to be able to differentiate between different dosage units.

Oral liquids such as solution, syrups and elixirs can be prepared in the form of dosage units so that a given quantity contains a given amount of the compound. Syrups can be made by dissolving the compound in an aqueous solution with a suitable taste, while elixirs are made using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,

Preservatives, flavor additives, e.g. Peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, including can also be added.

Dosage unit formulations for oral administration can optionally be enclosed in microcapsules. The formulation can also be prepared by prolonging or retarding the release, such as by coating or embedding particulate material in polymers, wax, etc.

The compounds of the formula I and salts, solvates and physiologically functional derivatives thereof can also be in the form of liposome delivery systems, such as e.g. administer small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be made from various phospholipids, e.g. Cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the salts, solvates and physiologically functional derivatives thereof can also be supplied using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds can also be coupled with soluble polymers as targeted drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide phenol, polyhydroxyethylaspartamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the compounds can be linked to a class of biodegradable polymers which are suitable for achieving a controlled release of a pharmaceutical, for example polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxy- pyrans, polycyanoacrylates and cross-linked or amphipatic block copolymers of hydrogels.

Pharmaceutical adapted for transdermal administration

Formulations can be used as independent patches for longer, more narrow

Contact with the recipient's epidermis. For example, the active ingredient can be supplied from the patch by means of iontophoresis, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated into an ointment, the active ingredient can be used either with a paraffinic or with a water-miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas. Pharmaceutical formulations adapted for nasal administration, in which the carrier substance is a solid, contain a coarse one

Powder with a particle size in the range of 20-500, for example

Micrometers, which is administered in the manner in which snuff is taken up, i.e. by rapid inhalation via the nasal passages from a container with the powder held close to the nose.

Suitable formulations for administration as a nasal spray or nasal drops with a liquid as carrier include

Active ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalation include fine particulate dusts or mists which can be generated by means of various types of pressurized metering dispensers with aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostatics and solutes by which the formulation is rendered isotonic with the blood of the recipient to be treated; as well as aqueous and non-aqueous sterile suspensions, which can contain suspending agents and thickeners. The formulations can be presented in single dose or multiple dose containers, e.g. sealed ampoules and vials, and stored in freeze-dried (lyophilized) condition so that only the addition of the sterile carrier liquid, e.g. water for injections, is required immediately before use. Injection solutions and suspensions prepared according to the recipe can be made from sterile powders, granules and tablets.

It is understood that the formulations may contain, in addition to the above-mentioned ingredients, other means common in the art with respect to the particular type of formulation; for example, formulations suitable for oral administration may contain flavorings.

A therapeutically effective amount of a compound of Formula I depends on a number of factors, including e.g. the age and weight of the animal, the exact condition of the disease that requires treatment, its severity, the nature of the formulation and the route of administration, and is ultimately determined by the treating doctor or veterinarian. However, an effective amount of a compound of the invention is generally in the range of 0.1 to 100 mg / kg of body weight of the recipient (mammal) per day and particularly typically in the range of 1 to 10 mg / kg of body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, which amount as a single dose per day or more usually in a series of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a proportion of the effective amount of the compound of the invention per se.

The compounds of the formula I and their physiologically acceptable salts can be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction,

Arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, migraines, tumors, tumor diseases and / or tumor metastases.

The invention further relates to medicaments containing at least 5 a compound of formula I and / or their pharmaceutically usable

Derivatives, solvates and stereoisomers, including their mixtures in all proportions, and at least one other active pharmaceutical ingredient.

10 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 stereo

^ c isomers, including their mixtures in all proportions, and

(b) an effective amount of another drug ingredient.

The set contains suitable containers, such as boxes or boxes, 0 individual bottles, bags or ampoules. The set can contain, for example, separate ampoules, in each of which an effective amount of a compound of formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and an effective amount of a further active pharmaceutical ingredient are dissolved or dissolved lyophilized form is present. The invention further relates to the use of compounds of the formula I 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, migraine,

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

All temperatures above and below are given in ° C. In the examples below, "customary workup" means: if necessary, water is added, if necessary, depending on the constitution of the

End product to pH values between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, the organic phase dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; Mobile solvent: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): El (electron impact ionization) M ⁺

ESI (Electrospray lonization) (M + H) ⁺ (unless otherwise stated)

example 1

Preparation of 1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [3-methyl-4- (3-oxo-morpholin-4-yl) phenyl ]ureido} phenyl ) urea ("AV)

1.1 1 - (4-Chloro-phenvD-3- (4-hydroxy-2-nitro-phenyl) -urethane 3: 3.5 g (22.7 mmol) of 4-amino-3-nitro-phenol are mixed in one Solvent mixture of 50 mL DCM and 25 mL THF dissolved, then 3.56 g (22.7 mmol) 4-chlorophenyl isocyanate 2 are added and then stirred at RT. After stirring for 20 h, the mixture is worked up in the customary manner. This gives 6.98 g (98%) 3; MS (FAB) m / z = 308 (M + H) ⁺ .

1.2 1- (2-Amino-4-hvdroxy-phenvπ-3- (4-chloro-phenvπ-urethane 4: 1, 0 g (3.185 mmol) 3 are dissolved in a solvent mixture of 25 mL DCM and 25 mL THF. Then 0.25 g of Raney nickel (moist) are added and hydrogen is introduced while stirring, and after stirring for 5 hours at RT, the mixture is worked up in the customary manner, giving 0.74 g (Y = 82%) of 4; MS (FAB) m / z = 278 (M + H) ⁺ .

1.3 "A1": 74.23 mg (0.36 mmol) 4- (4-amino-2-methylphenyl) - morpholin-3-one 5 are dissolved in 6 mL DCM, then 72.56 mg (0 , 36 mmol) of 4-nitro-phenyl chloroformate and 29.06 μL (0.36 mmol) of pyridine were added and the mixture was stirred at RT for 1 h. 100 mg (0.36 mmol) of 4 and 183.67 μL (1, 08 mmol) of Λ / -ethyl-diisopropyl-amine are added to this reaction mixture. After stirring at RT for 20 h, the mixture is worked up in the customary manner and 32 mg (Y = 18%) of "A1" are obtained; MS (FAB) m / z = 510 (M + H) ⁺ .

The following compounds are obtained analogously

1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [3-chloro-4- (3-oxomorpholin-4-yl) phenyl ]ureido} phenyl) - urea ("A2"), 1 - (4-chlorophenyl) -3- (4-hydroxy-2- {3- [4- (2-oxo-2 / - / - pyridin-1-yl) phenyl ] -ureido} -phenyl) urea ("A3"),

1- (4-chlorophenyl) -3- (5-hydroxy-2- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl ]ureido} phenyl) - urea,

1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [2-fluoro-4- (3-oxomorpholin-4-yl) phenyl ]ureido} phenyl) - urea, 1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [2-methyl-4- (3-oxomorpholin-4-yl) phenyl ]ureido} phenyl) - urea.

Example 2

Preparation of 1- (4-chlorophenyl) ~ 3- (4- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1-oxy-pyridine -3-yl) urea ("B 1")

2.1 1 - (4-Amino-pyridine-3-vD-3- (4-chlorophenyl-urethane 3: 1, 09 g (10 mmol) pyridine-3,4-diamine Λ_ in a solvent mixture of 25 mL DCM and 25 mL THF, then 1, 57 g (10 mmol) 4-chlorophenyl isocyanate 2 are added and then stirred at RT. After stirring for 20 h, the mixture is worked up as usual. 1.0 g (38% ) 3; MS (FAB) m / z = 263 (M + H) ⁺ .

2.2 1- (4-Chlorophenvn-3- (4-f3-r3-methyl-4- (3-oxo-morpholin-4-vn-phenvn-ureido) pyridin-3-yl) urea ("BO "):

336 mg (1, 63 mmol) of 4- (4-amino-2-methyl-phenyl) -morpholin-3-one 5 are dissolved in 30 mL DCM, then 328 mg (1, 63 mmol) of 4-nitro-phenyl in succession -chloroformate and 131.3 μL (1.63 mmol) pyridine added and stirred at RT for 1 h. Be to this reaction mixture

430 mg (1.63 mmol) 3 and 553 μL (3.26 mmol) Λ / -ethyl-diisopropyl-amine were added. After stirring at RT for 20 h, the mixture is worked up in the customary manner and 282 mg (Y = 33%) of "BO" are obtained; MS (FAB) m / z = 495 (M + H) ⁺ .

2.3 "B1": 76 mg (0.143 mmol) "BO" are dissolved in 10 mL 2-propanol, and 283 mg (0.572 mmol) magnesium monoperoxyphthalate hexahydrate are added and the mixture is stirred at RT for 2 days. The mixture is then worked up in the customary manner and 40 mg (Y = 52%) "B1" are obtained in this way; MS (FAB) m / z = 512 (M + H) ⁺ .

The following compounds are obtained analogously

1- (2-chloro-4- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl] urido} pyridin-3-yl) -3- (4-chloro -phenyl) urea ("B2"),

1- (4-chlorophenyl) -3- (3- {3- [3-methyl-4- (3-oxomorpholin-4-yl) - phenyl] -ureido} -pyridin-2-yl) - urea ("B3"),

1- (4-chlorophenyl) -3- (3- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1-oxypyridin-4 yl) -hamstoff,

1- (4-chlorophenyl) -3- (3- {3- [2-fluoro-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1-oxypyridin-4 -yl) urea, 1- (4-chlorophenyl) -3- (3- {3- [2-methyl-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1 oxy-pyridin-4-yl) -urea.

Example 3

The preparation of 1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [3-methyl-4- (3-oxo-morpholin-4-yl) phenyl] -ureido} - phenyl) urea is carried out by reacting

The reaction takes place at room temperature in dichloromethane in the presence of NaHC0 ₃ .

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 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

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

A mixture of 1 kg of active ingredient of 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 dye.

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 sterile. Each ampoule contains 10 mg of active ingredient.

Claims

claims

1. Compounds of formula I.

wherein

X-Y-D-E CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH,

CH = N-CH = N, N ⁺ (-0 CH-CH = CH, CH = N ⁺ (-0 ^' ) -CH = CH,

CH = CH-N ⁺ (-0 ^" ) = CH, CH = CH-CH = N ⁺ (-0 ^" ), NH-CO-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH,

CH = CH-NH-CO, in which the H atoms of the -CH groups by shark, A, OH,

OA, A-COO-, Ph- (CH ₂ ) _n -COO-, cycloalkyl- (CH ₂ ) _n -COO-, A-CONH-, A-CONA-,

Ph-CONA-, N ₃ , NH ₂ , N0 ₂ , CN, COOH, COOA, CONH ₂ ,

CONHA, CON (A) ₂ , O-allyl, O-propargyl and / or

O-benzyl can be substituted, Ph is unsubstituted or one, two or three times by A,

OA, OH or shark substituted phenyl, R ¹ shark, -C ≡CH, -C ≡CA, OH or OA,

R ² H, shark or A,

R ³ 2-oxo-1 H-pyridin-1 -yl, 2- or unsubstituted or mono- or disubstituted by A, OH and / or OA, 2-

Oxo-1 / - / - pyrazin-1-yl, 2-oxopiperidin-1-yl, 2-oxo- pyrrolidin-1-yl, 2-oxo- [1, 3] oxazinan-3-yl, 3-oxomorpholin-4-yl, 2-oxo-tetrahydro-pyrimidin-1-yl, 3-oxo-

2 / - / - pyridazin-2-yl, 4-oxo-1H-pyridin-1-yl, 2-oxo-imidazolidin-1-yl, 2,6-dioxopiperidin1-yl, 2-oxopiperazin-1 -yl, 2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl, 2-oxo-1, 3-oxazolidin-3-yl, 2-caprolactam-1-yl (= 2-oxo-azepan-1-yl), 2-azabicyclo [2.2.2] octan-3-one-2-yl, 5,6-dihydro-1 / - / - pyrimidin-2-oxo -1 -yl, 4H- [1,4] oxazin-4-yl, 2-imino-pipehdin-1-yl, 2-imino-pyrrolidin-1-yl, 3-imino-morpholin-4-yl, 2- imino-imidazolidin-1-yl or 2-imino-1 / - / - pyrazin-1-yl,

A unbranched, branched or cyclic alkyl having 1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine,

Shark F, Cl, Br or I, n 0, 1, 2 or 3, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

2. Compounds according to claim 1, wherein R ^{1 is} shark or -C ≡ € -H, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios.

3. Compounds according to claim 1 or 2, wherein R ^{1 is} shark, as well as their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all ratios.

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

XYDE CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, N ⁺ (-0 ^' ) = CH-CH = CH, CH = N ⁺ (-0> CH = CH, CH = CH-N ⁺ (-0 CH, CH = CH-CH = N ⁺ (-0-),

NH-CO-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH or CH = CH-NH-CO, where the H atoms of the -CH groups are represented by shark, A, OH and / or OA may be substituted, as well as their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

5. Compounds according to one or more of claims 1-4, wherein X-Y-D-E CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, N ⁺ (-0 CH-CH = CH, CH = N ⁺ (-0 ^" ) -CH = CH,

CH = CH-N ⁺ (-0 CH or CH = CH-CH = N ⁺ (-0 ^" ), in which the H atoms of the -CH groups can be substituted by shark, OH and / or OA, and their pharmaceutically acceptable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

6. Compounds according to one or more of claims 1-5, wherein R ³ 2-oxo-l H-pyridin-l -yl, 2-oxo-1 H-pyrazin-1 -yl, 2-oxopiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2- oxo

[1,3] oxazinan-3-yl, 3-oxomorpholin-4-yl, 2-oxotetrahydro-pyrimidin-1-yl, 3-oxo-2H-pyridazin-2-yl, 4-

Oxo-1 is H-pyridin-1 -yl, 2-oxo-imidazolidin-1 -yl or 2-oxopiperazin-1-yl, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

7. Compounds according to one or more of claims 1-6, wherein R ^{3 is} 2-oxo-l H-pyridin-1-yl or 3-oxomorpholin-4-yl, and their pharmaceutically usable derivatives, solvates, salts and Stereoisomers, including their mixtures in all

Conditions.

8. Compounds according to one or more of claims 1-7, wherein X-Y-D-E CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, N ⁺ (-0 ^" ) = CH-CH = CH, CH = N ⁺ (-0 ^" ) -CH = CH,

CH = CH-N ⁺ (-0 ^" ) = CH or CH = CH-CH = N ⁺ (-0 ^" ), in which the H atoms of the -CH groups can be substituted by shark, OH and / or OA, R ¹ shark,

R ² H, shark or A,

R ³ 2-oxo-1 H-pyridin-1 -yl, 2-oxo-1 H-pyrazin-1 -yl, 2-oxopiperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2- Oxo- [1, 3] oxazinan-3-yl, 3-oxo-morpholin-4-yl, 2-oxotetrahydro-pyrimidin-1-yl, 3-oxo-2 / - -pyridazin-2-yl, 4 - Oxo-1 H-pyridin-1-yl, 2-oxo-imidazolidin-1-yl or 2-oxopiperazin-1-yl,

A with unbranched, branched or cyclic alkyl

1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine,

Hai F, Cl, Br or I, and their pharmaceutically usable derivatives, solvates, salts and stereoisomers, including their mixtures in all

Conditions.

9. Compounds according to claim 1 selected from the group 1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -phenyl) -urea,

1- (4-chlorophenyl) -3- (4- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl ]ureido} pyridin-3-yl) - urea,

1- (4-chlorophenyl) -3- (4- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1-oxypyridin-3 yl) -hamstoff,

1- (2-Chloro-4- {3- [3-methyl-4- (3-oxo-morpholin-4-yl) phenyl] ureido} pyhdin-3-yl) -3- (4-chloro phenyl) urea,

1- (2-Chloro-4- {3- [3-chloro-4- (3-oxo-morpholin-4-yl) phenyl] ureido} pyridin-3-yl) -3- (4-chloro phenyl) urea,

1 - (4-chlorophenyl) -3- (4-hydroxy-2- {3- [4- (2-oxo-2H-pyridin-1 - yl) phenyl] urido} phenyl) urea,

1- (4-chlorophenyl) -3- (3- {3- [3-methyl-4- (3-oxomorpholin-4-yl) - phenyl] -ureido} -pyridin-2-yl) - urea,

1- (4-chlorophenyl) -3- (3- {3- [3-methyl-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1-oxypyridin-4 yl) urea,

1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [2-fluoro-4- (3-oxomorpholin-4-yl) phenyl ]ureido} phenyl) - urea, 1- (4-chlorophenyl) -3- (4-hydroxy-2- {3- [2-methyl-4- (3-oxomorpholin-4-yl) phenyl ]ureido} phenyl) - urea,

1- (4-chlorophenyl) -3- (3- {3- [2-fluoro-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1-oxypyridin-4 yl) -hamstoff,

1- (4-chlorophenyl) -3- (3- {3- [2-methyl-4- (3-oxomorpholin-4-yl) phenyl] -ureido} -1-oxypyridin-4 yl) urea,

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

Conditions.

10. A process for the preparation of compounds of formula I according to ₅ claims 1-9 and their pharmaceutically usable derivatives,

Solvates, salts and stereoisomers, characterized in that a) a compound of the formula II

then with a compound of formula III 5

R ³

wherein

R ² and R ^{3 have} the meanings given in claim 1,

is implemented

or

b) a compound of formula IV

R ³

wherein XYDE, R ² and R ^{3 have} the meanings given in claim 1,

with a compound of formula V

wherein R ^{1 has} the meaning given in claim 1, implements,

or

c) converting a radical X-Y-D-E into another radical X-Y-D-E by oxidizing the radical X-Y-D-E and / or converting a base or acid of the formula I into one of its salts.

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

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

13. Medicament containing at least one compound of the formula I according to one or more of claims 1 to 9 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and, if appropriate, carriers and / or auxiliaries.

14. Medicament containing at least one compound of formula I according to one or more of claims 1 to 9 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all proportions, and at least one further active pharmaceutical ingredient.

15. Use of compounds according to one or more of the

Claims 1 to 9 and / or their physiologically acceptable salts and solvates 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.

16. 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 9 and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and

(b) an effective amount of another drug ingredient.

17. Use of compounds of the formula I according to one or more of claims 1 to 9 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 active pharmaceutical ingredient.

18. Intermediate compounds of formula 11-1

wherein

XYDE CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N,

NH-CO-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH, CH = CH-NH-CO, where the H atoms of the -CH groups are by shark, A, OH, OA , A-COO-, Ph- (CH ₂ ) _n -COO-,

Cycloalkyl- (CH ₂ ) _n -COO-, A-CONH-, A-CONA-, Ph-CONA-, N ₃ , NH ₂ , N0 ₂ , CN, COOH, COOA, CONH ₂ , CONHA, CON (A) ₂ , O-allyl, O-propargyl and / or O-benzyl may be substituted,

Ph unsubstituted or one, two or three times by A,

OA, OH or shark substituted phenyl,

R ¹ shark, -C ≡CH, -C ≡ £ -A, OH or OA,

A with unbranched, branched or cyclic alkyl

1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine,

Shark F, Cl, Br or I, n 0, 1, 2 or 3, and their salts.

19. Intermediate compounds according to claim 18, wherein X-Y-D-E CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH,

CH = CH-N = CH, CH = CH-CH = N, N = CH-N = CH,

CH = N-CH = N, in which the H atoms of the -CH groups can be substituted by shark, OH and / or OA, R ¹ shark, A with unbranched, branched or cyclic alkyl

1-10 C atoms, in which 1-7 H atoms can also be replaced by F and / or chlorine,

Shark F, Cl, Br or I, and their salts.