MXPA06008347A - Urea derivatives - Google Patents

Abstract

Novel compounds of formula (I), wherein X-Y-D-E, R1, R2 and R3 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

DERIVATIVES OF UREA DESCRIPTION OF THE INVENTION The invention relates to compounds of the formula I, where XYDE 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-C0, wherein the H atoms of the -CH- groups can be substituted with Hal, A, OH, OA, A-COO-, Ph- (CH2) n-C00-, cycloalkyl- (CH2) n -COO-, A-CONH-, A- CONA-, Ph-CONA-, N3, NH2, N02, CN, COOH, COOA, CONH2, CONHA, CON (A) 2, O-allyl, O-propargyl and / or O-benzyl, Ph means unsubstituted or mono phenyl , di or trisubstituted with A, OA, OH or Hal, R1 means Hal, -O = CH, -C = CA, OH or OA, R2 means H, Hal or A, R3 means 2-oxo-lH-pyridin-1 -yl, 2-oxo-lH-pyrazin- REF.:173816 1-yl, 2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo- [1, 3] oxazin-3-yl, 3-oxo-morpholin-4 - ilo, 2-oxo-tetrahydro-pyrimidin-1-yl, 3-oxo-2H-pyridazin-2-yl, 4-oxo-lH-pyridin-1-yl, 2-oxo-imidazolidin-1-yl, 2 , 6-dioxo-piperidin-1-yl, 2-oxo-piperazin-1-yl, 2,6-dioxo-piperazin-1-yl, 2,5-dioxo-pyrrolidin-1-yl, 2-oxo-1 , 3-oxazolidin-3-yl, 2-caprolactam-1-yl (= 2-oxo-azepane-1-yl), 2-aza-bicyclo [2.2.2] -octan-3-on-2-yl, 5,6-dihydro-l-pyrimidin-2-oxo-l-yl, 4H- [1,] oxazin-4-yl, 2-imino-piperidin-1-yl, 2-imino-pyrrolidin-1-yl, 3- imino-morpholin-4-yl, 2-imino-imidazolidin-1-yl or 2-imino-lH-pyrazin-1-yl unsubstituted or mono- or di-substituted with A, OH and / or OA, A means alkyl unbranched, branched or cyclic with 1-10 C atoms, where also 1-7 H atoms may be replaced by F and / or chlorine, Hal means F, Cl, Br or I, n means 0, 1, 2 or 3, as well as its derivatives, solvates, salts and stereoisomers of utility farm medicine, including their mixtures in all proportions. The invention was aimed at finding new compounds with valuable properties, in particular those that can be used for the preparation of medicaments. It was found that the compounds of the formula I and their salts have very valuable pharmacological properties and are well tolerated. In particular, they exhibit factor Xa inhibitory properties and, therefore, can be used to combat and prevent boembolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, post-angioplasty restenosis and claudicatio intermittens. The compounds of the formula. In accordance with the invention, factor Vlla, factor IXa and thrombin can also be inhibitors of the coagulation factor in the blood coagulation cascade. Aromatic heterocycles with factor Xa inhibitory activity are known, for example, from WO 96/10022.

The carboxylic acid amide derivatives are known from WO 02/48099 and WO 02/57236, the pyrrolidine derivatives are described in WO 02/100830. Other heterocyclic derivatives are known from WO 03/045912. Substituted benzothiophene-anthranilamides are described as factor Xa inhibitors by Y.-L. Chou et al. in Bioorg. Med. Chem. Lett. 13 (2003) 507-511 and 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 action against the activated coagulation protease, known as factor Xa, or to the inhibition of other activated serine proteases, such as factor Vlla, Factor IXa or thrombin. Factor Xa is one of the proteases that participates in the complex process of blood coagulation. Factor Xa catalyzes the conversion of prothrombin into thrombin. Thrombin cleaves fibrinogen to fibrin monomers which, after crosslinking, contribute elementally to the formation of thrombi. An activation of thrombin can result in the presence of thromboembolic diseases. Nevertheless, an inhibition of thrombin can inhibit the formation of fibrin that participates in the formation of thrombi. The inhibition of thrombin can be measured, for example, by the method of G. F. Cousins et al. in Circulation 1996, 94, 1705-1712. An inhibition of factor Xa can prevent, in this way, thrombin from forming. The compounds of the formula I according to the invention and their salts are involved in the blood coagulation process by inhibiting factor Xa, thereby inhibiting the formation of thrombi. The inhibition of factor Xa through the compounds according to the invention and the measurement of the anticoagulant and antitrobotics activity can be determined by conventional in vi tro or in vivo methods. J. Hauptmann et al. describe an appropriate method, for example, in Thrombosis and Haemostasis 1990, 63, 220-223. The inhibition of factor Xa can be measured, for example, by the method of T. Hará et al. in Thromb. Haemostas. 1994, 71, 314-319. The coagulation factor Vlla initiates the extrinsic part of the coagulation cascade after binding with tissue factor and contributes to the activation of factor X in factor Xa. Inhibition of factor Vlla thus prevents the formation of factor Xa and thus a subsequent formation of thrombin. The inhibition of factor Vlla by the compounds according to the invention and the measurement of anticoagulant and antithrombotic activity can be determined by means of conventional in vi tro or in vivo methods. A conventional method for measuring the inhibition of factor Vlla is described, for example, by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81. The coagulation factor IXa is generated in the intrinsic coagulation cascade and also participates in the activation of factor X in factor Xa. Consequently, an inhibition of factor IXa can prevent in a different way that factor Xa is formed. The inhibition of factor IXa by means of the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in vi tro or in vivo methods. For example, J. Chang et al. describe an appropriate method in Journal of Biological Chemistry 1998, 273, 12089-12094. The compounds according to the invention can also be used for the treatment of tumors, tumor diseases and / or tumor metastasis. T. Taniguchi and N. R. Lemoine. indicated a correlation between TF tissue factor factor Vlla and the development of several types of cancer in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis of Pancreatic Cancer), 57-59. The publications listed below describe an anti-tumor action of the inhibitors of TF-VII and factor Xa for various types of tumors: K. M. Donnelly et al. in Thro b. 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 the formula I can be used as medicated active ingredients in human and veterinary medicine, in particular, for the treatment and prevention of thromboembolic conditions such as thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, restenosis post-angioplasty, claudicatio intermittens, venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina and apoplectic attack based on thrombosis. The compounds according to the invention are also used for the treatment or prophylaxis of atherosclerotic diseases such as coronary artery disease, cerebral arterial disease or peripheral arterial disease. The compounds are also used in combination with other thrombolytic agents in myocardial infarction, in addition for prophylaxis for post-tropositic reocclusion, percutaneous transluminal angioplasty (PTCA) and coronary bypass operations. The compounds according to the invention are also used for the prevention of a rethrombosis in microsurgery, also as anticoagulants in connection with artificial organs or in hemodialysis. The compounds are also used for the cleaning of catheters and medical aids in patients in vivo, or as anticoagulants to preserve blood, plasma and other blood products in vi tro. The compounds according to the invention. they are also used for those diseases in which the coagulation of the blood contributes crucially with the course of the disease or represents a source of secondary pathology as, for example, in cancer, including metastasis, inflammatory diseases, including arthritis, and diabetes.

The compounds according to the invention are also used for the treatment of migraine (F. Morales-Asin et al., Headache, 40, 2000, 45-47). The invention also relates to the use of compounds of the formula I, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, for preparing a medicament for the prevention and treatment of thromboembolic diseases. and / or thrombosis as a consequence of surgical intervention, diseases of genetic origin with greater propensity to thrombosis, arterial and venous vascular system affections, heart failure, atrial fibrillation, thrombophilia, tinnitus and / or sepsis. Those uses are preferred, in which the surgical interventions are selected from the group of operations of thorax, operations' in the abdominal area, orthopedic interventions, replacement of the hip and knee joint, CABG. { Coronary Artery Bypass Grafting), artificial replacement of heart valves, operations through the use of a heart-lung machine, vascular surgery, organ transplants and the use of central venous catheters. The use of anticoagulants in tinnitus therapy is described by R. Mora et al. in International Tinnitus Journal (2003), 9 (2), 109-111. It is also an object of the invention to use compounds of the formula I to prepare a medicament for the prevention and treatment of thromboembolic diseases and / or thrombosis in adults and children. In the treatment of the diseases described, the compounds according to the invention are also used in combination with. other active compounds such as, for example, 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 at the same time or before or after. Particular preference is given to the simultaneous administration with aspirin, in order to avoid the recurrence of thrombus formation. The compounds according to the invention are also used in combination with platelet glycoprotein receptor antagonists (Ilb / IIIa) which inhibit the aggregation of blood platelets. The subject of the invention are the compounds of the formula I and their salts, as well as a process for preparing the compounds of the formula I according to claims 1-9, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, characterized in that a) a compound of the formula II is reacted wherein X-Y-D-E and R1 have the meanings indicated in claim 1, with a chloroformate derivative in an intermediate carbamate derivative, which is then reacted with a compound of the formula III wherein R2 and R3 have the meanings indicated in the claim 1, or b) a compound of the formula IV is reacted wherein X-Y-D-E, R2 and R3 have the meanings indicated in claim 1, with a compound of the formula V where R1 has the meaning indicated in. claim 1, or c) a radical X-Y-D-E is converted to another radical X-Y-D-E, by oxidizing the radical X-Y-D-E and / or a base or an acid of the formula I is converted into one of its salts. Also the subject of the invention are the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers, as well as the hydrates and solvates of these compounds. Solvates of the compounds are understood to be the adductions of solvent molecules inert to the compounds formed due to their mutual attraction force. Solvates are, for example, monohydrates or dihydrates or alcoholates. Derivatives of pharmaceutical use are, for example, the salts of the compounds according to the invention and also the so-called prodrug compounds. By prodrug derivatives are meant the compounds of formula I which were modified, for example, with alkyl or acyl groups, sugars or oligopeptides, which are rapidly cloned in the organism to form the active compounds according to the invention. Also included herein are the biodegradable polymer derivatives of the compounds according to the invention, as described, for example, 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, for example mixtures of two diastereoisomers, for example, in the ratio 1: 1, 1: 2, 1: 3, 1: 4. , 1: 5, 1:10, 1: 100 or 1: 1000.

This involves, with particular preference, mixtures of stereoisomeric compounds. For all the radicals that occur several times, as for example A, their meanings are independent of each other. Higher and lower, radicals or parameters X-Y-D-E, R1, R2 and R3 have the meanings indicated in formula I, unless otherwise expressly stated.

A is 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, also ethyl, propyl, isopropyl, butyl, isobutyl, sec. -butyl or ter. -butyl, 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, l-ethyl -2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, for example, trifluoromethyl is also preferred. A also means cycloalkyl. Cycloalkyl means, with. preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Therefore, A also preferably means cyclopentylmethyl, cyclohexylmethyl, A means, with particular preference, alkyl having 1, 2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. -butyl, ter. -butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1,1,1-trifluoroethyl. OA preferably means methoxy, trifluoromethoxy, ethoxy, propoxy, butoxy or ter. -butoxi. XYDE means preferably 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-C0-CH = CH, CH = CH-C0-NH, C0-NH-CH = CH, CH = CH-NH-C0, wherein the H atoms of the -CH- groups may be substituted with Hal, A, OH and / or OA XYDE in particular 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 ~), wherein the H atoms of the -CH- groups can be substituted with Hal (preferably F or Cl), A (preferably methyl), OH and / or OA. R1 preferably denotes Hal or -C = C-H, especially Hal (preferably F or Cl). R2 means H, Hal (preferably F or Cl) or A (preferably methyl). R3 preferably denotes 2-oxo-lH-pyridin-1-yl, 2-oxo-lH-pyrazin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo - [1, 3] oxazinan-3-yl, 3-oxo-morpholin-4-yl, 2-oxo-tetrahydro-pyrimidin-1-yl, 3-oxo-2H-pyridazin-2-yl, 4-oxo- lH-pyridin-1-yl, 2-oxo-imidazolidin-1-yl or 2-oxo-piperazin-1-yl, with special preference 2-oxo-lH-pyridin-1-yl or 3-oxo-morpholin-4 -ilo. The compounds of the formula I can have one or several chiral centers and, consequently, can be present in various stereoisomeric forms. Formula I comprises all these forms.

Accordingly, the invention relates in particular to those compounds of the formula I, wherein at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed through the following subformulas a-Ih, which correspond to formula I and wherein the radicals not designated in greater detail have the meaning indicated in formula I, but where they are labeled RR11. means Hal or -C = CH; in Ib R1 means Hal; in X X - Y - D - E 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 + (-O") = CH, CH = CH-CH = N + (-0"), NH-C0-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH or CH = CH-NH-CO, wherein the H atoms of the -CH- groups can be substituted with Hal, A, OH and / or OA; in Id XYDE 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 + (-O ") = CH-CH = CH, CH = N + (-0") - CH = CH, CH = CH-N + (- 0 _) = CH, CH = CH-CH = N + (-0") or NH-CO-CH = CH, wherein the H atoms of the -CH- groups may be substituted with Hal, A, OH and / or OA; where R3 is 2-oxo-lH-pyridin-1-yl, 2-oxo-lH-pyrazin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2- oxo [1, 3] oxazinan-3-yl, 3-oxo-morpholin-4-yl, 2-oxo-tetrahydro-pyrimidin-1-yl, 3-oxo-2H-pyridazin-2-yl, 4-oOxo- lH-pyridin-1-yl, 2-oxo-imidazolidin-1-yl or 2-oxo-piperazin-1-yl; in If R3 means 2-oxo-lH-pyridin-1-yl or 3-oxo-morpholin-4-yl; in XYDE Ig 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 + (-O") = CH or CH = CH-CH = N + (-O "), wherein the H atoms of the -CH- groups can be substituted with Hal, OH and / or OA, R1 means Hal, R2 means H, Hal or A, R3 means 2-oxo-lH-pyridin-1-yl, 2-oxo-lH-pyrazin-1-yl, 2-oxo-piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo- [l , 3] oxazinan-3-yl, 3-oxo-morpholin-4-yl, 2-oxo-tetrahydro-pyrimidin-1-yl, 3-oxo-2H-pyridazin-2-yl, 4-oxo-lH-pyridin -l-yl, 2-oxo-imidazolidin-1-yl or 2-oxo-piperazin-1-yl, A "means unbranched, branched or cyclic alkyl with 1-10 carbon atoms, wherein also 1-7 atoms of H can be replaced by F and / or chlorine, Hal means F, Cl, Br or I, in Ih XYDE 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 + (-O ") = CH-CH = CH, CH = N + (- O ") - CH = CH, CH = CH-N + (-0 ~) = CH or CH = CH-CH = N + (-O "), wherein the H atoms of the -CH- groups can be substituted with Hal, OH and / or OA, R1 means Hal, R2 means H, Hal or A, R3 means 2-oxo-lH -pyridin-1-yl or 3-oxo-morpholin-4-yl, A means alkyl with 1, 2, 3, 4, 5 or 6-C atoms means F, Cl, Br or I; as well as its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions. The compounds of the formula I can be obtained preferably by reacting compounds of the formula II with a chloroformate derivative, for example 4-nitrophenylchloroformate, in an intermediate carbamate, and. making him react later with a compound of formula III. The reaction is carried out, in general, in an inert solvent, in the presence of an acid-binding agent, preferably a hydroxide, a carbonate or a bicarbonate of alkali or alkaline earth metals, or another salt of a weak acid of alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium. It is also favorable to add an organic base such as triethylamine, dimethylaniline, N, N'-dimethylenediamine, pyridine or quinoline. Depending on the conditions used, the reaction time ranges from a few minutes to 14 days, and the reaction temperature ranges from about 0 ° to 150 °, usually between 20 ° and 130 °, with special preference between 60 and 90 °. Suitable inert solvents are, for example, 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 dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitroderivatives such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the aforementioned solvents ... The starting compounds of formula II are generally novel, those of formula III are generally known. The compounds of the formula I can also be obtained by reacting compounds of the formula IV with compounds of the formula V. The reaction is generally carried out in an inert solvent, in the presence of an acid-binding agent, with preferably a hydroxide, a carbonate or a bicarbonate of alkali or alkaline earth metals, or another salt of a weak acid of alkali or alkaline earth metals, preferably of potassium, sodium, calcium or cesium. It is also favorable to add an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. Depending on the conditions used, the reaction time ranges from a few minutes to 14 days, the reaction temperature ranges from about 0 ° to 150 °, usually between 20 ° and 130 °. Suitable inert solvents are, for example, 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 mono-ethyl ether (ethyl 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 dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitroderivatives such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of the mentioned solvents. The starting compounds of formula IV are generally novel, those of formula V are generally known. If desired, the starting substances can also be formed in situ so that they are not isolated from the reaction mixture, but are instead immediately converted to the compounds of the formula I. The compounds of the formula I and also the starting substances for their preparation are additionally obtained by methods known per se, as described in the literature (for example, in standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of organic chemistry] , Georg-Thieme-Veriag, Stuttgart), to be precise, under reaction conditions that are known and appropriate for the reactions mentioned. The variants known per se can also be used here, but are not mentioned here in greater detail. The invention also relates to intermediate compounds of the formula II-1 where XYDE 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, NH-CO-CH = CH, CH = CH-CO-NH, CO-NH-CH = CH or CH = CH-NH-CO, wherein the H atoms of the -CH- groups can be substituted with Hal, A, OH, OA, A-COO-, Ph- (CH2) n -COO-, Cycloalkyl- (CH2) n -COO-, A-CONH-, A- CONA- , Ph-CONA-, N3, NH2, N02, CN, COOH, COOA, CONH2, CONHA, CON (A) 2, O-allyl, O-propargyl and / or O-benzyl, Ph means unsubstituted or mono-, di- or trisubstituted phenyl with A, OA, OH or Hal, R1 means Hal, -G = CH, -C = CA, OH or OA, A means unbranched, branched or cyclic alkyl with 1-10 C atoms, wherein also 1-7 H atoms can be replaced by F and / or chlorine , Hal means F, Cl, Br or I, n means 0, 1, 2 or 3, as well as their salts. Intermediate compounds of the formula II-1 are preferred, where XYDE 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 or CH = N-CH = N, wherein the H atoms of the -CH- groups may be substituted with Hal, OH and / or OA, R1 means Hal, A means unbranched, branched or cyclic alkyl with 1-10 C atoms, wherein also 1-7 H atoms can be replaced by F and / or chlorine, Hal means F, Cl, Br or I, as well as their salts . Especially preferred are the intermediate compounds of the formula II-1, wherein XYDE 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 or CH = N-CH = N, where the H atoms of the -CH- groups can be substituted with Hal, OH and / or OA, R1 means Hal, A means alkyl with 1, 2, 3, 4, 5 or 6 atoms C, Hal means F, Cl, Br or I, as well as their salts. Pharmaceutical salts and other forms The compounds according to the invention mentioned can be used in their non-saline final form. On the other hand, the present invention also comprises the use of these compounds in the form of their pharmaceutically innocuous salts which can be derived from various organic and inorganic acids and bases according to procedures known to those skilled in the art. The pharmaceutically innocuous salt forms of the compounds of the formula I are prepared in a large majority in a conventional manner. Provided that the compound of formula I contains a carboxylic acid group, one of its appropriate salts can be formed by reacting the compound with a suitable base in the salt by the addition of corresponding bases. Bases of this type are, for example, alkali metal hydroxides, among them potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alcoholates, for example potassium ethanolate and sodium propanolate; as well as different organic bases such as piperidine, diethanolamine and N-methylglutamine. The aluminum salts of the compounds of the formula I are also counted here. In certain compounds of the formula I acid addition salts are formed by treating these compounds with pharmaceutically innocuous organic and inorganic acids, for example hydrohalic acids such as hydrochloric acid, hydrobromic acid or hydroiodic acid, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, as well as alkyl and monoarylsulphonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, as well as other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, among the pharmaceutically acceptable acid addition salts of the compounds of formula I are the following: acetate, adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, canferate, canfersulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanpropionate, digluconate, dihydrogen-phosphate, dinitrobenzoate, dodecyl sulfate, -ethansulfonate, fumarate, galacraterate (from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hipurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogen-phosphate, "2-naphthalenesulfonate" , nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate-, phenylacetate, 3-phenylpropionate, phosphate, fos fonato, phthalate, which do not represent any limitation. In addition, among the basic salts of the compounds according to the invention are aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III) salts , of manganese (II), of potassium, of sodium and of zinc, which should not represent any limitation. Among the above-mentioned salts, ammonium is preferred; the alkali metal salts sodium and potassium, as well as the alkaline earth metal salts calcium and magnesium. Among the salts of the compounds of formula I which are derived from non-toxic, pharmaceutically acceptable organic bases, are primary, secondary and tertiary amine salts, substituted amines, including also natural substituted amines, cyclic amines and basic ion exchange resins. , for example arginine, betaine, caffeine, - Chloroprocaine, choline, N, N'-dibenzylethylenediamine (benzathine), 'dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, -2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpipéridine, glucamine, glucosamine, histidine, hydrabamide, isopropylamine, lidocaine, Usin, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine-, polyamine resins, procaine, purine, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, as well as co- or tris- (hydroxymethyl) -methylamine (tromethamine), which should not represent any limitation. Compounds of the present invention containing basic groups can be quaternized with nitrogen, with agents such as (C_C4) alkyl halides, for example methyl, ethyl, isopropyl chloride, bromide and iodide and ter. -butyl; dialkyl (C_-C) -sulfates, for example dimethyl-, diethyl- and diamylsulfate; alkyl halides (Cio-Cis), for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide, and also arylalkyl halides (C_-C4), for example benzyl chloride and phenethyl bromide. salts of this type can be prepared according to the invention soluble in both water and oil.

Among the above-mentioned preferred pharmaceutical salts are acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, isuccinate, hipurate, hydrochloride, hydrobromide, isethionate, γ-mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, phosphate, sodium, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, which should not represent any limitations. The acid addition salts of basic compounds of the formula I are prepared by contacting the free basic form with a sufficient amount of the desired acid, the salt being obtained in the usual manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in the usual manner. The basic free forms are distinguished in a sense from their corresponding salt forms in terms of certain physical properties, such as solubility in polar solvents; however, within the scope of the invention, the salts correspond to their corresponding free basic forms. As mentioned, the pharmaceutically innocuous base addition salts of the compounds of the formula I are formed with metals or amines such as alkaline or 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 the acid compounds according to the invention are prepared by contacting the free acid form with a sufficient amount of the desired base, the salt being obtained in the usual manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in the usual manner. The free acid forms are distinguished in a sense from their corresponding salt forms with respect to certain physical properties such as solubility in polar solvents; however, within the scope of the invention, the salts correspond, moreover, to their relevant free acid forms. If a compound according to the invention contains more than one group which can form pharmaceutically innocuous salts of this type, the invention also comprises multiple salts. Typical multi salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trichlorhydrate, which should not represent any limitation. As regards the above, it can be seen that, by "pharmaceutically safe salt" in the present context, it is meant an active principle that contains a compound of the formula I in the form of one of its salts, especially when this salt form it confers to the active principle improved pharmacokinetic properties, in comparison with the free form of the active principle or another saline form of the active principle that was previously used. The pharmaceutically safe salt form of the active ingredient can also give to this active principle only a desired pharmacokinetic property that it did not previously have, and can even positively affect the pharmacodynamics of this active principle with respect to its therapeutic efficacy in the body. The compounds of the formula I can be chiral due to their molecular structure and, therefore, can be presented in various enantiomeric forms. For that also .can exist in racemic or optically active form. As the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, the use of the enantiomers may be desired. In these cases, the final product or even the intermediates can be separated into enantiomeric compounds by chemical or physical actions known to those skilled in the art or even used as such in the synthesis. In the case of racemic amines, the diastereomers are formed from the mixture by reaction with an optically active resolving agent. As resolution agents are appropriate, 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, appropriately N-protected amino acids (for example, N-benzoylproline or N-benzenesulfonylproline) or the different optically active camphorsulfonic acids. The chromatographic resolution of the enantiomers by means of an optically active resolving agent (for example, dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivative methacrylate polymers immobilized on silica gel) is also advantageous. Suitable eluents for this purpose are mixtures of aqueous or alcoholic solvents such as, for example, hexane / isopropanol / acetonitrile, for example in the ratio of volumes of 82: 15: 3. The invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts to obtain pharmaceutical preparations, in particular by non-chemical methods. In this case, they can be converted into an appropriate dosage form together with at least one solid, liquid and / or semi-liquid excipient or adjuvant and, if desired, in combination with one or more active ingredients. comprise at least one compound of formula I and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, as well as optionally excipients and / or coadjuvants. of doses containing per predetermined quantity of active ingredient per unit of dosage, A unit of this type may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, with special preference, 5 mg to 100 mg of a compound according to the invention, in accordance with the pathological condition treated, the route of administration and the age, the weight and the condition of the patient, or can be ad administering pharmaceutical formulations in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or a partial dose, as indicated above, or a corresponding fraction thereof of an active ingredient. On the other hand, pharmaceutical formulations of this type can be prepared with a method of general knowledge in the specialized pharmaceutical field. The pharmaceutical formulations can be adapted to be administered by any appropriate route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including the subcutaneous, intramuscular, intravenous or intradermal route). Formulations of this type can be prepared with all known processes in the specialized pharmaceutical field, for example by bringing together the active principle with the excipient (s) or adjuvants. Pharmaceutical formulations adapted for oral administration can be administered as separate units such as, for example, capsules or tablets; powders or granulates; solution or suspensions in aqueous or non-aqueous liquids; edible foams or mousses; or liquid emulsions of oil in water or liquid emulsions of water in oil. In this way, for example, in the oral administration in the form of a tablet or capsule, the active component can be combined with a non-toxic and pharmaceutically innocuous oral inert excipient, such as, for example, ethanol, glycerin, water, etc. Powders are prepared by grinding the compound to an appropriate fine size and mixing it with a crushed pharmaceutical excipient in the same way as, for example, an edible carbohydrate such as, for example, starch or mannitol. There may also be a flavoring, a preservative, a dispersant and a colorant. The capsules are obtained by preparing a powder mixture as described above and filling molded gelatin shells with it. Lubricants such as, for example, high dispersion silicic acid, 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 a solubilizer such as, for example, agar-agar, calcium carbonate or sodium carbonate can also be added in order to improve the availability of the medicament after the capsule is ingested. In addition, if desired or necessary, suitable binders, lubricants and disintegrants, as well as colorants, can be incorporated into the mixture. Suitable binders are starch, gelatin, natural sugars such as, for example, glucose or beta-lactose, corn sweeteners, natural and synthetic gum such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc. The tablets are formulated by preparing, for example, a powdery mixture, granulating or compressing it dry, adding a lubricant and a disintegrant and compressing everything into tablets. A pulverulent mixture is prepared by mixing a comminuted compound in a suitable manner with a diluent or a base, as described above, and optionally with a binder such as, for example, carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a reagent the solution as, for example, paraffin, a resorption accelerator such as, for example, a quaternary salt and / or an absorption agent such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as, for example, syrup, starch, paste, acadia or solutions of cellulosic or polymeric materials, and pressing it through a screen. As an alternative for the granulation, the powder mixture is passed through a tabletting machine, where inhomogeneous molded lumps are formed which are split into granules. The granulates can be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil, in order to prevent them from sticking to the molten molds for tablets. The lubricated mixture is then compressed to form tablets. The compounds according to the invention can also be combined with a fluid inert excipient and then compressed directly into tablets without performing granulation or dry compression steps. There may also be a transparent or non-transparent protective layer composed of a shellac coating, a layer of sugar or polymeric material and a shiny layer of wax. To these coatings dyes can be added to differentiate the different dose units. Oral liquids, such as solutions, syrups and elixirs, can be prepared in the form of dose units, so that a given amount contains a predetermined amount of compound. Syrups can be prepared by dissolving the compound in an aqueous solution with appropriate flavor, while the elixirs are prepared using a non-toxic alcoholic vehicle.The suspensions can be formulated by dispersing the compound in a non-toxic vehicle. solubilizers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, etc. Formulations of dosage units for oral administration may optionally be included in microcapsules The formulation may thus be prepared so as to prolong or delay the release as, for example, by coating or inclusion of particulate material in polymers, waxes, etc. The compounds of the formula I as well as their salts, solvates and physiologically functional derivatives can be in administering in the form of liposome delivery systems such as, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from various phospholipids such as, for example, cholesterol, stearylamine or phosphatidylcholines; The compounds of the formula I, as well as their salts, solvates and physiologically functional derivatives can be supplied using monoclonal antibodies as individual supports, to which the binding molecules are coupled. The compounds can also be coupled with soluble polymers as targeting medicated carriers. Polymers of this type can comprise polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamide phenol or polyethylene oxide polylysine, substituted with palmitoyl radicals. In addition, the compounds can be coupled to a class of biodegradable polymers that are suitable for achieving a controlled release of a drug, for example, polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and crosslinked block copolymers. or amphipathic of hydrogels. Pharmaceutical formulations adapted for transdermal administration can be administered as separate patches for prolonged close contact with the epidermis of the recipient. In this way, for example, the active principle of the patch can be administered by means of iontophoresis, as is generally described in Pharmaceutical Research, 3 (6), 318 (1986). The pharmaceutical compositions adapted for topical administration can be formulated in the form of ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. _ For eye treatments or other external tissues, for example, the mouth and skin, the formulations are preferably applied as ointment or cream -topics. In case of formulating an ointment, the active principle can be applied with either a paraffinic cream base or a miscible one with water. Alternatively, the active ingredient can be formulated in a cream with a creamy base of oil in water or a base of water in oil. Pharmaceutical formulations adapted to topical application in the eyes include ophthalmic drops, wherein the active principle is dissolved or suspended in an appropriate support, especially an aqueous solvent. Pharmaceutical formulations adapted to topical application in the mouth comprise oral dissolution tablets, lozenges and mouth rinses.

Pharmaceutical formulations adapted to rectal application can be administered in the form of ovules or enemas. Pharmaceutical formulations adapted for nasal administration, in which the carrier substance is a solid substance, contain a coarse powder with a granulometry within the range, for example, 20-500 micrometers, which is administered in the manner in which it was aspirated snuff, that is, inhaling it quickly through the nasal passages from a container with the powder held near the nose. Suitable formulations for administration as a nasal spray or nasal drops with a liquid as a support substance comprise active ingredient solutions in water or oil. Pharmaceutical formulations adapted for administration by inhalation comprise powders of fine particles or mists that can be generated by means of different types of pressurized 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 sterile aqueous and non-aqueous injectable solutions, containing antioxidants, buffers, bacteriostats and solutes, through which the formulation becomes isotonic with the blood of the patient under treatment; as well as sterile aqueous and non-aqueous suspensions which may contain suspending agents and thickeners. The formulations can be administered in single dose, or multiple, containers, for example, sealed ampoules and vials and stored in the lyophilized state, so that only the addition of the sterile carrier liquid, e.g., water for injectable purposes, is required immediately before. to use Injectable solutions and solutions prepared according to the recipe can be prepared from sterile powders, granules and tablets. It is understood that the formulations, in addition to the components mentioned above in particular, may contain other agents customary in the specialized field with respect to the corresponding type of formulation; in this way, the appropriate formulations for oral administration may contain flavors. An amount of therapeutic efficacy of a compound of the formula I depends on a number of factors, including for example the age and weight of the animal, the exact health status that requires treatment, as well as its severity, the nature of the formulation as well as the route of administration, and ultimately is determined by the attending physician or veterinarian. However, an effective amount of a compound according to the invention generally varies in the range of 0.1 to 100 mg / kg of body weight of the receptor (mammal) per day and especially, typically, in the range of 1 to 10. mg / kg of body weight per day. Thus, for an adult 70 kg mammal the effective amount per day would usually be 70 to 700 mg, where this amount may be administered as a single dose per day or usually in a series of partial doses (such as, for example, , two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of one of its physiologically functional derivatives can be determined per se as part of the effective amount of the compound according to the invention. The compounds of formula I and their physiologically acceptable salts can be used in the combat and prevention of thromboembolic conditions such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, post-angioplasty restenosis, claudicatio intermittens, migraine , tumors, tumor diseases and / or tumor metastasis. Furthermore, the subject of the invention are medicaments which contain at least one compound of formula I and / or its derivatives, solvates and stereoisomers of pharmaceutical use, including their mixtures in all proportions, and at least one other active drug ingredient.

Another object of the invention is a kit consisting of separate packages of (a) an effective amount of a compound of formula I and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, and (b) an effective amount of another medicament active ingredient. The kit contains appropriate containers such as boxes, bottles, sachets or individual ampoules. The kit may contain, for example, separate ampoules each containing an effective amount of a compound of formula I and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including mixtures thereof in all proportions, and an amount effective of another active drug substance dissolved or in lyophilized form. Another object of the invention is, in addition, the use of compounds of the formula I and / or their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, for the preparation of a medicament for the treatment of thrombosis, myocardial infarction, arteriesclerosis, inflammation, apoplexy, angina pectoris, post-angioplasty restenosis, claudicatio intermittens, migraine, tumors, tumor diseases and / or tumor metastasis, in combination with at least one other active drug ingredient. Previously and subsequently, all temperatures are indicated in ° C_. In the examples below, "conventional processing" means that, if necessary, water is added, if necessary it is adjusted - depending on the constitution of the final product - to pH values between 2 and 10, extracted with acetate of ethyl or dichloromethane, separated, the organic phase is dried over sodium sulfate, evaporated and purified by chromatography on silica gel and / or by crystallization. Rf values on silica gel; eluent: ethyl acetate / methanol 9: 1. Mass spectrometry (MS): The (ionization by means of electronic impact) M + ESI (ionization by electrospray) (M + H) + (provided it is not indicated otherwise).

Example 1 Preparation of 1- (4-chloro-phenyl) -3- (4-hydroxy-2-. {3- [3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] - ureido.}.-phenyl) -urea ("Al") 1. 1- (4-Chloro-phenyl) -3- (4-hydroxy-2-nitro-phenyl) -urethane 3: 3.5 g (22.7 'mmol) of 4-amino-3-nitro-phenol 1 are dissolved in a solvent mixture of 50 ml of DCM and 25 ml of THF, then added 3.56 g (22.7 mmol) of 4-chloro-phenyl-isocyanate 2 and then stirring at room temperature. After stirring for 20 h, it is worked up in the usual manner. In this way 6.98 g (98%) of 3 are obtained; MS (FAB) m / z = 308 (M + H) +. 1.2 l- (2-Amino-4-hydroxy-phenyl) -3- (4-chloro-phenyl) -urethane 4: Dissolve 1.0 g (3.185 mmol) of 3 in a solvent mixture of 25 ml of DCM and 25 ml of THF. Then 0.25 g of Raney nickel (wet) is added and hydrogen is introduced under stirring. After stirring for 5 h at room temperature, it is worked up in a usual manner and in this way 0.74 g (R = 82%) of 4 are obtained; MS (FAB) m / z = 278 (M + H) +. 1.3"Al": Dissolve 74.23 mg (0.36 mmol) of 4- (4-amino-2-methyl-phenyl) -morpholin-3-one 5 in 6 ml of DCM, then add 72.56 mg successively ( 0.36 mmol) of 4-nitro-phenyl-chloroformate and 29.06 ml (0.36 mmol) of pyridine and stirring for 1 h at room temperature. To this reaction mixture is poured 100 mg (0.36 mmol) of 4 and 183.67 μl (1.08 mmol) of N-ethyl-diisopropylamine. After stirring for 20 h at room temperature, it is worked up in a usual manner and in this way 32 mg (R = 18%) of "Al" are obtained; MS - (FAB) m / z = 510 (M + H) +. The following compounds are obtained analogously 1- (4-chloro-phenyl) -3- (4-hydroxy-2. {3- [3-chloro-4- (3-oxo-morpholin-4-yl) phenyl] -ureido.}.-phenyl) -urea ("A2"), 1- (4-chloro-phenyl) -3- (4-hydroxy-2- { 3- [4- (2-oxo -2H-pyridin-1-yl) -phenyl] -ureido.}. -phenyl) -urea ("A3"), 1- (4-chloro-phenyl) -3- (5-hydroxy-2- { 3- [3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido.} - phenyl) -urea, 1- (4-chloro-phenyl) -3- (4-hydroxy) -2- { 3- [2-fluoro-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido.}. -phenyl) -urea, 1- (4-chloro-phenyl) - 3- (4-hydroxy-2-. {3- [2-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido} - phenyl) -urea.

Example 2 Preparation of 1- (4-chloro-phenyl) -3- (4-. {3- [3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido] .}. -l-oxy-pyridin-3-yl) -urea ("Bl") 2. 1- (4-Amino-pyridin-3-yl) -3- (4-chloro-phenyl-urethane 3: 1.09 g (10 mmol) of pyridine-3,4-diamine 1 are dissolved in a mixture of solvents of 25 ml of DCM and 25 ml of THF, then 1.57 g (10 mmol) of 4-chloro-phenyl-isocyanate 2 are added and the mixture is stirred at room temperature. In this way, 1.0 g (38%) of 3 MS (FAB) m / z = 263 (M + H) +. 2.2 1- (4-chloro-phenyl) -3- (4- {3- [3-Methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido}. Pyridin-3-yl) -urea ("BO"): 336 mg are dissolved ( 1.63 mmol) of 4- (4-amino-2-methyl-phenyl) -morpholin-3-one in 30 ml of DCM, then 328 mg (1.63 mmol) of 4-nitro- phenyl chloroformate and 131; 3 μl (1.63 mmol) of pyridine were added and the mixture was stirred for 1 h at room temperature, and 430 mg (1.63 mmol) of 3 and 553 μl (3.26 mmol) were added to this reaction mixture. ) of N-ethyl-diisopropyl-amine After stirring for 20 h at room temperature, it is processed in the usual manner and In this way 282 mg (R = 33%) of "B0" are obtained; MS (FAB) m / z = 495 (M + H) +. 2.3"Bl": Dissolve 76 mg (0.143 mmol) of "B0" in 10 ml of 2-propanol and mix with 283 mg (0.572 mmol) of magnesium monoperoxyphthalate hexahydrate and stir for 2 days at room temperature. It is then worked up in a usual manner and in this way 40 mg (R = 52%) of "Bl" are obtained; MS (FAB) m / z = 512 (M + H) +. The following compounds are obtained analogously 1- (2-chloro-4-. {3- [3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido} -pyridin -3-yl) -3- (4-chloro-phenyl) -urea ("B2"), 1- (4-chloro-phenyl) -3- (3-. {3- [3-methyl-4-] (3-oxo-morpholin-4-yl) -phenyl] -ureido.} - pyridin-2-yl) -urea ("B3"), 1- (4-chloro-phenyl) -3- (3- {3- [3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido.} - l-oxy-pyridin-4-yl) -urea, 1- (4-chloro) phenyl) -3- (3- {3- [2-fluoro-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido} -l-oxy-pyridin-4-yl. ) -urea, 1- (4-chloro-phenyl) -3- (3. {3- [2-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido}. -l-oxy-pyridin-4-yl) -urea.

Example 3 The preparation of 1- (4-chloro-phenyl) -3- (4-hydroxy-2-. {3- [3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido.}.-phenyl) -urea is carried out by reaction of The reaction is carried out at room temperature in dichloromethane in the presence of NaHCO 3. Pharmacological data Affinity for receptors Table 1 The following examples relate to pharmaceutical preparations: Example A: Blisters for injection A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogen phosphate in 3 1 of bidistilled water is adjusted to a value of pH 6.5 using 2N hydrochloric acid, filtered in sterile form, transferred to ampule bottles for injection, lyophilized under sterile conditions and sealed in sterile form. Each vial-ampoule for injection 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 soya 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 of the formula I, 9.38 g of NaH2P04 • 2 H20, 28.48 g of Na2HP04 • 12 H20 and 0.1 g of benzalkonium chloride in 940 is prepared my double-distilled water. The solution is adjusted to a pH of 6.8, completed to 1 1 and sterilized by irradiation. This solution can be used in the form of ophthalmic drops. Example D: Ointment 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions. Example E: Tablets A mixture of 1 kg of active ingredient of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a manner conventional to form tablets, such that each tablet contains 10 mg of active ingredient. Example F: Coated tablets Analogously to Example E, the tablets are pressed and then coated in a conventional manner with a sucrose cover, potato starch, talc, gum tragacanth and coloring. Example G: Capsules 2 kg of active ingredient of the formula I are placed in a conventional manner in hard gelatin capsules, so that each capsule contains 20 mg of active ingredient. Example H: Ampoules A solution of 1 kg of active ingredient of the formula I in 60 1 of bidistilled water is sterile filtered, transferred to ampoules, lyophilized under sterile conditions and sealed under sterility. Each ampoule contains 10 mg of active ingredient. It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (19)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compounds of the formula I characterized by XYDE meaning 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, wherein the H of the -CH- groups can be substituted with Hal, A, OH, OA, A-COO-, ph- (CH2) n -COO-, cycloalkyl- (CH2) n -COO-, A-CONH-, A - CONA-, Ph ~ CONA-, N3, NH2, N02, CN, COOH, COOA,
1. CONH2, CONHA, CON (A) 2, O-allyl, O-propargyl and / or 0- benzyl, Ph is phenyl unsubstituted or mono-, di- or trisubstituted by A, OA, OH or Hal, R1 denotes Hal, -C = CH, -C = CA, OH or OA, R2 means H, Hal or A, - R3 means 2-oxo-lH-pyridin-1-yl, 2-oxo-lH-pyrazin-1-yl, 2-oxo- piperidin-1-yl, 2-oxo-pyrrolidin-1-yl, 2-oxo- [1, 3] oxazinan-3-yl, 3-oxo-morpholin-4-yl, 2-oxo-tetrahydro- pyrimidin-l-yl, 3-oxo-2H- pyridazin-2-yl, 4-oxo-lH yl-pyridin-l-yl-imidazolidin-1, 2-oxo-, 2, 6-dioxo-piperidin-l- ilo, 2- '_; oxo-piperazin-1-yl, 2, 6-dioxo-piperazin-1-yl, - .2,5-dioxo-pyrrolidin-1-yl, 2-oxo-l, 3- oxazolidin-3-yl, 2-caprolactam-1-yl (= 2-oxo-azepane-1-yl), 2-aza-bicyclo [2.2.2] -octan-3-on-2-yl, 5, 6-dihydro- lH-pyrimidin yl-2-oxo-l-yl oxazin-4-yl 2-imino-pyrrolidin-l-, 4H- [1, 4] imino 2- yl-piperidin-1-, 3 - imino-morpholin-4-yl, 2-imino-imidazolidin-l-yl or 2-imino-yl-lH-pyrazin-l unsubstituted or mono- or disubstituted by A, OH and / or OA, A denotes alkyl n or branched, branched or cyclic with 1-10 C atoms, wherein also 1-7 H atoms may be replaced by F and / or chlorine, Hal means F, Cl, Br or I, n means 0, 1, 2 or 3, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
2. 2. Compounds according to claim 1, characterized in that R1 means Hal or -C = C-H, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
3. 3. Compounds according to claim 1 or 2, characterized in that R1 stands for Hal, as well as its derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions.
4. 4. Compounds according to one or more of claims 1-3, characterized in that XYDE 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 ^ -O ") = CH-CH = CH, CH = N + (-O") -CH = CH, CH = CH-N + (-O ") = CH, CH = CH-CH = N + (- 0"), NH-C0-CH = CH, CH = CH-CO-NH, CO-NH- CH = CH or CH = CH-NH-CO, wherein the H atoms of the -CH- groups may be substituted with Hal, A, OH and / or OA, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions. Compounds according to one or more of claims 1-4, characterized in that X-Y-D-E 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 or CH = CH-CH = N + (-0"), where the H atoms of the -CH- groups may be substituted with Hal, -OH and / or OA, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions. 6. Compounds according to one or more of claims 1-5, characterized in that R3 means 2-oxo-lH-pyridin-1-yl, 2-oxo-lH-pyrazin-1-yl, 2-oxopiperidin-l- yl, 2-oxopyrrolidin-yl-l, 2- oxo- [l, 3] oxazinan-3-yl, 3-oxo-morpholin-4-yl, 2-oxo- tetrahydro-yl-pyrimidin-1, 3 -oxo-2H-pyridazin-2-yl-, 4- oxo-lH-pyridin-1-yl, 2-oxo-imidazolidin-l-yl or 2-oxo- piperazin-1-yl, and derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions. 7. Compounds according to one or more of claims 1-6, characterized in that R3 means 2-oxo-lH-pyridin-1-yl or 3-oxo-morpholin-4-yl, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, including their mixtures in all proportions. Compounds according to one or more of claims 1-7, characterized in that XYDE 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 or CH = CH-CH = N + (- 0" "), where the H atoms of the -CH- groups may be substituted with Hal, OH and / or OA, R1 means Hal, R2 means H, Hal or A, R3 means 2-oxo-lH-pyridin-1-yl, 2-oxo-lH-pyrazin-1-yl, 2-oxo-piperidin-1-yl , 2-oxo-pyrrolidin-1-yl, 2-oxo- [1, 3] oxazinan-3-yl, 3-oxo-morpholin-4-yl, 2-oxo-tetrahydro-pyrimidin-1-yl, 3- oxo-2H-pyridazin-2-yl, 4-oxo-lH-pyridin-1-yl, 2-oxo-imidazolidin-1-yl or 2-oxo-piperazin-1-yl, A means unbranched, branched or cyclic with 1-10 C atoms, where also 1-7 H atoms can be replaced by F and / or chlorine, Hal means F, Cl, Br or I, as well as their derivatives, solvates, salts and stereoisomers of utility pharmaceutical company, including its s mixtures in all proportions. 9. Compounds according to claim 1, characterized in that they are selected from the group 1- (4-chloro-phenyl) -3- (4-hydroxy-2-. {3- [3-methyl-4- (3 -oxo-morpholin-4-yl) -phenyl] -ureido.}. -phenyl) -urea, 1- (4-chloro-phenyl) -3- (4-. {3- [3-methyl-4-] (3-oxo-morpholin-4-yl) -phenyl] -ureido.} - pyridin-3-yl) -urea, 1- (4-chloro-phenyl) -3- (4-. {3- 3- [ 3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido.). ^ 1-oxy-pyridin-3-yl) -urea, 1- (2-chloro-4-. { 3- [3-methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido.} - pyridin-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-chloro-phenyl) -3- (4-hydroxy-2- { 3- [4- (2-oxo-2H-pyridin-1-yl) - phenyl] -ureido.}. phenyl) -urea, 1- (4-chloro-phenyl) -3- (3. {3- [3-methyl-4- (3-oxo-morpholin-4-yl] ) -phenyl] -ureido.}.-pyridin-2-yl) -urea, 1- (4-chloro-phenyl) -3- (3- { 3- [3-methyl-4- (3-oxo -morpholin-4-yl) -phenyl] -ureido.}. -l-oxy -pyridin-4-yl) -urea, 1- (4-chloro-phenyl) -3- (5-hydroxy-2-. { 3- [3-methyl ^ -4- (3-oxo-morpholin-4-yl) -phenyl] -ureido} phenyl) -urea, 1- (4-chloro-phenyl) -3- (4-hydroxy-2-. {3- [2-fluoro-4- (3-oxo-morpholin-4-yl) -phenyl) ] -ureido.}. phenyl) -urea, 1- (4-chloro-phenyl) -3- (4-hydroxy-2- { 3- [2-methyl-4- (3-oxo-orfolin- 4-yl) -phenyl] -ureido.}. -phenyl) -urea, 1- (4-chloro-phenyl) -3- (3-. {3- [2-fluoro-4- (3-oxo- morpholin-4-yl) -phenyl] -ureido.} - l-oxy-pyridin-4-yl) -urea, 1- (4-chloro-phenyl) -3- (3- { 3- [2 -methyl-4- (3-oxo-morpholin-4-yl) -phenyl] -ureido.} - l-oxy-pyridin-4-yl) -urea, as well as its useful derivatives, solvates, salts and stereoisomers pharmaceutical, including their mixtures in all proportions. 10. Process for preparing compounds of the formula I according to claims 1-9, as well as their derivatives, solvates, salts and stereoisomers of pharmaceutical utility, characterized in that a) a compound of the formula II is reacted wherein X-Y-D-E and R1 have the meanings indicated in claim 1, with a chloroformate derivative in an intermediate carbamate derivative, which is then reacted with a compound of the formula III wherein R2 and R3 have the meanings indicated in claim 1, or b) a compound of the formula IV is reacted wherein X-Y-D-E, R and R have the meanings indicated in claim 1, with a compound of the formula V wherein R1 has the meaning indicated in claim 1, or c) a radical X-Y-D-E is converted to another radical X-Y-D-E, the radical X-Y-D-E is oxidized and / or a base or an acid of the formula I is converted into one of its salts. 11. Compounds of the formula I according to one or more of claims 1 to 9, characterized in that they are used as inhibitors of the coagulation factor Xa. 12. Compounds of the formula I according to one or more of claims 1 to 9, characterized in that they are used as inhibitors of the clotting factor Vlla. 13. Medicaments characterized in that they comprise at least one compound of the formula I according to one or more of claims 1 to 9 and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, as well as optionally excipients and / or adjuvants. 14. Medicaments characterized in that they comprise at least one compound of the formula I according to one or more of claims 1 to 9 and / or its derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, and at least another active medication ingredient. 1
5. 5. Use of compounds according to one or more of claims 1 to 9 and / or their physiologically acceptable salts and solvates to prepare a medicament for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, post-angioplasty restenosis, claudicatio intermittens, migraine, tumors, tumor diseases and / or tumor metastasis. 1
6. 6. Kit characterized in that it consists of separate packages of (a) an effective amount of a compound of the formula I according to one or more of claims 1 to 9 and / or its derivatives, solvates and estefeoisomers of pharmaceutical utility, including its mixtures in all proportions, and (b) an effective amount of another active drug ingredient. 1
7. 7. Use of compounds of formula I according to one or more of claims 1 to 9 and / or their derivatives, solvates and stereoisomers of pharmaceutical utility, including their mixtures in all proportions, for preparing a medicament for the treatment of "Thrombosis, myocardial infarction, arteriosclerosis, inflammations, stroke, angina pectoris, post-angioplasty restenosis, claudicatio intermittens, migraine, tumors, tumor diseases and / or tumor metastasis, in combination with at least one other active drug ingredient. intermediaries of the formula Il-l characterized by XYDE meaning 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, wherein the H atoms of the -CH- groups can be substituted with Hal, A, OH, OA, A-COO-, Ph- (CH2) n -COO-, cycloalkyl- (CH2) n -COO-, A-CONH-, A- CONA -, Ph-CONA-, N3, NH2, N02, CN, COOH, COOA, CONH2, CONHA, CON (A) 2, O-allyl, O-propargyl and / or 0-benzyl, Ph means unsubstituted phenyl or mono, -di or trisubstituted with A, OA, OH or Hal, R1 means Hal, -C = CH, -C = CA, OH or OA, A means unbranched, branched or cyclic alkyl with 1-10 C atoms, wherein also 1-7 H atoms may be replaced by F and / or chlorine, Hal means F, Cl, Br or I, n means 0, 1, 2 or 3, as well as their salts 19. Intermediates according to claim 18, characterized in that XYDE means CH = CH-CH = CH, N = CH-CH = CH, CH = N-CH = CH, CH = CHN = CH, CH = CH-CH = N, N = CH-N = CH, CH = N-CH = N, in do The H atoms of the -CH- groups may be substituted with Hal, OH and / or OA, R1 means Hal, A means unbranched alkyl, branched cyclic q with 1-10 C atoms, wherein also 1-7 H atoms can be replaced by F and / or chlorine, Hal means F, Cl, Br or I, as well as their salts.