EP1385818A2 - Derives de biurethane - Google Patents

Derives de biurethane

Info

Publication number
EP1385818A2
EP1385818A2 EP02722151A EP02722151A EP1385818A2 EP 1385818 A2 EP1385818 A2 EP 1385818A2 EP 02722151 A EP02722151 A EP 02722151A EP 02722151 A EP02722151 A EP 02722151A EP 1385818 A2 EP1385818 A2 EP 1385818A2
Authority
EP
European Patent Office
Prior art keywords
oxo
solvates
formula
stereoisomers
mixtures
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02722151A
Other languages
German (de)
English (en)
Inventor
Werner Mederski
Bertram Cezanne
Dieter Dorsch
Christos Tsaklakidis
Johannes Gleitz
Christopher Barnes
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1385818A2 publication Critical patent/EP1385818A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to compounds of the formula
  • R 3 H unsubstituted or simply by S0 2 A, S0 2 NHA or
  • X (CH 2 ) n Y is absent or piperidine-1, 4-diyl, z CH or N,
  • CONHA CONA 2
  • NACHO NHCOA
  • NACOA NHCOA
  • NHS0 2 A NHCHO, NHCOA, NACOA, NHS0 2 A,
  • NASO 2 A CHO, COA, S0 2 NH 2 , S0 2 NHA or S0 2 NA 2 substituted phenyl,
  • CONH 2 CONHA, CONA 2 , NHCHO, NACHO, NHCOA, NACOA,
  • NHSO 2 A, NAS0 2 A, CHO, COA, S0 2 NH 2 , S0 2 NHA or S0 2 NA 2 can be substituted,
  • a unbranched or branched alkyl having 1 -6 C atoms, wherein one or two CH 2 groups by O or S atoms and / or by -CH CH groups and / or 1 -7 H atoms by F may be replaced, Hai F, CI, Br or I, n mean 0, 1 or 2, and their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios.
  • the invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability.
  • 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 claudication intermittently.
  • the compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VI la, factor IXa and thrombin in the blood coagulation cascade.
  • Aromatic amidine derivatives with antithrombotic activity are known, for example, from EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO 00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO 00/71515 or WO 00/71516 known.
  • Cyclic guanidines for the treatment of thromboembolic diseases are described, for example, in WO 97/08165.
  • Aromatic heterocycles with factor Xa inhibitory activity are, for example known from WO 96/10022. Substituted N - [(aminoiminomethyl) phenylalkyl] azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
  • the antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory action against the activated coagulation protease, known under the name factor Xa, or to the inhibition of other activated serine proteases such as factor 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 disorders. However, inhibition of thrombin can inhibit fibrin formation involved in thrombus formation. The measurement of the inhibition of thrombin can e.g. using the method of G.F. Cousins et al. in Circulation 1996, 94, 1705-1712.
  • Inhibition of factor Xa can thus prevent thrombin from being formed.
  • the compounds of formula I according to the invention and their salts interfere with the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombi.
  • the inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods.
  • a suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.
  • the measurement of the inhibition of factor Xa can e.g. using the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.
  • the coagulation factor VIa initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of the factor X to factor Xa. Inhibition of factor VIIa thus prevents the formation of factor Xa and thus the subsequent formation of thrombin.
  • the inhibition of the factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be carried out according to customary in vitro or in vivo methods.
  • Coagulation factor IXa is generated in the internal coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed.
  • the inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is 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.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angiopiasty, intermittent claudication, venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina and thrombosis-based stroke.
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angiopiasty, intermittent claudication, venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial ischemia, unstable angina and thrombosis-based stroke.
  • the compounds according to the invention are also used for the treatment or prophylaxis of atherosclerotic diseases such as coronary arterial disease, cerebral arterial disease or peripheral arterial disease.
  • the compounds are also used in combination with other thrombolytics for myocardial infarction, as well as prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angiopiasty (PTCA) and coronary bypass surgery.
  • PTCA percutaneous transluminal angiopiasty
  • the compounds of the invention are also used for
  • the compounds are also used in the cleaning of
  • Blood coagulation contributes significantly to the course of the disease or is a source of secondary pathology, such as cancer including metastasis, inflammatory diseases including arthritis and diabetes.
  • the compounds 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 according to claim 1 and their salts, characterized in that
  • R 2 , R 3 , X, Y and Z have the meaning given in claim 1, and / or convert a base or acid of the formula I into one of their salts.
  • the invention also relates to the optically active forms
  • Solvates are e.g. Mono- or dihydrates or
  • Prodrug derivatives are understood with z. B. alkyl or acyl groups,
  • 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.
  • 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-dimethylpropyi, 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,
  • Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl,
  • Alkylene preferably means methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched alkylene.
  • -COA acyl
  • acyl preferably means acetyl, propionyl, but also butyryl
  • Pentanoyl hexanoyl or e.g. Benzoyl.
  • Ph means phenyl, Me methyl, Et ethyl, Hai preferably means F, Cl or Br, but also I.
  • R 1 is preferably H, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms,
  • R 2 is preferably H, F or Cl.
  • R 3 is preferably simply substituted by S0 2 A or phenyl
  • Ar means e.g. unsubstituted phenyl, naphthyl or biphenyl, further preferably e.g. by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, sulfonamido , Methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl mono-, di
  • Ar particularly preferably denotes, for example, phenyl which is unsubstituted or substituted once or twice by shark, A, OH or methoxy. Het means, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl,
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 1 -, 2- or 3-pyrrolidinyl, tetrahydro-1 -, -2 - or -4-imidazolyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1 -, -3- or -4-pyr
  • Dihydro-2H-1,5-benzodioxepin-6- or -7-yl further preferably 2,3-dihydro-benzofuranyl or 2,3-dihydro-2-oxo-furanyl.
  • Het preferably means a mononuclear saturated or unsaturated heterocycle having 1 to 2 N and / or O atoms, which can be unsubstituted or mono- or disubstituted by carbonyl oxygen, OH or OA.
  • Het means in particular a mononuclear saturated, unsaturated or aromatic heterocycle having 1 to 2 N and / or O atoms which is mono- or disubstituted by carbonyl oxygen.
  • the compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these forms.
  • the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be identified by the following
  • R 2 is H
  • R 3 is simply phenyl or het substituted by SO 2 A or S0 2 NH 2 ;
  • R 3 is simply substituted by S0 2 A or S0 2 NH 2 phenyl or het, het is a mononuclear saturated or unsaturated heterocycle having 1 to 2 N and / or O atoms which is unsubstituted or mono- or disubstituted by carbonyl oxygen, OH or OA can be substituted mean;
  • R 3 is simply substituted by S0 2 A or S0 2 NH 2 phenyl or het, het pyridyl, 2-oxopiperidin-1 -yl, 2-oxopyrrolidin-1 -yl, 2-oxo-
  • Ig Het denotes a mononuclear saturated or unsaturated heterocycle having 1 to 2 N and / or 0 atoms, which may be unsubstituted or mono- or disubstituted by carbonyl oxygen, OH or OA;
  • 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 reaction is usually carried out in an inert solvent.
  • 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);
  • Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene
  • 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.
  • 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.
  • Amides such as acetamide, dimethylacetamide or dimethyl
  • esters can be saponified, for example, with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 °.
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • So inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarbonate, sulfonic or Sulfuric acids, e.g.
  • Salts with physiologically unacceptable acids for example picrates, can be used for the isolation and / or purification of the compounds of the formula I.
  • compounds of the formula I with bases for example sodium or potassium hydroxide or carbonate
  • bases for example sodium or potassium hydroxide or carbonate
  • physiologically harmless organic bases e.g. Ethanolamine can be used.
  • 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.
  • the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or can already be used as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active release agent.
  • Suitable release agents are, for example, optically active acids, such as the R and S forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (eg N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • Chromatographic separation of enantiomers with the aid of an optically active separating agent is also advantageous.
  • an optically active separating agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers fixed on silica gel
  • Aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile e.g. in a ratio of 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 preparation of pharmaceutical preparations, 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.
  • the invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.
  • Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin , Carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly.
  • Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions for parenteral use, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for which topical application ointments, creams or powder or as a nasal spray.
  • the new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables.
  • the specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, for example one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, for example one or more vitamins.
  • the compounds of the formula I and their physiologically acceptable salts can be used to combat and prevent thrombo-embolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angiopiasty, intermittent claudication, tumors, tumor diseases and / or tumor metastases be used.
  • thrombo-embolic diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angiopiasty, intermittent claudication, tumors, tumor diseases and / or tumor metastases be used.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a variety of factors, for example on the effectiveness of the particular compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. Oral application is preferred.
  • the invention furthermore relates to medicaments comprising at least one compound of the formula I and / or their pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
  • the invention also relates to a set (kit) consisting of separate packs of
  • the set contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules.
  • suitable containers such as boxes or boxes, individual bottles, bags or ampoules.
  • the set can e.g. separate
  • Derivatives, solvates and stereoisomers, including their mixtures in all proportions, and an effective amount of another active pharmaceutical ingredient are dissolved or in lyophilized form.
  • 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 angiopiasty, intermittent claudication, tumors, tumor diseases and / or tumor metastases, in combination with at least one other active pharmaceutical ingredient.
  • Ph phenyl
  • R 2 H
  • N- (4-Chlorophenylaminocarbonyl) -N '- [4- (2-oxo-1-piperidyl) phenylaminocarbonyl] -N'- ⁇ henylhydrazine 1.1 A solution of 9.83 g of phenylhydrazine in 100 ml of THF is mixed with a solution of 15.35 g of 4-chlorophenyl isocyanate in 50 ml of THF under a nitrogen atmosphere and heated under reflux for 2 hours: after conventional work-up, 25.1 g are obtained N- (4-chlorophenylaminocarbonyl) -N'-phenylhydrazine ("AA"), El 277, m.p. 187-189.
  • AA N- (4-chlorophenylaminocarbonyl) -N'-phenylhydrazine
  • 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.
  • 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.
  • a solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH 2 P0 • 2 H 0, 28.48 g of Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml twice distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.
  • Example E tablets A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.
  • Example F coated tablets
  • Example E tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.
  • Example G capsules
  • each capsule contains 20 mg of the active ingredient.
  • a solution of 1 kg of active ingredient of the formula I in 60 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

De nouveaux composés de formule (I), dans laquelle X, Y, Z, R, R<1>, R<2> et R<3> ont la signification indiquée dans la revendication 1, sont des inhibiteurs du facteur de coagulation Xa et peuvent être utilisés pour la prophylaxie et/ou la thérapie de maladies thromboemboliques ainsi que le traitement de tumeurs.
EP02722151A 2001-03-20 2002-02-27 Derives de biurethane Withdrawn EP1385818A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10113402 2001-03-20
DE10113402A DE10113402A1 (de) 2001-03-20 2001-03-20 Biurethanderivate
PCT/EP2002/002095 WO2002074735A2 (fr) 2001-03-20 2002-02-27 Derives de biurethane

Publications (1)

Publication Number Publication Date
EP1385818A2 true EP1385818A2 (fr) 2004-02-04

Family

ID=7678165

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02722151A Withdrawn EP1385818A2 (fr) 2001-03-20 2002-02-27 Derives de biurethane

Country Status (10)

Country Link
US (1) US6943179B2 (fr)
EP (1) EP1385818A2 (fr)
JP (1) JP2004531494A (fr)
CN (1) CN1498206A (fr)
CA (1) CA2441427A1 (fr)
DE (1) DE10113402A1 (fr)
HU (1) HUP0303512A2 (fr)
MX (1) MXPA03008394A (fr)
WO (1) WO2002074735A2 (fr)
ZA (1) ZA200308060B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1558606A4 (fr) * 2002-10-02 2008-05-07 Bristol Myers Squibb Co Diaminoalkyle contenant du lactame, acides amines beta, acides amines alpha et leurs derives utilises en tant qu'inhibiteurs du facteur xa
DE10302500A1 (de) 2003-01-23 2004-07-29 Merck Patent Gmbh Carbonsäureamidderivate
US7205318B2 (en) * 2003-03-18 2007-04-17 Bristol-Myers Squibb Company Lactam-containing cyclic diamines and derivatives as a factor Xa inhibitors
MXPA05010444A (es) 2003-04-03 2005-11-04 Merck Patent Gmbh Compuestos de carbonilo.
KR20050109617A (ko) 2003-04-03 2005-11-21 메르크 파텐트 게엠베하 혈전증 치료용 응집 인자 ｘａ 저해제로서의피라졸리딘-１,２-디카르복실디페닐아미드 유도체
CA2550012A1 (fr) * 2003-12-17 2005-06-30 Takeda Pharmaceutical Company Limited Derives d'uree, processus de production correspondant et utilisation
DE102004004731A1 (de) * 2004-01-30 2005-08-18 Merck Patent Gmbh Harnstoffderivate
US7371743B2 (en) * 2004-02-28 2008-05-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2197364A1 (fr) * 1996-02-15 1997-08-16 Toshikazu Suzuki Compose phenolique et methode de preparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02074735A2 *

Also Published As

Publication number Publication date
CA2441427A1 (fr) 2002-09-26
DE10113402A1 (de) 2002-09-26
MXPA03008394A (es) 2004-01-29
US20040097550A1 (en) 2004-05-20
JP2004531494A (ja) 2004-10-14
WO2002074735A3 (fr) 2003-11-27
HUP0303512A2 (hu) 2004-01-28
WO2002074735A2 (fr) 2002-09-26
US6943179B2 (en) 2005-09-13
CN1498206A (zh) 2004-05-19
ZA200308060B (en) 2004-07-23

Similar Documents

Publication Publication Date Title
EP1633346B1 (fr) Derives d&#39;acide pyrrolidine-1,2-dicarboxylique-1- (4-ethinyl-phenyl)-amide|-2- (phenyl)-amide| utilises comme inhibiteurs des facteurs de coagulation xa et viia pour le traitement de thromboses
DE10102322A1 (de) Phenylderivate
EP1341755A1 (fr) Derives d&#39;amides d&#39;acides carboxyliques et leur utilisation dans le traitement de troubles thrombo-emboliques et de tumeurs
DE10112768A1 (de) Phenylderivate 3
WO2004002477A1 (fr) Derives de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(thioxo-heterocyclyl)-phenyl-amide, derives d&#39;imino-heterocyclyle correspondants et composes derives servant d&#39;inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses
EP1562939B1 (fr) Carboxamides
EP1385818A2 (fr) Derives de biurethane
DE10117823A1 (de) Oxalsäurederivate
EP1414456B1 (fr) Derives de phenyle en tant qu&#39;inhibiteurs du facteur xa
EP1441726A1 (fr) Derives d&#39;amide d&#39;acide phenoxy-n-&#39;4-(isothiazolidine-1,1-dioxyde-2-yl)-phenyl-valerianique et autre composes servant d&#39;inhibiteurs du facteur de coagulation xa pour le traitement de troubles thromboemboliques et de tumeurs
WO2003084533A1 (fr) N-`4-(2-imino-pyrrolidin-1-yl)phenyl!-acetemide et derives de piperidine correspondant servant d&#39;inhibiteurs de facteur xa pour traiter des maladies thromboemboliques
WO2002006269A1 (fr) Derives d&#39;aminoacide cycliques
WO2004065369A1 (fr) Derives d&#39;amide d&#39;acide carboxylique et utilisation de ces composes en tant qu&#39;inhibiteurs du facteur xa
WO2002008177A2 (fr) Derives d&#39;acide 1-amino-1,1-dialkylcarboxylique substitues en n
WO2003093235A1 (fr) Amides d&#39;acide carboxylique servant d&#39;inhibiteurs du facteur de coagulation xa
DE10110325A1 (de) Phenylderivate 2
EP1549304A1 (fr) Amides heterocycliques et leur utilisation dans le traitement de maladies thromboemboliques et de tumeurs
WO2003074479A1 (fr) Derives de semicarbazides et leur utilisation en tant qu&#39;antithrombotiques
EP1399449A1 (fr) Derives d&#39;hydrates de carbone
EP1633745A1 (fr) Derives d&#39;aroyl-semicarbazide pour lutter contres les maladies thromboemboliques
DE10218974A1 (de) Carnonsäureamide
WO2002010127A1 (fr) Derives d&#39;acetamide et leur utilisation en tant qu&#39;inhibiteurs du facteur de coagulation xa et viia
DE10236868A1 (de) Carbonsäureamide
EP1309573A1 (fr) Derives d&#39;urethane

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030721

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20060901