EP1549304A1 - Amides heterocycliques et leur utilisation dans le traitement de maladies thromboemboliques et de tumeurs - Google Patents

Amides heterocycliques et leur utilisation dans le traitement de maladies thromboemboliques et de tumeurs

Info

Publication number
EP1549304A1
EP1549304A1 EP03750577A EP03750577A EP1549304A1 EP 1549304 A1 EP1549304 A1 EP 1549304A1 EP 03750577 A EP03750577 A EP 03750577A EP 03750577 A EP03750577 A EP 03750577A EP 1549304 A1 EP1549304 A1 EP 1549304A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
solvates
mono
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Withdrawn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
EP03750577A
Other languages
German (de)
English (en)
Inventor
Dieter Dorsch
Bertram Cezanne
Werner Mederski
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 EP1549304A1 publication Critical patent/EP1549304A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to compounds of the formula
  • A which can be substituted by OR SR N (R Ar, Het, cycloalkyl, CN, COOR 'or CON (R 2 ) 2 , R 2 H, A, - [C (R 3 ) 2Jn -Ar, - [C (R 3 ) 2 ] n -Het, - [C (R 3 ) 2 ] n -cycloalkyl,
  • T is a mono- or dinuclear saturated, unsaturated or aromatic carbo- or heterocycle with 0 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by shark, A, - [C ( R 3 ) 2 ] ⁇ -Ar,
  • R 2 ' H A, - [C (R 3 ) 2 ] n -Ar ⁇ - [C (R 3 ) 2 ] n -Het' ( - [C (R 3 ) 2 ] n -cycloalkyl, - [C (R 3 ) 2 ] n -N (R 3 ) 2 or - [C (R 3 ) 2 ] n -OR 3 ,
  • R 2 " H, A, - [C (R 3 ) 2 ] n -Ar 'or - [C (R 3 ) 2 ] n -cycloalkyl, - [C (R 3 ) 2 ] n -N (R 3 ) 2 or - [C (R 3 ) 2 ] n -OR 3 ,
  • 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 intermittent claudication.
  • Inhibitors of the coagulation factors factor VI la, factor IXa and thrombin of the blood coagulation cascade are Inhibitors of the coagulation factors factor VI la, factor IXa and thrombin of the blood coagulation cascade.
  • Aromatic amidine derivatives with antithrombotic activity are e.g. from EP 0 540 051 B1, WO 98/28269, WO 00/71508, WO 00/71511, WO 00/71493, WO 00/71507, WO 00/71509, WO 00/71512, WO 00/71515 or WO 00 / 71516 known.
  • Cyclic guanidines for the treatment of thromboembolic diseases are e.g. described in WO 97/08165.
  • Aromatic heterocycles with factor Xa inhibitory activity are e.g. known from WO 96/10022. Substituted N - [(aminoiminomethyl) phenylalkyl] azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
  • Factor Xa is one of the proteases involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of
  • thrombin Prothrombin in thrombin. Thrombin cleaves fibrinogen into fibrin monomers which, after cross-linking, make an elementary contribution to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders. However, inhibiting 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 carried out according to customary in vitro or in vivo
  • Methods are determined.
  • a suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis S90, 63, 220-223.
  • the measurement of the inhibition of factor Xa can, for example, by the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.
  • the coagulation factor Vlla 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 development of factor Xa and thus a subsequent one
  • Thrombin formation The inhibition of the factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods.
  • a common method for measuring factor VIIIa inhibition is e.g. by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.
  • Coagulation factor IXa is generated in the intrinsic coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed.
  • the inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in vitro or in vivo methods. A suitable method is e.g. by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.
  • the compounds according to the invention can furthermore be used for the treatment of tumors, tumor diseases and / or tumor metastases.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the treatment and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, venous thrombosis,131monal 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, further for prophylaxis for reocclusion after thrombolysis, percutaneous transluminal angioplasty (PTCA) and coro-artery bypass surgery.
  • thrombolytics for myocardial infarction
  • prophylaxis for reocclusion after thrombolysis
  • percutaneous transluminal angioplasty PTCA
  • coro-artery bypass surgery coro-artery bypass surgery.
  • the compounds are also used in the cleaning of
  • Source of secondary pathology such as cancer including metastasis, inflammatory diseases including
  • the compounds of the invention are also used to treat migraines (F. Morales-Asin et al., Headache, 40, 2000, 45-47).
  • the compounds of the invention are used in combination with other thrombolytically active compounds, such as the "tissue plasminogen activator" t-PA, modified t-PA, streptokinase or urokinase.
  • t-PA tissue plasminogen activator
  • modified t-PA modified t-PA
  • streptokinase streptokinase
  • urokinase urokinase
  • 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 formula I and their salts and a process for the preparation of compounds of formula I according to claims 1-16 and their pharmaceutically usable derivatives, solvates and stereoisomers, characterized in that
  • R 1 , W, X, Y and T have the meaning given in claim 1,
  • the invention also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • Solvates of the compounds are understood to mean the addition of inert solvent molecules to the compounds, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or alcoholates.
  • Prodrug derivatives are understood with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which in the organism quickly to the effective invention
  • the invention also relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers, for example in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000th
  • mixtures of the compounds of the formula I according to the invention for example mixtures of two diastereomers, for example in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000th
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, more preferably for example Trifluoromethyl.
  • Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl,
  • Alkylene preferably means methylene, ethylene, propylene, butylene, pentylene or hexylene, furthermore branched alkylene.
  • COR 2 means, for example, CHO or -COA.
  • -COA acyl preferably means acetyi, propionyi, and also butyryl,
  • Pentanoyl hexanoyl or e.g. Benzoyl.
  • Ar means, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert.-
  • Ar is preferably, for example, phenyl which is unsubstituted or mono-, di- or trisubstituted by shark, A, OR 2 , SO 2 A, COOR 2 or CN.
  • Ar particularly preferably means, for example, unsubstituted or mono- or disubstituted by shark, A, OA, S0 2 A, S0 2 NH 2; COOR 2 or CN substituted phenyl, such as phenyl, 2-methylsulfonylphenyl, 2-aminosulfonylphenyl,
  • Ar very particularly preferably denotes unsubstituted phenyl, 4-chlorophenyl or 2-methylsulfonylphenyl.
  • Y is preferably Het-diyl or Ar-diyl, particularly preferably unsubstituted or substituted 1, 4- by A, OA, Cl or F
  • Phenylene also pyridine-diyl, preferably pyridine-2,5-diyl or
  • Y means in particular unsubstituted or simply substituted by methyl, ethyl, propyl, Cl or F 1, 3- or 1, 4-phenylene.
  • Het means e.g. 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2 -, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2 -, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazoM-, -4- or -5-yl, 1, 2,4-triazoM-, -3- or 5-yl, 1st - or 5-tetrazolyl, 1, 2,3-oxadiazol-4- or -5-yl, 1, 2,4-oxadiazol-3- or - 5-yl, 1, 3,4-thiadiazol-2- or - 5-yl, 1, 2,4-thiadiazol-3- or -5-yl, 1, 2,3-thi
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2 - or -3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5- pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or - 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-
  • T preferably denotes a mononuclear saturated or unsaturated heterocycle with 1 to 2 N and / or O atoms, which is mono- or disubstituted by carbonyl oxygen.
  • T means in particular piperidin-1-yl, pyrrolidin-1-yl, 1 / - / - pyridin-1-yl, morpholin-4-yl, mono- or disubstituted by carbonony-oxygen,
  • T also preferably denotes pyridinyl, in particular pyridin-4-yl.
  • D preferably denotes thienyl, furyl, simply substituted by shark,
  • R 1 is preferably, for example, H or unsubstituted phenyl, thienyl or alkyl having 1-6 C atoms.
  • R 2 is preferably, for example, H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • n is preferably 0 or 1.
  • m is preferably 2.
  • the compounds of 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 expressed by the following sub-formulas Ia to Im, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • Ib D denotes mono- or disubstituted thienyl ring
  • Ic R 2 denotes H or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; in Id R 1 H or unsubstituted phenyl, thienyl or alkyl with 1-6
  • le X is NH or 0;
  • Ig Y Ar-diyl or Het-diyl
  • R 1 H or unsubstituted phenyl, thienyl or alkyl with 1-6
  • the starting materials can, if desired, also be formed in situ so that they are not isolated from the reaction mixture but immediately reacted further to give the 0 compounds of formula I.
  • the reaction is usually carried out in an inert solvent
  • an acid-binding agent preferably an alkali or
  • a weak acid of the alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium.
  • an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or an excess of the phenol component of the formula II or of the alkylation derivative of the formula III can also be favorable.
  • 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. 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); Nitrites such as acetonitrile
  • Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide
  • 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.
  • Compounds of the formula I can further preferably be obtained by reacting compounds of the formula IV with compounds of the formula V.
  • the reaction is usually carried out in an inert solvent and under conditions as stated above.
  • L is preferably Cl, Br, I or a free or a reactively modified OH group, such as e.g. an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms
  • Activated esters are conveniently formed in situ, e.g. B. by adding HOBt or N-hydroxysuccinimide.
  • the reaction is usually carried out in an inert solvent, in the presence of an acid-binding agent, preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula V.
  • an acid-binding agent preferably an organic base such as DIPEA, triethylamine, dimethylaniline, pyridine or quinoline or an excess of the carboxy component of the formula V.
  • an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali or alkaline earth metals preferably potassium, sodium, calcium or cesium, can be favorable.
  • the reaction time is between a few minutes and 14 days
  • the reaction temperature is between approximately -30 ° and 140 °, normally between -10 ° and 90 °, in particular between approximately 0 ° and approximately 70 °.
  • the above-mentioned are suitable as inert solvents.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and / or hydroxyl groups contain corresponding protected amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom, 0 carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'denotes an amino protective group and / or those which replace the H atom a hydroxy group carry a hydroxy protecting group, e.g. those which correspond to the formula I e, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group.
  • Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable Q after the desired chemical reaction at other locations on the
  • acyl group is related to to understand the present procedure in the broadest sense. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially
  • Alkanoyl such as acetyi, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl like
  • Methoxycarbonyl ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOG (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ
  • Carbobenzoxy 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl like
  • Preferred amino protecting groups are BOC and Mtr, furthermore CBZ,
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction at other points in the
  • hydroxyl protective groups are not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred.
  • hydroxy protecting groups include Benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyi, with benzyl and tert-butyl being particularly preferred.
  • Tetrahydrofuran or dioxane Tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOG, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 °.
  • Hydrogenolytically removable protective groups can, for. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal).
  • a catalyst z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal.
  • Suitable solvents are the above, in particular z. B. alcohols such as methanol or ethanol or amides such as DMF.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B.
  • 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,
  • Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or
  • Glycol ethers such as ethylene glycol monomethyl or monoethyl ether
  • Esters can e.g. are saponified 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, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example
  • Formic acid acetic acid, propionic acid, pivalic acid, diethyl acetic acid,
  • Lactic acid tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethane disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acid, laurylsulfonic acid. Salts with physiologically unacceptable acids, for example picrates, c can be used for the isolation and / or purification of the compounds of the formula I.
  • compounds of formula I with bases can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal, or into the corresponding ammonium salts.
  • physiologically harmless organic bases e.g. Ethanolamine can be used. 5
  • 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 converted into enantiomeric compounds by chemical agents known to the person skilled in the art or physical measures, separated or already used as such in the synthesis.
  • diastereomers are formed from the mixture by reaction with an optically active release agent.
  • Suitable release agents are e.g. optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • Aqueous or alcoholic solvent mixtures such as e.g. Hexane / isopropanol / acetonitrile e.g. in the ratio 82: 15: 3.
  • the invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of a medicament (pharmaceutical preparation), in particular in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention furthermore 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.
  • Organic or inorganic substances in question 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, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, 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 e.g. can be used 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, taste and / or several other active substances, e.g. one or more vitamins.
  • auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances, e.g. one or more vitamins.
  • the compounds of the formula I and their physiologically acceptable salts can be used to combat and prevent thrombo-embolic diseases such as thrombosis, myocardial infarction,
  • Arteriosclerosis inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, migraines, tumors, tumor diseases and / or tumor metastases can be used.
  • the substances according to the invention are generally preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit.
  • the daily dosage is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a variety of factors, such as the effectiveness of the the particular connection used, age, body weight, general health, gender, diet, time and route of administration, rate of excretion,
  • the invention further relates to medicaments comprising at least one compound of the formula I and / or its pharmaceutically usable derivatives, solvates and stereoisomers, including their mixtures in all ratios, and at least one further active pharmaceutical ingredient.
  • the invention is also a set (kit) consisting of separate - j 5 packs of
  • the set contains suitable containers, such as boxes or cartons, individual bottles, bags or ampoules.
  • the set may, for example, separate contain 5 ampoules, each containing an effective amount of a compound of formula I and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, n and dissolved an effective amount of a further medicament active ingredient or is in lyophilized form.
  • the invention furthermore relates to the use of compounds of the formula I and / or their pharmaceutically usable derivatives, 5 solvates and stereoisomers, including their mixtures in all ratios, for the manufacture of a medicament for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty, intermittent claudication, migraine,
  • Tumors, tumor diseases and / or tumor metastases in combination with at least one other active pharmaceutical ingredient.
  • 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 of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH 2 P0 4 • 2 H 2 0, 28.48 g Na 2 HP0 4 • 12 H 2 0 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.
  • Example D ointment
  • 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 sterile. Each ampoule contains 10 mg of active ingredient.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés de formule (I), dans laquelle D, W, X, Y, T et R1 correspondent à la définition donnée dans la revendication 1 de la demande de brevet. Ces composés constituent des inhibiteurs du facteur de coagulation Xa et peuvent être utilisés pour la prévention et/ou le traitement de maladies thromboemboliques et pour le traitement de tumeurs.
EP03750577A 2002-10-10 2003-09-18 Amides heterocycliques et leur utilisation dans le traitement de maladies thromboemboliques et de tumeurs Withdrawn EP1549304A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE2002147226 DE10247226A1 (de) 2002-10-10 2002-10-10 Heterocyclische Amide
DE10247226 2002-10-10
PCT/EP2003/010400 WO2004035039A1 (fr) 2002-10-10 2003-09-18 Amides heterocycliques et leur utilisation dans le traitement de maladies thromboemboliques et de tumeurs

Publications (1)

Publication Number Publication Date
EP1549304A1 true EP1549304A1 (fr) 2005-07-06

Family

ID=32038439

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03750577A Withdrawn EP1549304A1 (fr) 2002-10-10 2003-09-18 Amides heterocycliques et leur utilisation dans le traitement de maladies thromboemboliques et de tumeurs

Country Status (7)

Country Link
US (1) US20060135515A1 (fr)
EP (1) EP1549304A1 (fr)
JP (1) JP2006510604A (fr)
AU (1) AU2003270223A1 (fr)
CA (1) CA2501706A1 (fr)
DE (1) DE10247226A1 (fr)
WO (1) WO2004035039A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105294669B (zh) * 2014-10-24 2019-01-22 山东凯森制药有限公司 一种第十因子抑制剂及其制备方法和应用
GB201712282D0 (en) * 2017-07-31 2017-09-13 Nodthera Ltd Selective inhibitors of NLRP3 inflammasome
KR20210108416A (ko) 2018-12-19 2021-09-02 레오 파마 에이/에스 Il-17의 소분자 조절제로서의 아미노산 아닐라이드

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL115420A0 (en) * 1994-09-26 1995-12-31 Zeneca Ltd Aminoheterocyclic derivatives
GB9823873D0 (en) * 1998-10-30 1998-12-30 Pharmacia & Upjohn Spa 2-ureido-thiazole derivatives,process for their preparation,and their use as antitumour agents
DE10063008A1 (de) * 2000-12-16 2002-06-20 Merck Patent Gmbh Carbonsäureamidderivate
EP1499591A1 (fr) * 2002-04-27 2005-01-26 MERCK PATENT GmbH Amides d'acide carboxylique servant d'inhibiteurs du facteur de coagulation xa

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004035039A1 *

Also Published As

Publication number Publication date
DE10247226A1 (de) 2004-04-22
CA2501706A1 (fr) 2004-04-29
JP2006510604A (ja) 2006-03-30
US20060135515A1 (en) 2006-06-22
AU2003270223A1 (en) 2004-05-04
WO2004035039A1 (fr) 2004-04-29

Similar Documents

Publication Publication Date Title
EP1720844B1 (fr) Derives pyrrolidino-1,2-dicarboxy-1-(phenylamide)-2-(4-(3-oxo-morpholino-4-yl9-phenylamide) et composes similaires pour l'utilisation comme inhibiteurs du facteur xa pour le traitement de maladies thromboemboliques
EP1633346B1 (fr) Derives d'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
EP1341755A1 (fr) Derives d'amides d'acides carboxyliques et leur utilisation dans le traitement de troubles thrombo-emboliques et de tumeurs
EP1558247A1 (fr) Derives de benzimidazole
DE10329457A1 (de) Ethinylprolinderivate
DE10112768A1 (de) Phenylderivate 3
WO2004002477A1 (fr) Derives de 2-(phenyl)-2h-pyrazol-3-acide carboxylique-n-4-(thioxo-heterocyclyl)-phenyl-amide, derives d'imino-heterocyclyle correspondants et composes derives servant d'inhibiteurs des facteurs de coagulation xa et/ou viia dans le traitement de thromboses
EP1562939B1 (fr) Carboxamides
DE10315377A1 (de) Carbonylverbindungen
DE10214832A1 (de) Phenylderivate 4
EP1414456B1 (fr) Derives de phenyle en tant qu'inhibiteurs du facteur xa
DE10155075A1 (de) Cyclische Sulfonamide
WO2005056528A1 (fr) Derives d'amide d'acide carboxylique
DE10302500A1 (de) Carbonsäureamidderivate
WO2002074735A2 (fr) Derives de biurethane
WO2003093235A1 (fr) Amides d'acide carboxylique servant d'inhibiteurs du facteur de coagulation xa
WO2002006269A1 (fr) Derives d'aminoacide cycliques
EP1549304A1 (fr) Amides heterocycliques et leur utilisation dans le traitement de maladies thromboemboliques et de tumeurs
DE10218974A1 (de) Carnonsäureamide
WO2004108718A1 (fr) Derives d'aroyl-semicarbazide pour lutter contres les maladies thromboemboliques
DE10236868A1 (de) Carbonsäureamide
DE10327428A1 (de) Ethinylprolinderivate
WO2003002568A1 (fr) Derives d'hydrates de carbone

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: 20050218

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

DAX Request for extension of the european patent (deleted)
RIN1 Information on inventor provided before grant (corrected)

Inventor name: BARNES, CHRISTOPHER

Inventor name: GLEITZ, JOHANNES

Inventor name: TSAKLAKIDIS, CHRISTOS

Inventor name: MEDERSKI, WERNER

Inventor name: CEZANNE, BERTRAM

Inventor name: DORSCH, DIETER

17Q First examination report despatched

Effective date: 20061030

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: 20080401