WO2000012479A1 - Derives de la 2-oxo-2h-choline - Google Patents

Derives de la 2-oxo-2h-choline Download PDF

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Publication number
WO2000012479A1
WO2000012479A1 PCT/EP1999/005315 EP9905315W WO0012479A1 WO 2000012479 A1 WO2000012479 A1 WO 2000012479A1 EP 9905315 W EP9905315 W EP 9905315W WO 0012479 A1 WO0012479 A1 WO 0012479A1
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WIPO (PCT)
Prior art keywords
methyl
oxo
quinoline
amidino
formula
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Application number
PCT/EP1999/005315
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German (de)
English (en)
Inventor
Horst Juraszyk
Hanns Wurziger
Dieter Dorsch
Hans-Peter Buchstaller
Sabine Bernotat-Danielowski
Guido Melzer
Soheila Anzali
Werner Mederski
Joachim Gante
Original Assignee
Merck Patent Gmbh
GANTE, Helga
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, GANTE, Helga filed Critical Merck Patent Gmbh
Priority to KR1020017002261A priority Critical patent/KR20010072862A/ko
Priority to PL99346045A priority patent/PL346045A1/xx
Priority to BR9913140-4A priority patent/BR9913140A/pt
Priority to AU51641/99A priority patent/AU5164199A/en
Priority to EP99936606A priority patent/EP1107954A1/fr
Priority to JP2000567512A priority patent/JP2002523494A/ja
Priority to SK265-2001A priority patent/SK2652001A3/sk
Priority to CA002342230A priority patent/CA2342230A1/fr
Publication of WO2000012479A1 publication Critical patent/WO2000012479A1/fr
Priority to NO20010996A priority patent/NO20010996L/no
Priority to HK02102249.3A priority patent/HK1042478A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • 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
    • 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
    • A61P9/10—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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • 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
    • C07D413/10—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 carbon chain containing aromatic 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention relates to compounds of the formula
  • R, R 1 are each independently H, A, - (CH 2 ) m -R, - (CH 2 ) m -OA or - (CH 2 ) m -Ar,
  • R b H, A or NH 2l Ar unsubstituted or mono-, di- or triple by A, cycloalkyl with 3-6 C atoms, OH, OA, shark, CN, N0 2 , CF 3 , NH 2 , NHA, NA 2 , pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, S0 2 NH 2 , S0 2 NHA, S0 2 NA 2 , - (CH 2 ) n -NH 2 , - (CH 2 ) n -NHA, - (CH 2 ) n -NA 2 , -0- (CH 2 ) n -NH 2 , -0- (CH 2 ) n -NHA, -0- (CH 2 ) ⁇ -NA 2 , -0- (CH 2 ) m -0- or R 5 substituted phenyl, naphthyl or biphenyl,
  • X is absent, alkylene with 1-4 C atoms or carbonyl
  • Y is absent, NH, O or S
  • the invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates of these compounds.
  • 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 pecto ⁇ s, restenosis after angioplasty and intermittent claudication.
  • the compounds of the formula I according to the invention can furthermore be inhibitors of the coagulation factors factor VIIa, factor IXa and thrombin of the blood coagulation cascade.
  • Aromatic amidine derivatives with antithrombotic activity are known, for example, from EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are described, for example, in WO 97/08165. Aromatic heterocycles with factor Xa inhibitory activity are known, for example, from WO 96/10022. Substituted N - [(aminoimino- methyl) 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 of 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. An inhibition of thrombin can, however, in the
  • Inhibit thrombus formation involved fibrin 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 e.g. by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.
  • the measurement of the inhibition of factor Xa can e.g. using the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.
  • the coagulation factor 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 formation of factor Xa and thus the subsequent formation of thrombin.
  • the inhibition of the factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods.
  • a common method for measuring the inhibition of factor VIIa is e.g. by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.
  • Coagulation factor IXa is generated in the intrinsic coagulation cascade and is also involved in the activation of factor X to factor Xa. Inhibition of factor IXa can therefore otherwise prevent factor Xa from being formed.
  • the inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable method is e.g. by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.
  • the compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for combating and preventing thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate .
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and claudication intermediate .
  • the invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that
  • Protective group sets free amino group, or
  • A means alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • A is preferably methyl, furthermore
  • Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Alkylene preferably means methylene, ethylene, propylene or butylene, furthermore branched alkyl cycles.
  • COA is acyl and preferably means formyl, acetyl, propionyl, but also butyryl, pentanoyl or hexanoyl.
  • R denotes H, A, - (CH 2 ) m -R 4 , - (CH 2 ) m -OA or - (CH 2 ) m -Ar, preferably H, A,
  • R denotes H, A, - (CH 2 ) m -R 4 , - (CH 2 ) m -OA or - (CH 2 ) m -Ar, preferably H, A, -CH 2 -R 4 or R 4 , in particular R 1 preferably denotes H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2 -CONH 2 , COOH or COOA, very particularly preferably H, A or COOH.
  • R 2 preferably denotes Ar, particularly preferably phenyl substituted simply by R 5 , very particularly preferably phenyl substituted simply by amidino.
  • R 3 is Ar, preferably unsubstituted or mono-, di- or trisubstituted by A, OA, shark, CN, CF 3 or unsubstituted or mono- or disubstituted by cycloalkyl with 3-6 C atoms, OH, NH 2 , NHA, NA 2 , pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, S0 2 NH 2l S0 2 NHA, S0 2 NA 2 , - (CH 2 ) n -NH 2 , - (CH 2 ) n -NHA , - (CH 2 ) n -NA 2 , -0- (CH 2 ) n -NH 2 , -O- (CH 2 ) n -NHA, -0- (CH 2 ) n -NA 2 , or R 5 substituted Phenyl, benzodioxol-5-yl, naphthyl or bi
  • Preferred substituents for biphenyl are amidino, fluorine, S0 2 NH 2 or S0 2 NHA.
  • Ar means unsubstituted or mono-, di- or triple by A, cycloalkyl with 3-6 C atoms, OH, OA, shark, CN, N0 2 , CF 3 , NH 2 , NHA, NA 2 , pyrrolidin-1-yl , Piperidin-1-yl, benzyloxy, S0 2 NH 2 , S0 2 NHA, S0 2 NA 2 , phenylsulfonamido, - (CH 2 ) n -NH 2 , - (CH 2 ) n -NHA, - (CH 2 ) n -NA 2 , -0- (CH 2 ) n -
  • Ar preferably denotes unsubstituted phenyl, naphthyl or biphenyl, further preferably e.g. by A, cyclopentyl, cyclohexyl, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyan, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidin-1-yl , Piperidin-1-yl, benzyloxy, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, aminomethyl,
  • Ar therefore preferably means, for example, 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-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p- (N, N -Dimethylamin
  • R 4 preferably means, for example, COOH, COOA or CONH 2 .
  • X is preferably absent, for example, carbonyl or alkylene, especially methylene or -CH (CH 3 ) -.
  • Y is preferably O.
  • n is preferably 0 or 1, and also 2 or 3.
  • the compounds of the formula I can have one or more chiral centers and therefore exist in various stereoisomeric forms.
  • Formula I encompasses all of these forms. Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
  • R 1 is H, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2 -CONH 2 , COOH or COOA; in Ic RH, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2 -CONH 2 ,
  • R 2 is simply phenyl substituted by R 5 ; in Id RH, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2 -CONH 2 ,
  • R 3 is simply substituted by CN or R 5 phenyl or
  • R 3 is simply substituted by CN or R 5 phenyl or
  • R 3 is simply substituted by CN or R 5 phenyl or
  • n 0 or 1; in Ig RH, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2 -CONH 2 ,
  • R 3 is simply substituted by CN or R 5 phenyl or
  • n 0 or 1
  • X is absent, alkylene or carbonyl
  • Y is absent or O; RH, A, -CH 2 -COOA, -CH 2 -COOH, -CH 2 -CONH 2 ,
  • R 2 is phenyl which is simply substituted by R 5 ,
  • R 3 is simply substituted by CN or R 5 phenyl or naphthyl, once or twice by R 5 , S0 2 NH 2 , S0 2 NHA or
  • the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.
  • Compounds of formula I can preferably be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.
  • Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to 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- Atoms which are connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group and / or those which replace an H- Atoms of a hydroxyl group carry a hydroxyl protective group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxyl protective group.
  • Preferred starting materials are also the oxadiazole derivatives, which can be converted into the corresponding amidino compounds.
  • the amidino group can be released from its oxadiazole derivative, for example, by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel) can be split off.
  • a catalyst e.g. Raney nickel
  • Suitable solvents are those specified below, in particular alcohols such as methanol or ethanol, organic acids such as acetic acid or propionic acid or mixtures thereof.
  • the hydrogenolysis is generally carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar.
  • the introduction of the oxadiazole group succeeds e.g. by reaction of the cyan compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformate, N, N'-carbonyldiimidazole or acetic anhydride.
  • amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule is. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms.
  • acyl group is to be understood in the broadest sense in connection with the present process.
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbo- benzoxy "), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr.
  • Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • hydroxyl protecting group is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups.
  • the nature and size of the hydroxyl protective groups is 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. Examples of hydroxy protecting groups include Benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-
  • Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1.
  • the reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).
  • the groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 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, especially 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. well on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.
  • Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as
  • Trichlorethylene 1, 2-dichloroethane, carbon tetrachloride, trifluoromethylbenzene, chloroform or dichloromethane
  • Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol
  • Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane
  • Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone
  • Amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); Nitriles such as acetonitrile
  • Sulfoxides such as dimethyl sulfoxide (DM
  • the conversion of a cyano group into an amidino group takes place by reaction with, for example, hydroxylamine and subsequent reduction of the N- Hydroxyamidine with hydrogen in the presence of a catalyst such as Pd / C.
  • ammonia can also be added to a nitrile.
  • the addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H 2 S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH 3 I, which in turn contains NH 3 reacts to the amidine, b) the nitrile is converted to the corresponding imidoester with an alcohol, for example ethanol in the presence of HCl, and treated with ammonia, or c) the nitrile is reacted with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.
  • an alkylating agent for example CH 3 I
  • R (R), R 1 , R 2 and / or R 3 is converted into one or more R, R 1 , R 2 , and / or R 3 , for example by acylating an amino group or nitro groups (e.g. by Hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanol) reduced to amino groups.
  • acylating an amino group or nitro groups e.g. by Hydrogenation on Raney nickel or Pd carbon in an inert solvent such as methanol or ethanol
  • 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 °.
  • free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and
  • 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.
  • an acid for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation.
  • 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.
  • compounds of formula I with bases can be added to the corresponding metal, in particular alkali metal or alkaline earth metal, or to the corresponding ones
  • 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 (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers fixed on silica gel) is also advantageous.
  • Suitable solvents are aqueous or alcoholic solvent mixtures such as hexane / isopropanol / acetonitrile, for example 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 production of pharmaceutical preparations, in particular by a non-chemical route. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active ingredients.
  • the invention further relates to 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, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions for parenteral use, wise oily or aqueous solutions, also suspensions, emulsions or implants, for topical application of ointments, creams or powders.
  • 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 formula I and their physiologically acceptable salts can be used in the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
  • 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 dose is preferably between about 0.02 and 10 mg / kg body weight.
  • the specific dose for each patient depends on a wide 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 and combination of drugs and severity of the respective disease to which the therapy applies. Oral application is preferred.
  • Fluoro-4-nitrobenzene with tetrabutylammonium fluoride in THF is obtained analogously to Synthesis 1988, 378-379, the compound 3- (4-nitrophenoxy) benzonitrile ("AB"), mp 113-114 °. 90.4 g of sodium hydrogen carbonate and 350 ml are added to a suspension of 78.4 g of "AB” and 68.0 g of hydroxylammonium chloride in 1 L of methanol
  • amidine derivatives are obtained analogously by hydrogenation with Raney nickel
  • carboxylic acid esters can first be alkylated, then hydrogenated to the amidino derivatives and finally saponified.
  • Example 7 The other compounds mentioned in Example 7 are also obtained analogously.
  • Sulfuric acid is obtained from 1-acetoxy-3-methyl-4-nitro-benzene. Subsequent bromination with NBS under irradiation gives 1-acetoxy-3-dibromomethyl-4-nitro-benzene, mp 130-131 °, El 353.
  • 3-Formyl-4 is obtained by reaction with sodium formate in water and ethanol -nitro-phenol, mp 145-146 °, El 167, which by reaction with benzyl bromide with potassium carbonate addition in DMF in 1-benzyloxy-3-formyl-4-nitro-benzene, mp 120-121 °, El 257 is converted.
  • the regioisomeric carboxylic acid derivatives (3-carboxy -...) from Example 3 are obtained as follows: a) By reacting 4-methyl-3-nitro-phenol with acetic anhydride and sulfuric acid, 1-acetoxy-4-methyl-3-nitro-benzene is obtained. Subsequent bromination with NBS under irradiation gives 1-acetoxy-4-dibromomethyl-3-nitro-benzene.
  • the regioisomeric 7-isomers are obtained analogously starting from 3-methyl-4-nitro-phenol.
  • Example 16 Analogously to Example 4, the compound 1- (7-cyano-naphthalin-2-ylmethyl) -7- (3-cyano-phenoxy] -3-ethoxycarbonyl-2-oxo-2H-quinoline, mp. 183.5 ° and therefrom 1- [7- (N-hydroxyamidino) - naphthalen-2-ylmethyl] -7- [3- (N-hydroxyamidino) phenoxy] -3-carboxy-2-oxo-2H-quinoline, mp .> 300 °.
  • Example 16 Example 16
  • 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 jar 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 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 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.

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

Abstract

L'invention concerne de nouveaux composés de formule (I), dans laquelle X, Y, R, R?1, R2, R3¿ et n ont la signification indiquée dans la revendication 1. Ces composés, qui sont des inhibiteurs du facteur de coagulation Xa, peuvent être utilisés pour la prophylaxie et/ou le traitement des maladies thromboemboliques.
PCT/EP1999/005315 1998-08-29 1999-07-26 Derives de la 2-oxo-2h-choline WO2000012479A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
KR1020017002261A KR20010072862A (ko) 1998-08-29 1999-07-26 2-옥소-2ｈ-퀴놀린 유도체
PL99346045A PL346045A1 (en) 1998-08-29 1999-07-26 2-oxo-2h
BR9913140-4A BR9913140A (pt) 1998-08-29 1999-07-26 Derivados 2-oxo-2h-quinolina
AU51641/99A AU5164199A (en) 1998-08-29 1999-07-26 2-oxo-(2h)-quinoline derivatives
EP99936606A EP1107954A1 (fr) 1998-08-29 1999-07-26 DERIVES DE LA 2-OXO-$i(2H)-CHOLINE
JP2000567512A JP2002523494A (ja) 1998-08-29 1999-07-26 ２−オキソ−２ｈ−キノリン誘導体
SK265-2001A SK2652001A3 (en) 1998-08-29 1999-07-26 2-oxo-i(2h)-quinoline derivatives
CA002342230A CA2342230A1 (fr) 1998-08-29 1999-07-26 Derives de la 2-oxo-2h-choline
NO20010996A NO20010996L (no) 1998-08-29 2001-02-27 2-okso-2H-kinolinderivater
HK02102249.3A HK1042478A1 (zh) 1998-08-29 2002-03-25 2-氧代-2h-喹啉衍生物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19839499.3 1998-08-29
DE19839499A DE19839499A1 (de) 1998-08-29 1998-08-29 2-Oxo-2H-chinolinderivate

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JP (1) JP2002523494A (fr)
KR (1) KR20010072862A (fr)
CN (1) CN1315942A (fr)
AR (1) AR021782A1 (fr)
AU (1) AU5164199A (fr)
BR (1) BR9913140A (fr)
CA (1) CA2342230A1 (fr)
DE (1) DE19839499A1 (fr)
HK (1) HK1042478A1 (fr)
HU (1) HUP0103212A3 (fr)
ID (1) ID27863A (fr)
NO (1) NO20010996L (fr)
PL (1) PL346045A1 (fr)
SK (1) SK2652001A3 (fr)
WO (1) WO2000012479A1 (fr)
ZA (1) ZA200102565B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2743074C2 (ru) 2014-08-01 2021-02-15 Нуэволюшон А/С Соединения, активные по отношению к бромодоменам

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JPS51128980A (en) * 1975-04-30 1976-11-10 Otsuka Pharmaceut Co Ltd Process for preparing 3,4- dihydrocarbostyril derivatives
US4070470A (en) * 1974-06-24 1978-01-24 Otsuka Pharmaceutical Co., Ltd. Platelet aggregation inhibiting carbostyrils, their compositions and method of use
DE2651581A1 (de) * 1976-11-12 1978-05-18 Merck Patent Gmbh Chinolonderivate und verfahren zu ihrer herstellung
AT347956B (de) * 1976-03-18 1979-01-25 Ici Ltd Verfahren zur herstellung von neuen chinol-2- on-4-yl-alkansaeuren und von deren basenadditionssalzen
WO1992004327A1 (fr) * 1990-09-07 1992-03-19 Schering Corporation Composes antiviraux et composes antihypertenseurs
EP0540051A1 (fr) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Dérivés aromatiques à fonction amidines et leurs sels
EP0561252A1 (fr) * 1992-03-16 1993-09-22 MERCK PATENT GmbH Dérivés de 2-oxoquinoline comme antagoniste d'angiotensine II
US5378694A (en) * 1990-09-07 1995-01-03 Schering Corporation Acyl and alkoxy substituted quinolines
WO1996010022A1 (fr) * 1994-09-26 1996-04-04 Zeneca Limited Derives aminoheterocycliques en tant qu'agents antithrombotiques ou anticoagulants
WO1996040679A1 (fr) * 1995-06-07 1996-12-19 Rhône-Poulenc Rorer Pharmaceuticals Inc. Composes d'(acide sulfinique, acide sulfonique, sulfonylamino ou sulfinylamino) n-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide substitues
EP0757039A1 (fr) * 1995-08-02 1997-02-05 MERCK PATENT GmbH Antagonistes du récepteur d'endothéline
WO1997008165A1 (fr) * 1995-08-23 1997-03-06 Boehringer Mannheim Gmbh Nouvelles guanidines cycliques, procede de production correspondant et medicaments
WO1999030696A1 (fr) * 1997-12-12 1999-06-24 Orion Corporation Methode de prevention et de traitement de la sideration myocardique

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Publication number Priority date Publication date Assignee Title
US4070470A (en) * 1974-06-24 1978-01-24 Otsuka Pharmaceutical Co., Ltd. Platelet aggregation inhibiting carbostyrils, their compositions and method of use
DE2611824A1 (de) * 1975-03-20 1976-09-30 Ici Ltd Chinolonderivate
JPS51128980A (en) * 1975-04-30 1976-11-10 Otsuka Pharmaceut Co Ltd Process for preparing 3,4- dihydrocarbostyril derivatives
AT347956B (de) * 1976-03-18 1979-01-25 Ici Ltd Verfahren zur herstellung von neuen chinol-2- on-4-yl-alkansaeuren und von deren basenadditionssalzen
DE2651581A1 (de) * 1976-11-12 1978-05-18 Merck Patent Gmbh Chinolonderivate und verfahren zu ihrer herstellung
US5378694A (en) * 1990-09-07 1995-01-03 Schering Corporation Acyl and alkoxy substituted quinolines
WO1992004327A1 (fr) * 1990-09-07 1992-03-19 Schering Corporation Composes antiviraux et composes antihypertenseurs
EP0540051A1 (fr) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Dérivés aromatiques à fonction amidines et leurs sels
EP0561252A1 (fr) * 1992-03-16 1993-09-22 MERCK PATENT GmbH Dérivés de 2-oxoquinoline comme antagoniste d'angiotensine II
WO1996010022A1 (fr) * 1994-09-26 1996-04-04 Zeneca Limited Derives aminoheterocycliques en tant qu'agents antithrombotiques ou anticoagulants
WO1996040679A1 (fr) * 1995-06-07 1996-12-19 Rhône-Poulenc Rorer Pharmaceuticals Inc. Composes d'(acide sulfinique, acide sulfonique, sulfonylamino ou sulfinylamino) n-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide substitues
EP0757039A1 (fr) * 1995-08-02 1997-02-05 MERCK PATENT GmbH Antagonistes du récepteur d'endothéline
WO1997008165A1 (fr) * 1995-08-23 1997-03-06 Boehringer Mannheim Gmbh Nouvelles guanidines cycliques, procede de production correspondant et medicaments
WO1999030696A1 (fr) * 1997-12-12 1999-06-24 Orion Corporation Methode de prevention et de traitement de la sideration myocardique

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

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HUP0103212A3 (en) 2002-06-28
KR20010072862A (ko) 2001-07-31
EP1107954A1 (fr) 2001-06-20
HK1042478A1 (zh) 2002-08-16
PL346045A1 (en) 2002-01-14
NO20010996D0 (no) 2001-02-27
JP2002523494A (ja) 2002-07-30
AU5164199A (en) 2000-03-21
BR9913140A (pt) 2001-05-08
NO20010996L (no) 2001-02-27
HUP0103212A2 (hu) 2002-05-29
ZA200102565B (en) 2002-06-28
SK2652001A3 (en) 2001-09-11
CA2342230A1 (fr) 2000-03-09
CN1315942A (zh) 2001-10-03
ID27863A (id) 2001-04-26
AR021782A1 (es) 2002-08-07
DE19839499A1 (de) 2000-03-02

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