WO2000051989A1 - Derives de pyrazol-3-one utilises comme inhibiteurs du facteur xa - Google Patents

Derives de pyrazol-3-one utilises comme inhibiteurs du facteur xa Download PDF

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Publication number
WO2000051989A1
WO2000051989A1 PCT/EP2000/001695 EP0001695W WO0051989A1 WO 2000051989 A1 WO2000051989 A1 WO 2000051989A1 EP 0001695 W EP0001695 W EP 0001695W WO 0051989 A1 WO0051989 A1 WO 0051989A1
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Prior art keywords
formula
compounds
amidino
ylmethyl
group
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PCT/EP2000/001695
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German (de)
English (en)
Inventor
Dieter Dorsch
Horst Juraszyk
Werner Mederski
Christos Tsaklakidis
Hanns Wurziger
Sabine Bernotat-Danielowski
Guido Melzer
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Merck Patent Gmbh
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Priority to CA002364908A priority Critical patent/CA2364908A1/fr
Priority to BR0008608-8A priority patent/BR0008608A/pt
Priority to MXPA01008844A priority patent/MXPA01008844A/es
Priority to AU29165/00A priority patent/AU2916500A/en
Priority to EP00907650A priority patent/EP1157010A1/fr
Priority to JP2000602216A priority patent/JP2002538143A/ja
Priority to KR1020017011000A priority patent/KR20010102428A/ko
Priority to SK1215-2001A priority patent/SK12152001A3/sk
Publication of WO2000051989A1 publication Critical patent/WO2000051989A1/fr
Priority to NO20014234A priority patent/NO20014234L/no

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    • 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
    • C07D413/08—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 alicyclic rings
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
    • 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

Definitions

  • the invention relates to compounds of the formula I.
  • R 1 , R 2 each independently of one another H, A, cycloalkyl- [C (R 7 R 7 )] ⁇ - or Ar- [C (R 7 R 7 ' )] n -,
  • R 3 , R 4 are each independently of one another H, Ar, Het, R 5 , where at least 5 of the two radicals is R,
  • R 7 , R 7 each independently of one another H or A, X, Y each independently of one another (CR 7 R 7 ) n ,
  • a alkyl having 1-20 C atoms, in which one or two CH 2 groups are represented by O or S atoms and / or through -CH CH groups and / or 1-7 H atoms can be replaced by F, Ar unsubstituted or one, two or three times by A, Ar ', Het,
  • Naphthyl Het a mono- or dinuclear saturated, unsaturated or aromatic heterocycle with 1 to 4 N-, O- and / or S-
  • CO-NR 7 R 7 ' , COR 7 , S0 2 NR 7 R 7' , S (0) n A and / or carbonyl oxygen can be substituted, Hai F, CI, Br or I, n 0, 1 or 2 mean, and their pharmaceutically acceptable salts and solvates.
  • the invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. Alcohololates, these compounds.
  • the object of the invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.
  • 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 Diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication are used.
  • 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 e.g. known from EP 0 540 051 B1.
  • Cyclic guanidines for the treatment of thromboembolic disorders 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 - [(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 activity against the activated coagulation protease, known under the name factor Xa, or to the inhibition of other activated serine proteases such as factor VIII, 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 e.g. by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.
  • the measurement of the inhibition of factor Xa can e.g. using the method of T. Hara et al. in thromb. Haemostas. 1994, 71, 314-319.
  • the coagulation factor VIa initiates the extrinsic part of the coagulation cascade after binding to the tissue factor and contributes to the activation of 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 factor VIa 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 described, for example, 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
  • one or more radicals R 1 , R 2 , R 3 and / or R 4 are converted into one or more radicals R 1 , R 2 , R 3 and / or R 4 ,
  • a means Al yi is unbranched (linear) or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, 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 e.g. Trifluoromethyl.
  • Cycloalkyi preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • Ar means unsubstituted or single, double or triple by A, Ar ', Het, OR 6 , NR 6 R 6' , N0 2 , CN, Hai, NR 6 COA, NR 6 COAr ', NR 6 S0 2 A, NR 6 S0 2 Ar ', COOR 6 , CO-NR 6 R 6' , CON 6 Ar ', COR 7 , COAr', S0 2 NR 6 R 6 ' , S (0) n Ar' or S (0) ⁇ A substituted phenyl, naphthyl or biphenyl.
  • Preferred substituents for biphenyl are fluorine, S0 2 NH 2 or S0 2 NHA.
  • Ar preferably denotes unsubstituted phenyl, naphthyl or biphenyl, further preferably e.g. by methyl, ethyl, propyl, isopropyl, butyl, fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyan, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino , Pyrrolidin-1-yl, piperidin-1-yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, tert.-butylsulfonamido, tert.-butylaminosulfonyl, dimethylsulfonamid
  • Ar ' is preferably unsubstituted phenyl or naphthyl, more preferably e.g. by methyl, ethyl, propyl, isopropyl, butyl, fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, cyan, nitro, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidine-1 -yl, piperidin-1-yl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, methoxycarbonyl, carboxy, dimethylaminocarbonyl, phenylamin
  • Ar particularly preferably means, for example, phenyl, naphthyl, biphenyl, 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- (N-methylaminocarbonyl) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxy
  • 6-methoxyphenyl 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
  • Ar 1 is preferably, for example, phenyl, naphthyl, 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- (N-methylaminocarbonyl) phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl,
  • Het preferably means, for example, 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-triazol-1-, -4- or -5-yl, 1, 2,4-triazol-1-, -3- or 5-yl, 1 - 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
  • the heterocyclic radicals can also be partially or completely hydrogenated.
  • Het can, for. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl,
  • Het is unsubstituted or one, two or three times by A, OR 7 , NR 7 R 7 ' , N0 2 , CN, Hai, NR 7 COA, NR 7 S0 2 A, COOR 7 , CO-NR 7 R 7' , COR 7 , S0 2 NR 7 R 7 ' , S (0) ⁇ A and / or carbonyl oxygen substituted.
  • Het means very particularly preferably e.g. Furyl, thienyl,
  • R 1 is preferably, for example, H, A, cycloalkyl-CH 2 - or Ar-CH 2 -, particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-
  • H methyl, ethyl, propyl, isopropyl, butyl, pentyl or hexyl is very particularly preferred.
  • R 2 preferably denotes, for example, H, A, cycloalkyl-CH 2 - or Ar-CH 2 -, very particularly preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, 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. H. is particularly preferred.
  • R 4 very particularly preferably denotes H, phenyl, phenyl, naphthyl or biphenyl which is monosubstituted by NH 2 S0 2-0 ,
  • R 6 , R 6 each independently of one another preferably mean, for example, H, methyl, ethyl, propyl, butyl or benzyl, very particularly preferably H, methyl, ethyl, propyl or butyl. 0
  • R 7 , R 7 each independently mean, for example, preferably H, methyl, ethyl or propyl, very particularly preferably H.
  • X, Y each independently mean, for example, preferably (CH 2 ) n , where n very particularly preferably denotes 0 or 1.
  • 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 expressed by the following sub-formulas la to le, 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 , R 2 each independently denotes H or A; in Ib R 3 , R 4 each independently of one another H, Ar or R 5 , where at least one of the two radicals is R 5 ,
  • Ar- (CH 2 ) n -CO-, COOA, OH or can be substituted by a conventional amino protecting group
  • R 3 , R 4 each independently of one another are H, Ar or R 5 , where ⁇ is at least one of the two radicals R 5 ,
  • X, Y each independently represent (CH 2 ) n ; in le R 1 A, 5
  • R 3 , R 4 are each independently of one another H, Ar or R 5 , where at least one of the two radicals is R 5 ,
  • R 6 each independently of one another H or A
  • Alkyl with 1-6 C atoms, X, Y are each independently of one another (CH 2 ) n .
  • 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 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 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 have one instead of the H atom Hydroxy group carry a hydroxy protecting group, e.g. 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. water-moist Raney nickel) can be split off.
  • a catalyst e.g. water-moist 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 reacting the ° cyan compounds with hydroxylamine and reacting with phosgene, dialkyl carbonate, chloroformate, N, N'-carbonyldiimidazole or acetic anhydride.
  • amino protecting group is well known and refers to
  • 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. He um-
  • acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups.
  • alkanoyl such as acetyl, propionyl, butyryl
  • Aralkanoyl such as phenylacetyl
  • Aryloxyalkanoyl such as POA
  • Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyl- oxycarbonyl), 2-iodoethoxycarbonyl
  • Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC
  • Arylsulfonyl such as Mtr.
  • Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
  • 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.
  • Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably carried out 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,
  • DMSO Dimethyl sulfoxide
  • 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.
  • the biphenyl-SO 2 NH 2 group is preferably used in the form of its tert-butyl derivative.
  • the tert-butyl group is split off, for example, using TFA with or without the addition of an inert solvent, preferably with the addition of a small amount of anisole (1-10% by volume).
  • 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 with an alcohol, for example ethanol in the presence of HCl converted into the corresponding imidoester and treated with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and then hydrolyzing the product.
  • an alkylating agent for example CH 3 I
  • R 1 , R 2 and R 4 each denote those radicals according to claim 1 which are not alkylatable and Y has the meaning given in claim 1, with a compound of formula III
  • R represents a radical which cannot be alkylated according to claim 1, e.g. a phenyl radical which is substituted by 5-methyl- [1, 2,4] oxadiazol-3-yl and in which L is Cl, Br, I or a free or functionally modified OH group.
  • L is preferably Cl, Br, I or a reactive modified one
  • OH group such as an activated ester, an imidazolide or alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
  • the pyrazolone ring system is built up according to known methods by reacting a suitable ⁇ -keto ester with hydrazine or a hydrazine dehvate.
  • 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 ethylamine 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.
  • acids that provide physiologically acceptable salts are suitable for this implementation.
  • 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, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon or sulfone - or sulfuric acids, e.g.
  • 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.
  • the pharmaceutical activity of the racemates or the stereo isomers 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.
  • 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 optionally 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 for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder.
  • 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, flavoring 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, flavoring 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 in the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclero- se, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication can be used.
  • thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclero- se, inflammation, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication 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 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 excretion and on the combination of drugs and severity of the respective disease, whichever therapy applies. Oral application is preferred.
  • the compound is obtained analogously by reacting "AB” with 3- (7-bromomethyl-naphthalin-2-yl) -5-methyl- [1, 2,4] oxadiazole and subsequent hydrogenation
  • 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)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (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)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés de la formule (I) où R?1, R2, R3, R4¿, X et Y, ayant la signification donnée dans la revendication 1, sont des inhibiteurs du facteur de coagulation Xa. Ils peuvent être utilisés pour prévenir et/ou traiter les maladies thromboemboliques.
PCT/EP2000/001695 1999-03-03 2000-02-29 Derives de pyrazol-3-one utilises comme inhibiteurs du facteur xa WO2000051989A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
CA002364908A CA2364908A1 (fr) 1999-03-03 2000-02-29 Derives de pyrazol-3-one
BR0008608-8A BR0008608A (pt) 1999-03-03 2000-02-29 Derivados de pirazol-3-ona
MXPA01008844A MXPA01008844A (es) 1999-03-03 2000-02-29 Derivados de la pirazol-3-ona.
AU29165/00A AU2916500A (en) 1999-03-03 2000-02-29 Pyrazole-3-on-derivative as factor xa inhibitors
EP00907650A EP1157010A1 (fr) 1999-03-03 2000-02-29 Derives de pyrazol-3-one utilises comme inhibiteurs du facteur xa
JP2000602216A JP2002538143A (ja) 1999-03-03 2000-02-29 第ｘａ因子阻害剤としての、ピラゾール−３−オン誘導体
KR1020017011000A KR20010102428A (ko) 1999-03-03 2000-02-29 인자 ｘａ 억제제로서의 피라졸-３-온 유도체
SK1215-2001A SK12152001A3 (sk) 1999-03-03 2000-02-29 Derivát pyrazol-3-ónu ako faktor Xa inhibítorov, spôsob jeho prípravy, jeho použitie a farmaceutický prostriedok, ktorý ho obsahuje
NO20014234A NO20014234L (no) 1999-03-03 2001-08-31 Pyrazol-3-on-derivater som faktor-Xa-inhibitorer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19909237.0 1999-03-03
DE19909237A DE19909237A1 (de) 1999-03-03 1999-03-03 Pyrazol-3-on-derivate

Publications (1)

Publication Number Publication Date
WO2000051989A1 true WO2000051989A1 (fr) 2000-09-08

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Country Status (17)

Country Link
EP (1) EP1157010A1 (fr)
JP (1) JP2002538143A (fr)
KR (1) KR20010102428A (fr)
CN (1) CN1342148A (fr)
AU (1) AU2916500A (fr)
BR (1) BR0008608A (fr)
CA (1) CA2364908A1 (fr)
CZ (1) CZ20013164A3 (fr)
DE (1) DE19909237A1 (fr)
HU (1) HUP0200242A3 (fr)
MX (1) MXPA01008844A (fr)
NO (1) NO20014234L (fr)
PL (1) PL350941A1 (fr)
RU (1) RU2001126566A (fr)
SK (1) SK12152001A3 (fr)
WO (1) WO2000051989A1 (fr)
ZA (1) ZA200108064B (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6455525B1 (en) 1999-11-04 2002-09-24 Cephalon, Inc. Heterocyclic substituted pyrazolones
DE102007044032A1 (de) 2007-09-14 2009-03-19 Bayer Healthcare Ag Substituierte heterocyclische Verbindungen und ihre Verwendung
DE102007048447A1 (de) 2007-10-10 2009-04-16 Bayer Healthcare Ag Substituierte Dihydropyrazolthione und ihre Verwendung
DE102008020113A1 (de) 2008-04-23 2009-10-29 Bayer Schering Pharma Aktiengesellschaft Substituierte Dihydropyrazolone und ihre Verwendung
EP2383269A2 (fr) 2006-10-26 2011-11-02 Bayer Pharma AG Dihydropyrazolones substitués pour le traitement des maladies cardiovasculaires
US8252817B2 (en) 2005-04-28 2012-08-28 Bayer Intellectual Property Gmbh Dipyridyl-dihydropyrazolones and their use
US8524699B2 (en) 2006-10-26 2013-09-03 Bayer Intellectual Property Gmbh Substituted dihydropyrazolones and use thereof as HIF-prolyl-4-hydroxylase inhibitors
US8609698B2 (en) 2006-10-26 2013-12-17 Bayer Intellectual Property Gmbh Substituted dipyridyl-dihydropyrazolones and use thereof
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
US9533972B2 (en) 2010-11-18 2017-01-03 Bayer Intellectual Property Gmbh Substituted sodium-1H-pyrazole-5-olate

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012255A1 (fr) * 2003-08-01 2005-02-10 Mitsubishi Pharma Corporation Remede pour maladies inflammatoires des articulations

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1997013757A1 (fr) * 1995-10-13 1997-04-17 Nissan Chemical Industries, Ltd. Derives de la pyrazolone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1997013757A1 (fr) * 1995-10-13 1997-04-17 Nissan Chemical Industries, Ltd. Derives de la pyrazolone
EP0987253A1 (fr) * 1995-10-13 2000-03-22 Nissan Chemical Industries, Limited Derives de la pyrazolone

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6831075B2 (en) 1999-11-04 2004-12-14 Cephalon, Inc. Heterocyclic substituted pyrazolones
US6455525B1 (en) 1999-11-04 2002-09-24 Cephalon, Inc. Heterocyclic substituted pyrazolones
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
US8252817B2 (en) 2005-04-28 2012-08-28 Bayer Intellectual Property Gmbh Dipyridyl-dihydropyrazolones and their use
US9085572B2 (en) 2005-04-28 2015-07-21 Bayer Intellectual Property Gmbh 4-(pyridin-3-yl)-2(pyridin-2yl)-1,2-dihydro-3H-pyrazol-3-one derivatives as specific HIF-pyrolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases
US8609698B2 (en) 2006-10-26 2013-12-17 Bayer Intellectual Property Gmbh Substituted dipyridyl-dihydropyrazolones and use thereof
EP2383269A2 (fr) 2006-10-26 2011-11-02 Bayer Pharma AG Dihydropyrazolones substitués pour le traitement des maladies cardiovasculaires
EP2546253A1 (fr) 2006-10-26 2013-01-16 Bayer Intellectual Property GmbH Dihydropyrazolones substitues pour le traitement des maladies cardiovaskulaires et hematologiques
US8389520B2 (en) 2006-10-26 2013-03-05 Bayer Intellectual Property Gmbh Substituted dihydropyrazolones for treating cardiovascular and hematological diseases
US8524699B2 (en) 2006-10-26 2013-09-03 Bayer Intellectual Property Gmbh Substituted dihydropyrazolones and use thereof as HIF-prolyl-4-hydroxylase inhibitors
DE102007044032A1 (de) 2007-09-14 2009-03-19 Bayer Healthcare Ag Substituierte heterocyclische Verbindungen und ihre Verwendung
DE102007048447A1 (de) 2007-10-10 2009-04-16 Bayer Healthcare Ag Substituierte Dihydropyrazolthione und ihre Verwendung
US8067407B2 (en) 2008-04-23 2011-11-29 Bayer Pharma Aktiengesellschaft Substituted dihydropyrazolones and their use
WO2009129945A1 (fr) 2008-04-23 2009-10-29 Bayer Schering Pharma Aktiengesellschaft Dihydropyrazolones substituées utilisées comme inhibiteurs de la hif-prolyl-4-hydroxylase
DE102008020113A1 (de) 2008-04-23 2009-10-29 Bayer Schering Pharma Aktiengesellschaft Substituierte Dihydropyrazolone und ihre Verwendung
US9533972B2 (en) 2010-11-18 2017-01-03 Bayer Intellectual Property Gmbh Substituted sodium-1H-pyrazole-5-olate

Also Published As

Publication number Publication date
EP1157010A1 (fr) 2001-11-28
MXPA01008844A (es) 2002-05-14
AU2916500A (en) 2000-09-21
PL350941A1 (en) 2003-02-24
CA2364908A1 (fr) 2000-09-08
BR0008608A (pt) 2002-01-02
ZA200108064B (en) 2003-01-02
HUP0200242A3 (en) 2002-12-28
JP2002538143A (ja) 2002-11-12
SK12152001A3 (sk) 2002-03-05
RU2001126566A (ru) 2004-02-27
DE19909237A1 (de) 2000-09-07
HUP0200242A2 (hu) 2002-11-28
NO20014234D0 (no) 2001-08-31
KR20010102428A (ko) 2001-11-15
NO20014234L (no) 2001-10-24
CN1342148A (zh) 2002-03-27
CZ20013164A3 (cs) 2001-12-12

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