WO2002072558A1 - Amides d'acide carboxylique antithrombotiques, leur production et leur utilisation comme medicaments - Google Patents

Amides d'acide carboxylique antithrombotiques, leur production et leur utilisation comme medicaments Download PDF

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WO2002072558A1
WO2002072558A1 PCT/EP2002/002615 EP0202615W WO02072558A1 WO 2002072558 A1 WO2002072558 A1 WO 2002072558A1 EP 0202615 W EP0202615 W EP 0202615W WO 02072558 A1 WO02072558 A1 WO 02072558A1
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group
amidino
methyl
phenyl
formula
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PCT/EP2002/002615
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German (de)
English (en)
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Henning Priepke
Herbert Nar
Jean Marie Stassen
Uwe Ries
Wolfgang Wienen
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Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority to JP2002571474A priority Critical patent/JP2004529905A/ja
Priority to EP02732472A priority patent/EP1370540A1/fr
Priority to MXPA03008186A priority patent/MXPA03008186A/es
Priority to CA002439231A priority patent/CA2439231A1/fr
Publication of WO2002072558A1 publication Critical patent/WO2002072558A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • 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
    • 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
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/70—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical

Definitions

  • Antithrombotic carboxamides their preparation and their
  • the invention relates to carboxamides of the formula
  • the object of the present application was to provide compounds with effects comparable to those described in DE 199 37 494, which, however, are easier to formulate due to their physicochemical properties.
  • Amidino group means.
  • the present application thus relates to the new compounds of the above general formula I and their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms can each be replaced independently of one another by a C 1 - 3 alkyl group or o a hydrogen atom by the group - ( CH 2 ) P -Rf can be replaced, where p is one of the numbers 0, 1, 2 or 3 and
  • R f is a hydroxycarbonyl, C 3 alkoxycarbonyl, aminocarbonyl,
  • C 3 - 7 cycloalkylamino-carbonyl group, 5 Ar optionally by a fluorine, chlorine or bromine atom, by a carboxy, carboxy -CC. 3 -alkyl, carboxy-C ⁇ - 3 -alkoxy, alkoxycarbonyl-C ⁇ - 3 - alkoxy, trifluoromethyl-, C ⁇ _ 3 -alkyl-, hydroxy-, C ⁇ - 3 -alkoxy-, phenyl- C ⁇ -3-alkoxy-, amino- , -C-3-alkylamino or di- (-C-3-alkyl) amino group substituted phenylene or naphthylene group, the phenylene group o by a further fluorine, chlorine or bromine atom or by a further fluorine, chlorine or bromine atom or by a further fluorine, chlorine or bromine atom or by a further fluorine, chlorine or bromine atom or by a further fluorine, chlorine or bro
  • R a and R b independently of one another each for a hydrogen atom or a C 3 alkyl, aminocarbonyl, C 1. 4 alkyloxycarbonyl, amidino, C 3 alkyl COHNC (NH), C 3 alkyl C (NH), imidazol-2-yl or 4,5-dihydroimidazol-2-yl group, or R a and Rb taken together form a C 2 -s-alkylenediyl group, and o denotes 0 or 1, it being possible for a phenyl or C- ⁇ s-cycloalkyl ring to be fused onto the above-mentioned 5- or 6-membered heterocyclic group via two adjacent ring atoms and the bicyclic heterocyclyl groups thus formed can be bound via the heterocyclic or carbocyclic part, Z 1 is a -CO-NR 3 - or -NR 3 -CO- group;
  • R 1 is a hydrogen, fluorine, chlorine or bromine atom, a hydroxyl group or an optionally substituted by one or more fluorine atoms C ⁇ -3-alkyl or C ⁇ - 3 alkoxy group
  • R 2 is a hydrogen atom or a C ⁇ . 3 -alkyl group
  • R 3 is a hydrogen atom or an optionally substituted by a carboxy group -C 3 alkyl group
  • R 4 is a cyano group, an aminomethyl group or an amidino group optionally substituted by one or two C 3 -alkyl groups.
  • n is the number 0 or 1
  • A is a methylene group in which one or two hydrogen atoms can be replaced independently of one another by a C 3 alkyl group or one
  • Hydrogen atom can be replaced by the group - (CH 2 ) p-Rf, where p is one of the numbers 0.1, 2 or 3 and R f is a hydroxycarbonyl, C ⁇ . 3 -alkoxycarbonyl-, aminocarbonyl-, C ⁇ - 3 -alkylaminocarbonyl-, C 1 - 3 -
  • Ar is a phenylene group optionally substituted by a fluorine, chlorine or bromine atom, by a methyl, hydroxyl, methoxy or benzyloxy group, which is substituted by a further methyl group can be;
  • R 1 is a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, difluoromethyl, hydroxyl or methoxy group
  • R 2 is a hydrogen atom or a methyl group
  • R 3 is a hydrogen atom or a methyl or ethyl group which is optionally substituted by a carboxy or C 3 alkoxycarbonyl group, and
  • R 4 represents a cyano group, an aminomethyl group or an amidino group.
  • A is a methylene group in which a hydrogen atom can be replaced by a C 1 - 3 alkyl group or by the group - (CH 2 ) P -Rf, where p is one of the numbers 0, 1, 2 or 3 and Rf is a hydroxycarbonyl, C ⁇ - 3 -alkoxycarbonyl-,
  • Ar is a phenylene group optionally substituted by a methyl, hydroxyl, methoxy or benzyloxy group,
  • R a RbN- (CH 2 ) o- in which R a and R b independently of one another each represent a hydrogen atom or a d- 3 -alkyl group, or R a and Rb taken together form a C 2 -s-alkylenediyl group, and o 0 or 1, wherein to this group via two adjacent carbon atoms of a phenyl or C 5 - 6 cycloalkyl ring is fused, and the bicyclic heterocyclyl groups thus formed are attached via the heterocyclic part, Z 1 is a -CO-NR 3 - or -NR 3 -CO- group;
  • R 1 is a hydrogen, fluorine, chlorine or bromine atom or a methyl or trifluoromethyl group
  • R 2 is a hydrogen atom
  • R 3 represents a hydrogen atom or a through a carboxy, methoxycarbonyl or
  • Preferred compounds of the formula 1 are those in which -Ar-R 4 is for a group of the formula
  • X represents a hydrogen atom, a halogen atom or a hydroxy group.
  • a further preferred embodiment of the inventions are the compounds of the formula IA, in which R 1 , R 2 , R 3 , R 4 , Ar, Het and Z 1 have the meanings given, and
  • R 5 represents a hydrogen atom, a C 1-3 alkyl group or a radical of formula
  • R f is a hydroxycarbonyl, C 3 alkoxycarbonyl, aminocarbonyl,
  • heterocyclic group as used above and below for the radical “Het” means saturated, unsaturated or aromatic 5- or 6-membered rings which, in addition to carbon atoms, have at least one heteroatom selected from the group consisting of nitrogen and oxygen and have sulfur.
  • heterocyclyl groups are preferred:
  • 5-membered heteroaryl groups which contain an optionally substituted imino group, an oxygen or sulfur atom, an optionally substituted imino group and an oxygen, sulfur or nitrogen atom, an optionally substituted imino group and two nitrogen atoms or one oxygen or sulfur atom and two nitrogen atoms, 6 -linked heteroaryl groups, the contain one or two nitrogen atoms, or saturated 5- or 6-membered heterocyclyl groups which contain the one or two nitrogen atoms, a nitrogen atom and an oxygen or sulfur atom, or one or two oxygen or sulfur atoms, the abovementioned 5- or 6-membered heterocyclyl groups can be fused onto two adjacent ring atoms, a phenyl ring or cycloalkyl ring and the bicyclic heterocyclyl groups thus formed can be bound via the heterocyclic or carbocyclic part.
  • the unsubstituted or monosubstituted phenyl groups mentioned in the definition of the abovementioned radicals or unsubstituted or monosubstituted phenyl parts contained in these radicals, and also the heterocyclyl groups mentioned above, can in each case additionally on a carbon atom, in each case by a fluorine, chlorine or bromine atom, by a
  • Trifluoromethyl, C- ⁇ - 3 alkyl or C ⁇ _3-alkoxy group may be substituted, unless otherwise stated.
  • Group can be replaced, furthermore the amino and imino groups mentioned in the definition of the abovementioned radicals can be substituted by a radical which can be split off in vivo.
  • Such groups are described, for example, in WO 98/46576 and by N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85
  • a group which can be converted into a carboxy group in vivo is, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C 6 alkanol, a phenyl C 3 alkanol, a C3-9 -Cycloalkanol, where a Cs-s-cycloalkanol can additionally be substituted by one or two C ⁇ -3-alkyl groups, a Cs-s-cycloalkanol in which one Methyl group in the 3- or 4-position by alkyl optionally an oxygen atom or by a by a C ⁇ - 3 alkyl, phenyl-C ⁇ _ 3, phenyl C ⁇ - 3 -alkoxycarbonyl or C 2 - 6 alkanoyl group substituted imino group replaced is and the cycloalkanol part can additionally be substituted by one or two C 3 alkyl groups, a C- ⁇ -cycloalkenol,
  • R ⁇ -CO-O- (RyCR z ) -OH in which R x is a Ci-s-alkyl, Cs- ⁇ -cycloalkyl, phenyl or phenyl- C ⁇ _3-alkyl group, R y is a hydrogen atom, a C ⁇ -3 -Alkyl-, Cs- 7 -cycloalkyl or phenyl group and R 2 represent a hydrogen atom or a C ⁇ - 3 alkyl group,
  • an imino or amino group in vivo for example a hydroxyl group, an acyl group such as one which may be mono- or by C-3-alkyl or C-3-alkoxy groups by fluorine, chlorine, bromine or iodine atoms disubstituted phenylcarbonyl group, where the substituents can be the same or different, a pyridinoyl group or a -C 6 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl group or allyloxycarbonyl group, a C 16 alkoxycarbonyl or C- M e-alkylcarbonyloxy group, in which Hydrogen atoms can be replaced in whole or in part by fluorine or chlorine atoms, such as the methoxycarbonyl,
  • C ⁇ - 6 -alkoxycarbonylgrup ⁇ e such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl distr, a 3-amino-propionyl group in which the amino group is mono- or disubstituted by Ci- ⁇ -alkyl or C 3 - 7 cycloalkyl groups and the substituents are the same or different can be a C ⁇ -3-alkylsulfonyl-C2- 4 -alkoxycarbonyl-, -C ⁇ -3-alkoxy-C 2 - 4 -alkoxy-
  • R x -CO-O- (R y CR z ) -O-CO- C ⁇ - 6 alkyl-CO-NH- (R d CR e ) -O-CO- or C ⁇ 6- alkyl-CO-O- (R d CRe) - (R d CR e ) -O-CO group, in which R x to R z are defined as mentioned above,
  • Rd and R e which can be the same or different, represent hydrogen atoms or C 3 alkyl groups to understand.
  • saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.
  • Particularly preferred compounds of the general formula I are those in which Het is a heterocyclic group bonded in the 4-position of the phenyl radical of the formula I selected from groups (a) to (g),
  • R a and Rb independently of one another each for a hydrogen atom or a C 3 alkyl, aminocarbonyl, C 1. 4 -alkyloxycarbonyl-, amidino-, C ⁇ - 3 -AlkylCOHNC (NH) -, C ⁇ - 3 -AlkylC (NH) -, Imidazol-2-yl or 4,5-Dihydroimidazol-2-yl group, or R a and Rb taken together a C2-5 -Akylendiyl distr, and o represents 0 or 1:
  • R 1 is a hydrogen atom or a substituent bonded in the 3-position of the phenyl radical in formula I selected from fluorine, chlorine, bromine, C 3 -C 3 -alkyl and
  • R 2 is a hydrogen atom or a C 3 alkyl group bonded in the 2-position of the phenyl radical in formula I, in particular hydrogen,
  • R 3 is a hydrogen atom
  • Ar is a phenyl group which is optionally substituted by a hydroxy group bonded in the 2-position
  • Rs is a phenyl group which is bonded in the 5-position of Ar, optionally by one or two
  • an optionally present amidino group can additionally be substituted by a C 6 alkoxycarbonyl or phenylcarbonyl group, and their salts.
  • the compounds of general formula I are obtained by processes known per se, for example by: a) a compound of formula II
  • R 1 , R 2 , Het and m are as defined in claims 1 to 6, with a compound of formula III
  • Amidino group which can be substituted by one or two C 3 alkyl groups, a compound of the formula optionally formed in the reaction mixture in the
  • R 1 , R 2 , Het, A, Ar, m and n are as defined in claims 1 to 6 and Z 4 represents an alkoxy, aralkoxy, alkylthio or aralkylthio group, with an amine of the general formula
  • R 6 and R 7 which may be the same or different, each represent a hydrogen atom or a C ⁇ - 3 alkyl group, or with it
  • the acylation (a) is advantageously carried out using a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane
  • an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • acylation can also be carried out with the free acid
  • Presence of an acid activating agent or a dehydrating agent e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N '-Carbonyldiimidazol or N.N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • the reaction (b) is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, with an amine of the general formula V or with an appropriate acid addition salt such as ammonium carbonate or ammonium acetate.
  • a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane
  • a compound of general formula IV is obtained, for example, by reacting an appropriate cyano compound with an appropriate alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting an appropriate amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding nitrile with hydrogen sulfide, advantageously in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the formed Thioamids with a corresponding alkyl or aralkyl halide.
  • an appropriate cyano compound with an appropriate alcohol such as methanol, ethanol, n-propano
  • the subsequent hydrolysis is advantageously carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol , Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane and the subsequent decarboxylation in the presence of an acid as described above at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof
  • a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in
  • the subsequent esterification is advantageously carried out with an appropriate alcohol in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran,
  • a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran,
  • Benzene / tetrahydrofuran or dioxane but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride , Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N.N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N.N'-garbonyldiimidazole or N, N'-thionyldiimidazole, triphenylphosphine / tetrachlorocarbonate or triphenylphosphonate, or triphenyl
  • any reactive groups present such as hydroxyl, carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction.
  • the protective radical for a hydroxyl group is the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group,
  • a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and, in addition, the phthalyl group for the amino group.
  • the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by means of ether cleavage, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • an aqueous solvent e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali base such as lithium hydroxide
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example using hydrogen in the presence a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 up to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • a methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • an oxidizing agent such as cerium (IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • a methoxy group is advantageously eliminated in the presence of boron tribromide in a solvent such as methylene chloride at temperatures 5 between -35 and -25 ° C.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
  • a phthalyl radical is preferably cleaved in the presence of
  • An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (l) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1, 4- Diazabicyclo- 5 [2.2.2] octane at temperatures between 20 and 70 ° C.
  • a catalytic amount of tetrakis (triphenylphosphine) palladium (O) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of
  • the compounds of general formula I obtained can be separated into their o enantiomers and / or diastereomers.
  • the compounds of general formula I obtained which occur in racemates, can be converted into their optical antipodes by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley 5 Interscience, 1971) and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active one Solvents or by reacting with an optically active substance which forms salts or derivatives, such as esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and separating the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different ones Solubilities, whereby the free antipodes can be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • an optically active substance which forms salts or derivatives such as esters or amides
  • optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • Suitable optically active alcohols are, for example, (+) - or (-) - menthol
  • optically active acyl radicals in amides are, for example, the (+) - or (-) - menthyloxycarbonyl radicals.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained contain a carboxy group, they can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the compounds of the general formula I with the exception of those compounds in which Ar represents a phenyl or naphthyl group substituted by the radicals R5, R ⁇ and R7 and R 5 represents a cyano group, and their tautomers, their stereoisomers and their physiologically tolerable salts have valuable pharmacological properties Properties on, in particular an antithrombotic effect, which is preferably based on a thrombin or factor Xa influencing effect, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect prolonging the aPTT time and on an inhibitory effect on related serine proteases such as, for , B. trypsin, urokinase, factor VIIa, factor IX, factor XI and factor XII.
  • Methodology Enzyme kinetic measurement with a chromogenic substrate.
  • the amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used.
  • the inhibition of enzyme activity by the test substance is determined at different test substance concentrations and from this the IC50 is calculated as the concentration that inhibits the factor Xa used by 50%.
  • Chromozym X substrate (Röche), final concentration: 200 ⁇ mol / l per
  • Test substance final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 ⁇ mol / l
  • the compounds produced according to the invention are well tolerated since no toxic side effects could be observed at therapeutic doses.
  • the new compounds are suitable for the prevention and treatment of venous and arterial thrombotic disorders, such as, for example, the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT (C) A), as well as the occiusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of the occurrence of shunts.
  • venous and arterial thrombotic disorders such as, for example, the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT (C) A), as well as the occiusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of the occurrence of shunts.
  • the compounds of the invention are for antithrombotic support in a thrombolytic Treatment, such as with Alteplase, Reteplase, Tenecteplase, Staphylokinase or Streptokinase, to prevent long-term restenosis after PT (C) A, to prevent and treat ischemic events in patients with unstable angina or non-transmural heart attack, to prevent metastasis and the growth of coagulation-dependent tumors and of fibrin-dependent inflammatory processes, for example in the treatment of pulmonary fibrosis, for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin-dependent tissue adhesions and / or scar tissue formation and for promoting wound healing processes.
  • a thrombolytic Treatment such as with Alteplase, Reteplase, Tenecteplase, Staphylokinase or Streptokinase
  • C PT
  • C thrombolytic Treatment
  • the new compounds and their physiologically tolerable salts can be used therapeutically in combination with inhibitors of platelet aggregation, such as fibrinogen receptor antagonists (for example abciximab, eptifibatide, tirofiban), with inhibitors for ADP-induced aggregation (for example clopidogrel, ticlopidine), with P 2 T- Receptor antagonists (eg Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (eg Terbogrel) can be used.
  • fibrinogen receptor antagonists for example abciximab, eptifibatide, tirofiban
  • inhibitors for ADP-induced aggregation for example clopidogrel, ticlopidine
  • P 2 T- Receptor antagonists eg Cangrelor
  • combined thromboxane receptor antagonists / synthetase inhibitors eg Terbogrel
  • the dosage required to achieve a corresponding effect is expediently 3 to 30 mg / kg, preferably 1 to 10 mg / kg for intravenous administration, and 5 to 50 mg / kg, preferably 3 to 30 mg / kg, 1 to each for oral administration 4 times a day.
  • the compounds of formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, e.g.
  • Reaction solution is heated to 100 ° C for 2 hours. After a further 12 hours at room temperature, the reaction solution is poured onto 200 ml of ice water. The yellow precipitate formed is extracted with ethyl acetate, with water and sat.
  • N- (5- Amidino-2-hydroxy-phenyl) -3-methyl-4- (2-tert.butoxycarbonylaminomethyl-benzimidazol-1-yl) -phenyl-acetamide are dissolved in 10 ml of ethanolic hydrochloric acid and stirred at 40 ° C for 15 minutes. The solution is evaporated, taken up in a little ethanol, covered with ether and stirred for 30 minutes. The solid formed is suction filtered and dried. Yield: 0.04 g (42% of theory),
  • the crude product is chromatographed on silica gel, eluting with dichloromethane / ethyl acetate (1: 0 and 1: 1).
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.
  • the ready-to-use solution is dissolved with water for
  • composition (1) active ingredient 50.0 mg
  • Preparation (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm.
  • This powder mixture is filled in a size 3 hard gelatin capsule on a capsule filling machine.
  • composition (1) active ingredient 350.0 mg (2) dried corn starch 46.0 mg
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled into size 0 hard gelatin capsules on a capsule filling machine.
  • 1 suppository contains: active ingredient 100.0 mg
  • Polyethylene glycol (M.G. 1500) 600.0 mg
  • the polyethylene glycol is melted together with polyethylene sorbitan monostearate.
  • the milled active substance is homogeneously dispersed in the melt at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

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Abstract

La présente invention concerne des amides d'acide carboxylique de la formule (I), où R1 à R4, het, Z1, A, Ar, et m ont la définition donnée dans la 1ère revendication, leurs tautomères, leurs stéréoisomères, leurs mélanges, leurs prodrogues et leurs sels, qui ont de précieuses propriétés. Les composés de la formule I susmentionnée, où R4 représente un groupe cyano, constituent de précieux produits intermédiaires pour la production des composés susmentionnés de la formule générale I, et les composés de la formule générale (I) susmentionnée, où R4 représente un des groupes amidino mentionnés dans la 1ère revendication, ont de précieuses propriétés pharmacologiques, notamment une action antithrombotique et une action d'inhibition du facteur Xa.
PCT/EP2002/002615 2001-03-13 2002-03-09 Amides d'acide carboxylique antithrombotiques, leur production et leur utilisation comme medicaments WO2002072558A1 (fr)

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JP2002571474A JP2004529905A (ja) 2001-03-13 2002-03-09 抗血栓性カルボン酸アミド、それらの調製及び医薬組成物としてのそれらの使用
EP02732472A EP1370540A1 (fr) 2001-03-13 2002-03-09 Amides d'acide carboxylique antithrombotiques, leur production et leur utilisation comme medicaments
MXPA03008186A MXPA03008186A (es) 2001-03-13 2002-03-09 Amidas de acidos carboxilicos antitromboticas, su preparacion y su uso como medicamentos.
CA002439231A CA2439231A1 (fr) 2001-03-13 2002-03-09 Amides d'acide carboxylique antithrombotiques, leur preparation et leur utilisation comme medicaments

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DE10111842A DE10111842A1 (de) 2001-03-13 2001-03-13 Antithrombotische Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel

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WO2004056784A1 (fr) * 2002-12-19 2004-07-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux amides d'acide carboxylique, leur production et leur utilisation en tant que medicaments
WO2005082895A1 (fr) 2004-02-28 2005-09-09 Boehringer Ingelheim International Gmbh Nouveaux carboxamides comme inhibiteurs du facteur xa
WO2006027135A1 (fr) * 2004-09-06 2006-03-16 F. Hoffmann-La Roche Ag Derives de 4-aminomethyl benzamidine et leur utilisation en tant qu'inhibiteurs du facteur viia
WO2007019083A1 (fr) * 2005-08-04 2007-02-15 Janssen Pharmaceutica N.V. Composes de pyrimidine utiles comme modulateurs des recepteurs de la serotonine
JP2008303211A (ja) * 2003-03-13 2008-12-18 Idemitsu Kosan Co Ltd 新規含窒素複素環誘導体及びそれを用いた有機エレクトロルミネッセンス素子
US7598255B2 (en) 2005-08-04 2009-10-06 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
WO2020153414A1 (fr) 2019-01-24 2020-07-30 武田薬品工業株式会社 Composé hétérocyclique et son utilisation
WO2021059017A1 (fr) 2019-09-25 2021-04-01 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation

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DE19929787A1 (de) * 1999-06-29 2001-01-04 Bayer Ag Neue 4-(2-Oxodihydrooxadiazinylphenyl)amide und ihre Verwendung
DE19937494A1 (de) * 1999-08-07 2001-02-08 Boehringer Ingelheim Pharma Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel
EP1078917A1 (fr) * 1998-02-17 2001-02-28 Ono Pharmaceutical Co., Ltd. Derives amidino utilises comme ingredients actifs et medicaments les contenant

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EP1078917A1 (fr) * 1998-02-17 2001-02-28 Ono Pharmaceutical Co., Ltd. Derives amidino utilises comme ingredients actifs et medicaments les contenant
DE19912690A1 (de) * 1999-03-20 2000-09-21 Boehringer Ingelheim Pharma Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel
DE19929787A1 (de) * 1999-06-29 2001-01-04 Bayer Ag Neue 4-(2-Oxodihydrooxadiazinylphenyl)amide und ihre Verwendung
DE19937494A1 (de) * 1999-08-07 2001-02-08 Boehringer Ingelheim Pharma Carbonsäureamide, deren Herstellung und deren Verwendung als Arzneimittel

Cited By (27)

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US7326791B2 (en) 2002-12-19 2008-02-05 Boehringer Ingelheim Pharma Gmbh & Co., Kg Carboxylic acid amides, the preparation thereof, and their use as pharmaceutical compositions
WO2004056784A1 (fr) * 2002-12-19 2004-07-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouveaux amides d'acide carboxylique, leur production et leur utilisation en tant que medicaments
JP2008303211A (ja) * 2003-03-13 2008-12-18 Idemitsu Kosan Co Ltd 新規含窒素複素環誘導体及びそれを用いた有機エレクトロルミネッセンス素子
US8618288B2 (en) 2003-09-17 2013-12-31 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
US8791103B2 (en) 2004-02-28 2014-07-29 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
KR101193823B1 (ko) 2004-02-28 2012-10-24 베링거 인겔하임 인터내셔날 게엠베하 Ｘａ 억제제로서 유용한 신규한 카복스아미드
US7371743B2 (en) 2004-02-28 2008-05-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
WO2005082895A1 (fr) 2004-02-28 2005-09-09 Boehringer Ingelheim International Gmbh Nouveaux carboxamides comme inhibiteurs du facteur xa
EA011245B1 (ru) * 2004-02-28 2009-02-27 Бёрингер Ингельхайм Интернациональ Гмбх Амиды карбоновых кислот в качестве ингибиторов фактора ха
JP2007523935A (ja) * 2004-02-28 2007-08-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｘａインヒビターとして使用するための新規なカルボキサミド
JP4657282B2 (ja) * 2004-02-28 2011-03-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｘａインヒビターとして使用するための新規なカルボキサミド
US7947700B2 (en) 2004-02-28 2011-05-24 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
US8445525B2 (en) 2004-02-28 2013-05-21 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
JP2008512364A (ja) * 2004-09-06 2008-04-24 エフ．ホフマン−ラ ロシュ アーゲー ４−アミノメチルベンズアミジン誘導体及び第ＶＩＩａ因子阻害剤としてのその使用
WO2006027135A1 (fr) * 2004-09-06 2006-03-16 F. Hoffmann-La Roche Ag Derives de 4-aminomethyl benzamidine et leur utilisation en tant qu'inhibiteurs du facteur viia
US7598255B2 (en) 2005-08-04 2009-10-06 Janssen Pharmaceutica Nv Pyrimidine compounds as serotonin receptor modulators
AU2006278759B2 (en) * 2005-08-04 2012-08-16 Janssen Pharmaceutica N.V. Pyrimidine compounds as serotonin receptor modulators
EA014495B1 (ru) * 2005-08-04 2010-12-30 Янссен Фармацевтика Н.В. Соединения пиримидина в качестве модуляторов серотониновых рецепторов
WO2007019083A1 (fr) * 2005-08-04 2007-02-15 Janssen Pharmaceutica N.V. Composes de pyrimidine utiles comme modulateurs des recepteurs de la serotonine
US8883808B2 (en) 2005-08-04 2014-11-11 Janssen Pharmaceutica N.V. Combination of 5-HT7 receptor antagonist and serotonin reuptake inhibitor therapy
NO340744B1 (no) * 2005-08-04 2017-06-12 Janssen Pharmaceutica Nv Pyrimidinforbindelser som serotoninreseptormodulatorer
US9126944B2 (en) 2013-02-28 2015-09-08 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9458110B2 (en) 2013-02-28 2016-10-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
US9828345B2 (en) 2013-02-28 2017-11-28 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
WO2020153414A1 (fr) 2019-01-24 2020-07-30 武田薬品工業株式会社 Composé hétérocyclique et son utilisation
WO2021059017A1 (fr) 2019-09-25 2021-04-01 Takeda Pharmaceutical Company Limited Composé hétérocyclique et son utilisation
US11952344B2 (en) 2019-09-25 2024-04-09 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof

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MXPA03008186A (es) 2004-01-29
UY27202A1 (es) 2002-10-31
DE10111842A1 (de) 2002-09-19

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