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WO2000050419A1 - Heterocycles bicycliques substitues et leur utilisation comme inhibiteurs de la thrombine - Google Patents

Heterocycles bicycliques substitues et leur utilisation comme inhibiteurs de la thrombine Download PDF

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Publication number
WO2000050419A1
WO2000050419A1 PCT/EP2000/001387 EP0001387W WO0050419A1 WO 2000050419 A1 WO2000050419 A1 WO 2000050419A1 EP 0001387 W EP0001387 W EP 0001387W WO 0050419 A1 WO0050419 A1 WO 0050419A1
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group
general formula
alkyl
compound
methyl
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PCT/EP2000/001387
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German (de)
English (en)
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Norbert Hauel
Herbert Nar
Henning Priepke
Uwe Ries
Jean Marie Stassen
Wolfgang Wienen
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Boehringer Ingelheim Pharma Kg
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Priority to AU29126/00A priority Critical patent/AU2912600A/en
Publication of WO2000050419A1 publication Critical patent/WO2000050419A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to new substituted bicyclic heterocycles of the general formula
  • Stereoisomers have valuable pharmacological properties, in particular an action which inhibits thrombin and prolongs the thrombin time.
  • the present application thus relates to the new compounds of the general formula I, their preparation, medicaments containing the pharmacologically active compounds of the formula I and their use.
  • R a is a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom, in which
  • a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or
  • R c represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C- * j__3-alkyl or C ] __3-alkoxy group and
  • R ] _ is as defined above, or a 5-membered heteroaromatic group which is bonded via a nitrogen atom and which contains one, two or three nitrogen atoms and which can be benzocondensed via two adjacent carbon atoms,
  • Thienyl groups can be mono- or disubstituted independently of one another and a carboxy group contained in the radicals mentioned can also be replaced by a group which can be converted into a carboxy group in vivo,
  • heteroaromatic group including an optionally fused-on phenyl part
  • the heteroaromatic group can also be partially hydrogenated, the dihydro derivatives being preferred, and the resulting -NH groups can also be replaced by the -NR • ] _ groups defined above,
  • Y is an oxygen or sulfur atom or one optionally substituted by a C ] __g-alkyl or C3_7-cycloalkyl group
  • Imino group, Xi, X2 / X3 and X4 each represent a methine group or
  • radicals X ] _, X ⁇ , X3 and X4 each have a nitrogen atom and the other radicals each have a methine group
  • B is an ethylene group in which a methylene group, which is either linked to the bicyclic heterocycle of the formula I or to the group Ar, by an oxygen or sulfur atom, by a sulfinyl, sulfonyl, carbonyl or -NR 1 - Group can be replaced, where R ] _ is defined as mentioned above,
  • Ar is optionally substituted by 'a fluorine, chlorine or bromine atom, by a trifluoromethyl, C -__ 3 alkyl or C] __3 alkoxy phenylene or naphthylene group,
  • Rk represents a hydrogen atom, a hydroxyl group or a residue which can be split off in vivo.
  • the compounds of the general formula I above which contain a residue which can be split off in vivo, thus represent so-called drugs and compounds of the general formula I which contain two residues which can be split off in vivo, so-called double prodrugs.
  • a group which can be converted into a carboxy group in vivo is, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C] __ g-alkanol, a phenyl-C;] __ 3-alkanol, a C3_9-cycloalkanol, wherein a C5_ 8 cycloalkanol additionally by one or two C] __ 3 alkyl groups can be substituted
  • cycloalkanol part can also be substituted by one or two C ⁇ _3 alkyl groups, a C4_7 cycloalkenol, a C3_5 ⁇ alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or phenyl-C3 -.5-alkynol with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-C] __ 3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms, which is additionally in the bicycloalkyl part by one or two C Q __3 alkyl groups can be substituted, a 1, 3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of the formula
  • R2 is a C 1-8 alkyl, C5_7 cycloalkyl, phenyl or phenyl
  • R3 is a hydrogen atom, a ⁇ _ 2 alkyl, C5_7 cycloalkyl or phenyl group and
  • R4 represents 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 a benzoyl or pyridinoyl group optionally substituted by a C 1 -C 3 -alkyl group, for example the benzoyl or p-ethyl group.
  • an acyl group such as a benzoyl or pyridinoyl group optionally substituted by a C 1 -C 3 -alkyl group, for example the benzoyl or p-ethyl group.
  • tinoyl group or a C ⁇ .
  • alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C 1 _ 1 g alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl -, Isopropoxycarbonyl-, Butoxycarbonyl-, tert.
  • the preferred prodrug residues for a carboxy group are a C 1 -g alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyc- lohexyloxycarbonyl group or phenyl-C] __ 3-alkoxycarbonyl group such as the benzyloxycarbonyl group and
  • a C ] __g-alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-Ci - ⁇ - alkoxycarbonyl group such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a C ] __3-alkyl group such as the benzoyl or 4-ethyl benzoyl group, a pyridinoyl group such as the nicotinoyl group,
  • the definition of the above-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms and alkanoyl parts which contain more than 3 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc. on.
  • R a is a 5-, 6- or 7-membered saturated heterocyclic ring bonded via a nitrogen atom, in which
  • a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or
  • a methylene group in the 4-position can be replaced by an oxygen atom or a -NR- * j_ group, where R ⁇ _ represents a hydrogen atom or a C- j __3 -alkyl group, and one or two further methylene groups can be replaced by carbonyl groups,
  • the 5- or 6-membered saturated heterocyclic rings described above can also be benzo-fused via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C 1 _3 -alkyl or C 1 _3-alkoxy group,
  • R c represents a hydrogen atom, a trifluoromethyl or C ⁇ _3 alkyl group
  • R ] _ is as defined above,
  • Thienyl groups can be mono- or disubstituted independently of one another and a carboxy group contained in the radicals mentioned can also be replaced by a group which can be converted into a carboxy group in vivo,
  • heteroaromatic group including an optionally fused-on phenyl part
  • the heteroaromatic group can also be dihydrogenated and the resulting -NH groups can also be replaced by the -NR ] _ groups defined above, _
  • Y is an oxygen atom or an imino group which is optionally substituted by a c 1-4 alkyl group
  • i, X2, X3 and X4 each represent a methine group
  • B is an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen atom, a carbonyl or -NR ⁇ group, where R ⁇ _ is defined as mentioned above,
  • Ar is a phenylene or naphthylene group which is optionally substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, Ci. 3 alkyl or C ⁇ - ⁇ - alkoxy group,
  • Rb represents a hydrogen atom or a residue which can be split off in vivo
  • R a is a 5- or 6-membered saturated heterocyclic ring bonded via a nitrogen atom, where a methylene group in the 2-position can be replaced by a carbonyl or sulfonyl group or
  • R ] _ represents a hydrogen atom or a C-j__3 alkyl group, can be replaced and one or two further methylene groups can be replaced by carbonyl groups in a ring thus obtained containing two heteroatoms,
  • 6-membered saturated heterocyclic rings described above can also be benzocondensed via two adjacent carbon atoms and the phenyl part can optionally be substituted by a C ] _.3 alkyl group,
  • R c represents a hydrogen atom or a C ] __3 alkyl group
  • R ] _ is as defined above,
  • Carboxy- (C ⁇ _2) -alkyl-, C] _. 2 -alkoxycarbonyl- (C * j__2) -alkyl-, phenyl, pyridyl, furanyl or thienyl groups can be mono- or disubstituted, the substituents being the same or different with the proviso that only one of the substituents is an aromatic or heteroaromatic radical and a carboxy group contained in the said radicals can also be replaced by a group which can be converted into a carboxy group in vivo,
  • Y is an imino group which is optionally substituted by a C- ] __3 -alkyl group
  • Xi, X2, X3 and X4 each represent a methine group
  • B is an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen atom or -NR 1 group, where R] _ is defined as mentioned above,
  • Ar is a phenylene group optionally substituted by a C] __ 3 alkyl group
  • R ] - represents a hydrogen atom or a residue which can be split off in vivo
  • the new compounds can be prepared by processes known per se, for example by the following processes:
  • R a , Xi to X4, Y, B and Ar are as defined at the beginning and
  • Z represents an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group with an amine the general formula
  • Rb ' represents a hydrogen tom or a hydroxy group.
  • the reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol / water, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C., preferably at temperatures between 20 and 120 ° C., with a compound of the general formula III or with an appropriate acid addition salt such as ammonium carbonate.
  • a compound of general formula III is obtained, for example, by reacting a compound of general formula I in which E represents a cyano group with a corresponding 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 pyri- din or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.
  • a solvent such as pyri-
  • Xi to X4, Y, B and Ar are as defined in the introduction and the R a 'group and E 1 have the meanings mentioned for the R a group and E with the proviso that the
  • R a 'group one by hydrolysis, treatment with an acid or
  • R a group has the meanings mentioned above or the
  • R a 'group one by hydrolysis, treatment with an acid or
  • a group which can be converted into a carboxy group is, for example, a carboxyl group protected by a protective radical, such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which expediently be converted into a carboxyl group by hydrolysis,
  • a protective radical such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which expediently be converted into a carboxyl group by hydrolysis
  • esters with tertiary alcohols e.g. the tert. Butyl esters which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and
  • esters with aralkanols e.g. the benzyl ester, which are expediently converted into a carboxyl group by means of hydrogenolysis.
  • the hydrolysis is expediently 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 at temperatures between -10 and 120 ° C, eg 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
  • a suitable solvent such as water, water / methanol
  • R a 'group and / or E' in a compound of the formula V contains, for example, the tert. Butyl or tert. Butyloxy- carbonylycuba, these can also by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or poly-phosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, Toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or thermally, if appropriate, in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably preferably in the presence of a catalytic amount of an acid such
  • the boiling point of the solvent used e.g. at temperatures between 40 and 120 ° C, split off.
  • Formula V for example, the benzyloxy or benzyloxycarbonyl group, these can also be hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 ° C, e.g. at room temperature and a hydrogen pressure of 1 to 5 bar.
  • a hydrogenation catalyst such as palladium / carbon
  • a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide
  • Xi to X4, Y, B, Ar and E are as defined in the beginning and
  • R a has the meanings mentioned for the R a with the proviso that R a " contains a carboxyl group or a group which can be converted into a corresponding ester group by means of an alcohol, with an alcohol of the general formula
  • R5 represents the alkyl part of one of the residues which can be removed in vivo, with the exception of the R2-CO-O- (R3CR4) group for a carboxyl group, or with its formamide acetals or with a compound of the general formula
  • Rg is the alkyl part of one of the residues which can be removed in vivo, with the exception of the R2-CO-O- (R4CR5) group for a carboxyl group and
  • Z2 is a leaving group such as a halogen atom, e.g. B. represent a chlorine or bromine atom.
  • the reaction with an alcohol of the general formula VII is advantageously carried out in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an alcohol of the general formula VII, if appropriate 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'-dicyclohexyl-carbodiimodicyclide, N, N 'N / N-hydroxysuccinimide, N, N '-carbonyldiimidazole
  • the reaction is advantageously carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferred as in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.
  • a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone
  • a reaction accelerator such as sodium or potassium iodide
  • a base such as sodium carbonate or potassium carbonate
  • R a , Xi to X4, Y, B and Ar are as defined in the introduction, with a compound of the general formula
  • Z3 is a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom.
  • a halogen atom e.g. a chlorine, bromine or iodine atom.
  • the reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used.
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide
  • the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert .butylate or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, performed.
  • a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethyl sulfoxide
  • a base such as sodium hydride, potassium carbonate, potassium tert .butylate or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, performed.
  • R a , X ⁇ to X 4 , Y, Ar and E are as defined above and
  • B ' represents an ethylene group in which a methylene group is replaced by a sulfenyl or sulfinyl group.
  • the oxidation is preferably carried out in a solvent or solvent mixture, e.g. in water, water / pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, and, depending on the oxidizing agent used, expediently carried out at temperatures between -80 and 100 ° C.
  • a solvent or solvent mixture e.g. in water, water / pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, and, depending on the oxidizing agent used, expediently carried out at temperatures between -80 and 100 ° C.
  • the oxidation is advantageously carried out with one equivalent of the oxidizing agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C.
  • a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -30 ° C, with iodobenzodichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid in glacial acetic acid or in
  • the oxidation is advantageously carried out starting from a corresponding sulfinyl compound with one or more equivalents of the oxidizing agent used or starting from a corresponding sulfenyl compound expediently using two or more equivalents of the oxidizing agent used, for example using hydrogen peroxide in glacial acetic acid / acetane hydride, trifluoroacetic acid or in formic acid at 20 to 100 ° C or in acetone at 0 to 60 ° C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid or potassium permanganate in glacial acetic acid, water / sulfuric acid or in acetone
  • a corresponding sulfonyl compound of the general formula I which is still may contain a small amount of the corresponding sulfinyl compound.
  • R a , Xi to X4, Y and Ar are as defined in the introduction, one of the radicals U or V represents an HO, HS, HOSO, HOS0 2 or HNR ] _ group and the other of the radicals represents a Z3CH2 group , where Ri is as defined at the beginning and Z3 is a nucleofuge leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom.
  • the reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or dimethylaminopyridine at temperatures between 20 ° C and the boiling point of the solvent used, a compound of the general formula XII or XIII, in which Z3 represents a halogen atom, can also be prepared in the reaction mixture.
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide
  • an inorganic or a tertiary organic base such as triethylamine, N-ethyl-diis
  • Cyano group and B an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen or sulfur atom or by an -NR ⁇ group, mean:
  • R a and Y are as defined above and X ⁇ 'to X 4 ' each represent a methine group, with a compound of the general formula
  • B ' represents an ethylene group in which the methylene group linked to the group Ar can be replaced by an oxygen or sulfur atom or by an -NR i group, or by their reactive derivatives.
  • reaction is expediently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, orthoacetate, tri-orthoacetate.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, orthoacetate, tri-orthoacetate.
  • reaction of a corresponding reactive compound of the general formula XV such as its esters, imidazolides or halides with an amine of the general formula XIV is preferably carried out in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.
  • a solvent such as methylene chloride, ether or tetrahydrofuran
  • a tertiary organic base such as triethylamine, N-ethyl diisopropylamine or N-methyl-morpholine
  • reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, ethanol or dioxane, optionally in the presence of a dehydrating agent, e.g.
  • the reaction is particularly preferably with a reactive oxalic acid derivative, for example an oxalic acid ester, oxalic acid halide or oxalic acid ester halide, with a diamine of the general formula XVI in a solvent such as methylene chloride, ether, ethanol or tetrahydrofuran and optionally in the presence of an organic base such as pyridine, triethylamine, N. -Ethyl-diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between o and 50 ° C.
  • a reactive oxalic acid derivative for example an oxalic acid ester, oxalic acid halide or oxalic acid ester halide
  • a diamine of the general formula XVI in a solvent such as methylene chloride, ether, ethanol or tetrahydro
  • R8 represents a hydrogen atom, a C] __ g-alkyl, C- ] _-. 4 -alkoxycarbonyl (Ci-.4) alkyl, phenyl, pyridyl, furanyl or thienyl group, or with their reactive derivatives.
  • reaction is expediently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, orthoacetate, tri-orthoacetate.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, if appropriate in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarboxylate, orthoacetate, tri-orthoacetate.
  • trachlorocarbon and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C.
  • a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine
  • reaction of a corresponding reactive compound of the general formula XVII such as its esters, imidazolides or halides with an amine of the general formula XVI is carried out, for example, in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl diisopropylamine or N-methyl-morpholine, which can simultaneously serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.
  • the reaction can also be carried out with a mixture of the carboxylic acid of the general formula XVIII and its anhydride.
  • Z2 is a leaving group such as a halogen atom, e.g. B. represents a chlorine or bromine atom, or with their reactive derivatives, and optionally subsequent alkylation of the nitrogen atom in the 4 position of the compound thus obtained.
  • a halogen atom e.g. B. represents a chlorine or bromine atom, or with their reactive derivatives, and optionally subsequent alkylation of the nitrogen atom in the 4 position of the compound thus obtained.
  • reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, optionally in the presence of a dehydrating agent, e.g.
  • reaction of a corresponding reactive compound of the general formula XVIII, such as its esters, imidazolides or halides, with an amine of the general formula XVI is preferably carried out in a solvent such as methylene chloride, ether or tetrahydrofuran and preferably in the presence of a tertiary organic base such as triethylamine, N- Ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent, at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 50 ° C, performed.
  • a solvent such as methylene chloride, ether or tetrahydrofuran
  • a tertiary organic base such as triethylamine, N- Ethyl-diisopropylamine or N-methyl-morpholine, which can also serve as a solvent
  • the subsequent subsequent alkylation of the nitrogen atom is carried out using a conventional alkylating agent, for example an alkyl halide, a sulfonic acid ester, e.g. a methanesulfonic acid or p-toluenesulfonic acid ester, advantageously in a solvent or solvent mixture such as methylene chloride, diethyl ether, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or benzene, optionally in the presence of an acid-binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride, potassium ter.
  • a conventional alkylating agent for example an alkyl halide, a sulfonic acid ester, e.g. a methanesulfonic acid or p-toluenesulfonic acid ester, advantageously in a solvent or solvent mixture such as methylene chloride, diethyl
  • butylate or in the presence of an organic base such as N-ethyl-diisopropylamine, N-methyl-morpholine, triethylamine or pyridine, which can also be used as a solvent at the same time, or by alcoholysis in the presence of a strong base, for ethylation, for example by ethanolysis in the presence of sodium ethylate, preferably at temperatures between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C.
  • an organic base such as N-ethyl-diisopropylamine, N-methyl-morpholine, triethylamine or pyridine, which can also be used as a solvent at the same time, or by alcoholysis in the presence of a strong base, for ethylation, for example by ethanolysis in the presence of sodium ethylate, preferably at temperatures between 0 and 100 ° C, for example at temperatures between room temperature and 50 ° C.
  • 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 trimethylsilyl, acetyl, benzoyl, tert comes as a protective residue for a hydroxyl group.
  • a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert. Butoxycarbonyl -, Benzyloxycarbonyl-, Benzyl -, Methoxy-benzyl- or 2, 4-Dimethoxybenzyl distr and for the amino group additionally the phthalyl group into consideration.
  • 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 cleaved off, for example, by hydrolysis, e.g. with hydrogen in the presence of 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 to 7 bar, but preferably of 3 to 5 bar.
  • hydrolysis e.g. with hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room
  • 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 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • the splitting off of a tert. Butyl or tert. Butyloxycarbonylrestes is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • a solvent such as methylene chloride, dioxane or ether.
  • a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (0), 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 (I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo - [2.2.2] octane at temperatures between 20 and 70 ° C.
  • a catalytic amount of tetrakis (triphenylphosphine) palladium (0) preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of
  • a compound of general formula III is obtained by reacting a corresponding nitrile, which in turn is advantageously obtained in accordance with processes f to k, with a corresponding thio or alcohol in the presence of hydrogen chloride or hydrogen bromide.
  • a compound of the general formulas V, VI, IX and XI used as starting material is advantageously obtained in accordance with a process of the present invention.
  • a starting compound of the general formula XII, in which U represents a halomethyl group is expediently obtained by ring closure of a corresponding ester, which is substituted in the o-position by a suitable halogen atom and a methoxyacetamido group, to give a corresponding bicyclic 2-alkoxymethyl compound, optionally subsequent Hydrolysis and, if appropriate, subsequent amidation of a carboxylic acid thus obtained with a corresponding amine, conversion of the alkoxymethyl compound thus obtained into the corresponding halomethyl compound which, if necessary, can subsequently be converted into the desired compound by means of a corresponding compound.
  • Carrying out the ring closure with a suitable carbonic acid derivative gives a starting compound of the general formula XII in which U represents a hydroxyl, mercapto or amino group.
  • the compounds of the general formulas IV, VII, VIII, X and XIII used as starting materials are obtained by trivial methods, for example by reduction of an aromatic ester which is substituted in the o-position by an optionally substituted amino group and a nitro group, and optionally subsequent ring closure the o-diamino compound thus obtained with a corresponding carboxylic acid.
  • the compounds of general formula I obtained which occur in race aten can be incorporated into their optical antipodes by methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", vol. 6, Wiley Interscience, 1971) and compounds of the general formula I with at least 2 asymmetric carbon atoms due to their physico-chemical differences separate 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 solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • 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 alcohol are (+) - or (-) menthol
  • the optically active acyl radical in amides is, for example, the (+) - or (-) - menthyloxycarbonyl radical.
  • 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 purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of the formula I obtained in this way contain a carboxy group, they can, if desired, be subsequently converted into their salts with inorganic or organic bases, in particular for pharmaceutical applications. fertilize in their physiologically acceptable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I and their salts have valuable properties.
  • A 1-methyl-2- (4-aminophenylaminomethyl) -5- (3-methyl-5-phenyl-pyrazol-1-yl) -benzimidazole hydrochloride
  • Material plasma, from human citrate blood.
  • the thrombin time was determined using a Biomatic BIO coagulometer from Sarstedt.
  • test substance was placed in the test vessels prescribed by the manufacturer with 0.1 ml human citrate plasma and 0.1 ml diethyl barbiturate buffer (DBA buffer). The mixture was incubated at 37 ° C for one minute. The coagulation reaction was started by adding 0.3 U test thrombin in 0.1 ml of DBA buffer. Depending on the device, the time taken for the clot to clot is measured by entering thrombin. Batches in which 0.1 ml of DBA buffer were added served as a control.
  • the effective substance concentration at which the thrombin time was doubled compared to the control was determined via a dose-response curve.
  • the new compounds and their physiologically compatible salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts or stents.
  • venous and arterial thrombotic diseases such as the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A)
  • PT ( C) A) angioplasty
  • peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts
  • the compounds according to the invention are for antithrombotic support in a thrombolytic treatment, such as, for example, with rt-PA or streptokinase, for preventing long-term restenosis according to PT (C) A, for preventing metastasis and the growth of coagulation-dependent tumors and of fibrin-dependent inflammatory processes suitable .
  • a thrombolytic treatment such as, for example, with rt-PA or streptokinase
  • C PT
  • the dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration and 0.1 to 50 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day.
  • the provided compounds of formula I optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol , Water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat or their suitable mixtures, in conventional galenical preparations such as tablets, dragees, capsules, powders, suspensions or suppositories.
  • inert customary carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water /
  • EKA mass spectra electrospray mass spectra of cations
  • 5- (2-aminophenylamino) benzimidazole was dissolved in 25 ml of tetrahydrofuran and 1 ml of pyridine, then 0.45 ml of ethyl oxalate chloride was added at 10 ° C. and the mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness and the residue was refluxed in 50 ml of dioxane for 2 hours. Then the dioxane was distilled off, the residue was mixed with about 50 ml of water and stirred with conc. Ammonia adjusted to pH 8. The precipitated product was filtered off and purified by column chromatography on silica gel.
  • Example 2 Prepared analogously to Example 1 from 1.0 g (2.45 mmol) of 1-methyl- 2- (4 -cyanophenyloxymethyl) -5- (4-oxo-3, 4-dihydro-phthalazin-1-yl) -benzimidazole, ethanolic hydrochloric acid, ethanol and Ammonium carbonate.
  • Example 2 Prepared analogously to Example 1 from 1.0 g (2.58 mmol) of 1-methyl-2- (4 -cyanophenyloxymethyl) -5- (1-isobutyl-1H-tetrazol-5-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
  • Example 2 Prepared analogously to Example 1 from 1-methyl -2- (4-cyanophenylaminomethyl) -5- (3-ethoxycarbonyl -5-tert-butyl-pyrazol-1-yl) benzimidazole, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
  • 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 injections.
  • (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 3 hard gelatin capsules on a capsule filling machine.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled on a capsule filling machine into hard gelatin capsules Gr6Be 0.
  • 1 suppository contains:
  • Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg

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Abstract

L'invention concerne de nouveaux hétérocycles bicycliques de formule générale (I), dans laquelle Ra, X1 à X4, Y, B, Ar et E sont tels que définis dans la revendication 1, ainsi que leurs tautomères, leurs stéréoisomères, leurs mélanges et leurs sels, lesquels présentent de précieuses propriétés. Les composés de la formule générale (I) susmentionnée dans lesquels (E) représente un groupe cyano constituent des produits intermédiaires précieux pour la fabrication des autres composés de la formule générale (I). Quant aux composés de la formule générale (I) susmentionnée dans lesquels E représente un groupe RbNH-C(=NH), ils présentent des propriétés pharmacologiques précieuses, en particulier un effet inhibiteur de la thrombine et de prolongement du temps de thrombine.
PCT/EP2000/001387 1999-02-24 2000-02-19 Heterocycles bicycliques substitues et leur utilisation comme inhibiteurs de la thrombine WO2000050419A1 (fr)

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AU29126/00A AU2912600A (en) 1999-02-24 2000-02-19 Substituted bicyclic heterocycles and the use thereof as thrombin inhibitors

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DE19907813A DE19907813A1 (de) 1999-02-24 1999-02-24 Substituierte bicyclische Heterocyclen, deren Herstellung und deren Verwendung als Arzneimittel
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Cited By (8)

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EP1148053A4 (fr) * 1999-01-26 2002-03-06 Ono Pharmaceutical Co Derives 2h-phthalazine-1-one et medicaments renfermant ces derives comme principe actif
US7115644B2 (en) 2002-09-13 2006-10-03 Boehringer Ingelheim Pharmaceuticals Inc. Heterocyclic compounds
WO2008067644A1 (fr) * 2006-12-04 2008-06-12 Boehringer Ingelheim International Gmbh Inhibiteurs de la réplication du vih
EP2234486A4 (fr) * 2007-12-19 2011-09-14 Scripps Research Inst Benzimidazoles et analogues comme inhibiteurs de la rho-kinase
US9221767B2 (en) 2013-01-18 2015-12-29 Bristol-Myers Squibb Company Substituted phthalazinones as rock inhibitors
WO2016187620A3 (fr) * 2015-05-21 2017-05-04 The Regents Of The University Of California Composés anti-cancereux
US9902702B2 (en) 2014-07-15 2018-02-27 Bristol-Myers Squibb Company Spirocycloheptanes as inhibitors of rock
US10640493B2 (en) 2016-06-24 2020-05-05 The Regents Of The University Of California Phthalazine derivatives as inhibitors of PARP1, PARP2, and/or tubulin useful for the treatment of cancer

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EP0531883A1 (fr) * 1991-09-06 1993-03-17 Dr. Karl Thomae GmbH Hétérocycles condensés à cinq chaînons, procédé pour leur fabrication et médicaments les contenant
WO1998037075A1 (fr) * 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments
WO2000001704A2 (fr) * 1998-07-04 2000-01-13 Boehringer Ingelheim Pharma Kg Benzimidazoles, leur preparation et leur utilisation comme medicaments
WO2000008014A1 (fr) * 1998-08-01 2000-02-17 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, en particulier a effet inhibiteur de la thrombine

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Publication number Priority date Publication date Assignee Title
EP0531883A1 (fr) * 1991-09-06 1993-03-17 Dr. Karl Thomae GmbH Hétérocycles condensés à cinq chaînons, procédé pour leur fabrication et médicaments les contenant
WO1998037075A1 (fr) * 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments
WO2000001704A2 (fr) * 1998-07-04 2000-01-13 Boehringer Ingelheim Pharma Kg Benzimidazoles, leur preparation et leur utilisation comme medicaments
WO2000008014A1 (fr) * 1998-08-01 2000-02-17 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, en particulier a effet inhibiteur de la thrombine

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6677333B1 (en) 1999-01-26 2004-01-13 Ono Pharmaceutical Co., Ltd. 2H-phthalazin-1-one derivatives and drug containing its derivatives as active ingredient
EP1148053A4 (fr) * 1999-01-26 2002-03-06 Ono Pharmaceutical Co Derives 2h-phthalazine-1-one et medicaments renfermant ces derives comme principe actif
US7115644B2 (en) 2002-09-13 2006-10-03 Boehringer Ingelheim Pharmaceuticals Inc. Heterocyclic compounds
WO2008067644A1 (fr) * 2006-12-04 2008-06-12 Boehringer Ingelheim International Gmbh Inhibiteurs de la réplication du vih
JP2010511635A (ja) * 2006-12-04 2010-04-15 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 Ｈｉｖ複製の阻害剤
US8039638B2 (en) 2006-12-04 2011-10-18 Boehringer Ingelheim International Gmbh Inhibitors of HIV replication
EP2234486A4 (fr) * 2007-12-19 2011-09-14 Scripps Research Inst Benzimidazoles et analogues comme inhibiteurs de la rho-kinase
US10385026B2 (en) 2013-01-18 2019-08-20 Bristol-Myers Squibb Company Phthalazinones and isoquinolinones as rock inhibitors
US9221767B2 (en) 2013-01-18 2015-12-29 Bristol-Myers Squibb Company Substituted phthalazinones as rock inhibitors
US9926282B2 (en) 2013-01-18 2018-03-27 Bristol-Myers Squibb Company Phthalazinones and isoquinolinones as rock inhibitors
US9902702B2 (en) 2014-07-15 2018-02-27 Bristol-Myers Squibb Company Spirocycloheptanes as inhibitors of rock
WO2016187620A3 (fr) * 2015-05-21 2017-05-04 The Regents Of The University Of California Composés anti-cancereux
US10562886B2 (en) 2015-05-21 2020-02-18 The Regents Of The University Of California Anti-cancer compounds
US11149025B2 (en) 2015-05-21 2021-10-19 The Regents Of The University Of California Anti-cancer compounds
US11708352B2 (en) 2015-05-21 2023-07-25 The Regents Of The University Of California Anti-cancer compounds
US10640493B2 (en) 2016-06-24 2020-05-05 The Regents Of The University Of California Phthalazine derivatives as inhibitors of PARP1, PARP2, and/or tubulin useful for the treatment of cancer
US11072600B2 (en) 2016-06-24 2021-07-27 The Regents Of The University Of California Phthalazine derivatives as inhibitors of PARP1, PARP2, and/or tubulin useful for the treatment of cancer
US12145925B2 (en) 2016-06-24 2024-11-19 Atlasmedx, Inc. Phthalazine derivatives as inhibitors of PARP1, PARP2, and/or tubulin useful for the treatment of cancer

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