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WO2004080970A1 - Nouveaux composes bicycliques aromatiques, leur production et leur utilisation en tant que medicaments - Google Patents

Nouveaux composes bicycliques aromatiques, leur production et leur utilisation en tant que medicaments Download PDF

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Publication number
WO2004080970A1
WO2004080970A1 PCT/EP2004/002282 EP2004002282W WO2004080970A1 WO 2004080970 A1 WO2004080970 A1 WO 2004080970A1 EP 2004002282 W EP2004002282 W EP 2004002282W WO 2004080970 A1 WO2004080970 A1 WO 2004080970A1
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Prior art keywords
group
alkyl
amino
carbonyl
substituted
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English (en)
Inventor
Henning Priepke
Uwe Ries
Herbert Nar
Kai Gerlach
Roland Pfau
Georg Dahmann
Wolfgang Wienen
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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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
    • C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • 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
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to new aromatic bicycles of the general formula
  • the compounds of the above general formula I, in which Ar is substituted by a cyano group, are valuable intermediates for the preparation of the other compounds of the general formula I, and the compounds of the above general formula I, which contain no cyano group, and their tautomers
  • Their enantiomers, their diastereomers, their mixtures and their salts, in particular their physiologically compatible salts with inorganic or organic acids or bases, have valuable pharmacological properties, in particular an antithrombotic effect and a factor Xa-inhibiting effect.
  • the present application thus relates to the new compounds of the general formula I above, their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.
  • X is a nitrogen atom or a methine group
  • Y is a methine group or a nitrogen atom which is optionally substituted by a d 3 -alkyl or amino group
  • Z is a nitrogen atom or a methine group
  • R 1 is an amino, C 5 alkylamino, C 3 - 7 cycloalkylamino or phenyl C 1-3 alkylamino group, each on the amine nitrogen atom by a phenylcarbonyl or phenylsulfonyl group or by one in the alkyl part, optionally by a Carboxy group, an in vivo convertible group into a carboxy group, an amino, C ⁇ -3-alkyl amino or di- (C ⁇ -3- alkyl) -amino group substituted C ⁇ - 3 alkyl or C ⁇ -3-alkyl -carbonyl group can be substituted,
  • a di (C ⁇ -5 -alkyl) amino or N- (C3-7-cycloalkyl) -C ⁇ -5 -alkylamino group the C ⁇ -5-alkyl part with the exception of the 1-position each by a hydroxy, -C ⁇ - 3 -alkoxy-, amino-, C ⁇ - 3 -alkylamino- or di- (C ⁇ - 3 -alkyl) -amino group can be substituted,
  • a 4- to 7-membered cycloalkyleneimmo group a methylene group which is not directly adjacent to the imino group, by a hydroxy, d- 3 -alkoxy-, amino-, C ⁇ - 3 -alkylamino- or di- (C ⁇ - 3 -alkyl) -amino group can be substituted,
  • a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, C 3 -3 alkylamino or di (C 3 -3 alkyl) amino group and / or a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkylene imino group can be replaced by a sulfur atom or by a sulfinyl or sulfonyl group or
  • a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimmo group can be replaced by an oxygen or sulfur atom or by an -NH-, -N (C 2 -3 -alkanoyl) -, sulfinyl or sulfonyl group and / or
  • a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimmo group can be replaced by a -NH-CO- group
  • C 3 alkyl amino C 3 alkyl, C 3 alkylamino C 3 alkyl, di (C 3 alkyl) amino C 3 alkyl -, Aminocarbonyl-, d- 3 -alkylamino-carbonyl-, N- (C 3- 7-cycloalkyl) -C ⁇ -5-alkylaminocarbonyl-, N- (phenyl-C ⁇ _.3-alkyl) -C ⁇ -5 - alkylaminocarbonyl- or di- (C ⁇ -3 -alkyl) -aminocarbonyl group substituted 2,5-dihydropyrrol-1-yl-carbbnyl or 1, 2,5,6-tetrahydropyridin1-yl-carbonyl group,
  • aminosulfonyl or aminocarbonyl group which is optionally substituted by one or two d- 3 -alkyl, phenyl-C 1-3 alkyl or C 3-7 cycloalkyl groups, where the substituents can be identical or different,
  • the methylene group in the 3- or 4-position in a C 5-7 cycloalkylcarbonyl group can be replaced by an -NH group in which
  • the hydrogen atom of the -NH group can be replaced by a C 3 alkyl, C 3 alkyl carbonyl, phenylcarbonyl or phenylsulfonyl group,
  • the phenyl substituents can be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, d- 3 -alkyl or C ⁇ - 3 -alkoxy group,
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom
  • R 3 is a hydrogen atom
  • a linear or branched d- ⁇ -alkyl group which may be replaced by a hydroxy, C ⁇ -3- alkyloxy, carboxy, C ⁇ - 3 alkoxy-carbonyl, amino, d-3-alkylamino, di- (C ⁇ - 3 -alkyl) -amino-, d- 3 -alkyl-carbonylamino-, -C ⁇ - 5 -alkoxy-carbonylamino- or phenyl-d- 3 -alkoxy-carbbnylamino group is substituted,
  • a 4- to 7-membered cycloalkyleneimino group or by a 4- to 7-membered cycloalkyl group in which one or two methylene groups separated at least by a methylene group are each replaced by an oxygen or sulfur atom or by an -NH or -N (d -3 -alkyl) group and in which, if the cycloalkyl group contains an -NH- or an -N (C ⁇ - 3 -AlkyI) - group, a methylene group adjacent to the nitrogen atom and, if the cycloalkyl group contains a total of two -NH- or -N (C ⁇ -3 -alkyl) - Contains groups, a methylene group adjacent to two nitrogen atoms can be replaced by a carbonyl group, are substituted, or
  • a phenyl or heteroaryl group each through a hydroxy, C -4 alkyloxy, benzyloxy, hydroxycarbonyl-d- 3- alkoxy, ds-alkyloxy-carbonyl-Ci-s-alkyloxy, aminocarbonyl-d-3 -alkyloxy-, d-3-alkylaminocarbonyl-C ⁇ - 3 -alkyloxy-, di- (C- ⁇ -3-alkyl) - amihocarbonyl-C ⁇ .
  • 3 -alkyloxy, carboxy, d- 3 -alkyloxy-carbonyl group may be substituted, and
  • Ar is a phenyl group substituted by the radicals R 4 , R 5 and R 6 , where
  • R 4 is a cyano group
  • R 7 is a hydrogen atom or ad -3 alkyl group and R 8 denotes ad -3 -alkyl group
  • R 5 is a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, d -3 - alkyl, hydroxy, hydroxy-C ⁇ -3 alkyl, d -3 alkoxy, benzyloxy, C1.3 alkoxy-d. 3 - alkyl, amino, C ⁇ -3 alkyl amino or di (C ⁇ -3 alkyl) amino group and
  • R 6 represents a hydrogen, fluorine, chlorine or bromine atom or a d 3 -alkyl group
  • heteroaryl group means a monocyclic group optionally substituted in the carbon skeleton by a C 3 alkyl, carboxy d 3 alkoxy carbonyl or C 3 alkoxy carbonylamino group 5- or 6-membered heteroaryl group is to be understood, wherein
  • the 6-membered heteroaryl group has one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group is an imino group optionally substituted by a C 3 -C 3 -alkyl or phenyl- 3 -3-alkyl group, an oxygen or sulfur atom or
  • a -C 3 alkyl amino -C. 3 -alkyl-, C ⁇ - 3 -alkylamino- d- 3 -alkyl-, di- (C ⁇ .3-alkyl) -amino-C ⁇ -3 -alkyl- or phenyl-C ⁇ -3 -alkyl group substituted imino group or an oxygen- or sulfur atom and additionally a nitrogen atom or
  • a phenyl ring may also be fused to the above-mentioned monocyclic heteroaryl groups via two adjacent carbon atoms
  • alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched
  • 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 d- ⁇ -alkanol, a phenyl-d- 3- alkanol, a C 3 -9- Cycloalkanol, where a C ⁇ -s-cycloalkanol can additionally be substituted by one or two C ⁇ - 3 alkyl groups, a C 5-8 cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by an imino group which is optionally substituted by a C 3 alkyl, phenyl C 3 alkyl, phenyl d 3 alkoxycarbonyl or C 2-6 alkanoyl group and the cycloalkanol part is additionally replaced by one or two C 3 alkyl groups may be substituted, a C 4 -7-cycloalkenol, a
  • R a is a C ⁇ -8 alkyl, C alkyl 5- cycloalkyl, phenyl or phenyl-C ⁇ -3,
  • R b is a hydrogen atom, a C 3 alkyl, C 7 cycloalkyl or phenyl group and
  • R c represents a hydrogen atom or a C 3 alkyl group.
  • Those compounds of the general formula (I) which contain a group which can be split off in vivo and those in which X, Y and Z and R 1 to R 3 are defined as mentioned at the beginning and Ar is defined with the proviso that Ar is on the nitrogen atom by one or two hydroxy, d- C3 alkyl, C ⁇ - 8 alkyl-carbonyl, C ⁇ -8 -alkoxy-carbonyl or benzoyl, or substituted amidino group by a group of formula II or a C Contains 3 -alkyl- amino-d- 3 -alkyl or di- (C ⁇ -3 -alkyl) amino-C ⁇ -3 -alkyl group, are prodrugs for those compounds of general formula (I) in which Ar is an amidino or contains aminoalkyl group.
  • Preferred compounds of the general formula I are those in which
  • X is a nitrogen atom or a methine group
  • Y is a methine group which is optionally substituted by a d- 3 -alkyl group
  • Z is a nitrogen atom or a methine group
  • R 1 is an amino, ds-alkylamino or C 3 - 7 cycloalkylamino group, each on the amine nitrogen atom by a group in the alkyl part, optionally by a carboxy group, an in vivo convertible group to a carboxy group, an amino, d- 3- alkyl - amino- or di- (-C 3 alkyl) amino group substituted d-3 alkyl or C 3 -3 alkyl carbonyl group can be substituted,
  • a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, C 3 -3 alkylamino or di (C 3 -3 alkyl) amino group and / or
  • a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkyleneimino group can be replaced by a sulfur atom or by sulfinyl or sulfonyl group or
  • a -CH2-CH2- group in a 5- to 7-membered cycloalkyleneimino group can be replaced by a -NH-CO- group, 'an optionally by ad -3 -alkyl-, amino-C ⁇ - 3 -alkyl-, C 1-3 -Alkylamino- -C ⁇ -3 -alkyl-, di- (C ⁇ -3 -alkyl) -amino-C ⁇ -3 -alkyl-, aminocarbonyl-, C ⁇ -3 -alkylamino- carbonyl-, N- (C 3 7- cycloalkyl) -C-5-alkylaminocarbonyl-, N- (phenyl-C ⁇ -3-alkyl) -C ⁇ -5-alkylaminocarbonyl or di- (d. 3 -alkyl) -aminocarbonyl group substituted 2,5-dihydropyrrole- 1-yl-carbonyl or 1,
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom
  • R 3 is a hydrogen atom
  • Ci-e-alkyl group which may be replaced by a
  • a phenyl or heteroaryl group each optionally by a hydroxy, d- 4 -alkyloxy, benzyloxy, hydroxycarbonyl-C ⁇ .3-alkoxy-, C1-3- alkyloxy-carbonyl-C ⁇ - alkyloxy, aminocarbonyl C ⁇ . 3 alkyloxy, C ⁇ -3 alkyl aminocarbonyl-C ⁇ - 3 alkyloxy, di- (3 C ⁇ - alkyl) aminocarbonyl-C ⁇ - 3 alkyloxy,
  • Carboxy, d- 3 alkyloxy-carbonyl group are substituted, is substituted, and
  • Ar is a phenyl group substituted by the radicals R 4 , R 5 and R 6 , where
  • R 4 is a cyano group
  • R 7 is a hydrogen atom or a C ⁇ .3 alkyl group
  • R 8 is a C -3 alkyl group
  • R ° is a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl, C1. 3 - alkyl, hydroxy, benzyloxy, amino or C 1-3 alkylamino group and
  • R 6 represents a hydrogen, chlorine or bromine atom or a C 3 alkyl group
  • heteroaryl group means a mono- optionally substituted in the carbon skeleton by a C 3 -C 3 -alkyl, carboxy, C 3 -3 -alkoxy-carbonyl or C 3 -alkoxy-carbonylamino group cyclic 5- or 6-membered heteroaryl group is to be understood, where
  • the 6-membered heteroaryl group has one, two or three nitrogen atoms and
  • the 5-membered heteroaryl group is an imino group optionally substituted by a C -3 alkyl or phenyl C 3 -3 alkyl group, an oxygen or
  • a -C 3 alkyl amino -C. 3 -alkyl-, C- ⁇ -3-alkylamino- C ⁇ - 3 -alkyl-, di- (C ⁇ -3 -alkyl) -amino-C ⁇ -3 -alkyl- or phenyl-C ⁇ -3 -alkyl group substituted imino group or an oxygen or sulfur atom and additionally one
  • a phenyl ring can be fused to the monocyclic heteroaryl groups mentioned above via two adjacent carbon atoms
  • alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched
  • X is a nitrogen atom or a methine group
  • Y is a methine group
  • Z represents a nitrogen atom or a methine group
  • R 1 is an amino, d -5 alkylamino or C 3-7 cycloalkylamino group, each of which on the amine nitrogen atom by a group in the alkyl part, optionally by a carboxy group, an in vivo convertible group to a carboxy group, an amino, Ci-s -Alkylamino- or di- (C ⁇ -3-alkyl) -amino group substituted C ⁇ - 3 -AIkyI or d -3 -alkyl- carbonyl group can be substituted, a 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein
  • 3 -alkyl-, aminocarbonyl-, C 1-3 -alkylamino-carbonyl- or di- (C ⁇ . 3 -alkyl) -aminocarbonyl distr can be substituted or
  • a methylene group not adjacent to the imino group can be substituted by a hydroxy, benzyloxy, amino, d- 3- alkylamino or di- (-C-- 3- alkyl) -amino group and / or
  • a methylene group in the 3-position of a 5-, 6- or 7-membered cycloalkyleneimino group can be replaced by a sulfur atom or by sulfinyl or sulfonyl group or
  • a methylene group in the 4-position of a 6- or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom or by an -NH-, -N (C 2-3 -alkanoyl) -, sulfinyl or sulfonyl group and / or
  • a -CH 2 -CH 2 - group in a 5- to 7-membered cycloalkyleneimino group can be replaced by a -NH-CO group
  • C 3 alkyl amino C 3 alkyl, C 3 alkylamino C 3 alkyl, di (C 3 alkyl) amino C 3 alkyl -, aminocarbonyl, C ⁇ -3 alkylamino carbonyl, N- (C 3 - 7 cycloalkyl) -5 -C ⁇ alkylaminocarbonyl, N- (phenyl-3 C ⁇ - alkyl) -C ⁇ . 5 - alkylaminocarbonyl or di (C ⁇ -3 alkyl) aminocarbonyl group substituted 2,5-dihydropyrrol-1-yl-carbonyl or 1, 2,5,6-tetrahydropyridin1-yl-carbonyl group,
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom
  • R 3 is a hydrogen atom
  • a linear or branched C 6 alkyl group which is optionally substituted by a hydroxy, C 3 alkyloxy, carboxy or C 3 alkoxy carbonyl group, or
  • Ar is a phenyl group substituted by the radicals R 4 and R 5 , where
  • R 4 is a cyano group
  • amidino group which is optionally substituted by one or two hydroxyl, C 8 -8- alkyl-carbonyl, Ci- ⁇ -alkoxy-carbonyl or benzoyl groups,
  • R 7 is a hydrogen atom or a C ⁇ -3 alkyl group and R 8 is a C -3 alkyl group
  • R 5 represents a hydrogen atom or a hydroxy group
  • alkyl and alkoxy groups contained in the definitions and which have more than two carbon atoms, unless stated otherwise, can be straight-chain or branched
  • X, Y, Z, R 2 , R 3 and Ar are as defined above and
  • R 1 is a C 3- 7 cycloalkylamino group which is substituted on the amine nitrogen atom by a C 3 -C 3 -alkyl carbonyl group,
  • the compounds of the general formula I are obtained by processes known per se, for example by the following processes:
  • R 1 , R 2 , X, Y and Z are defined as mentioned above and L represents a leaving group such as a halogen atom, a sulfonyloxy or aryloxy group, for example a chlorine, bromine or iodine atom, a trifluoromethylsulfonyloxy, phenyloxy or p- Nitrophenyloxy group,
  • the coupling reaction is advantageously carried out in a solvent such as toluene, dioxane, dimethoxyethane, dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, preferably in the presence of a base such as sodium te / t-butylate, bis (trimethylsilyl) lithium amide, potassium carbonate, cesium carbonate, ethyldiisopropylamine (Hünig base ) or triethylamine at a temperature between 0 ° C and 200 ° C, preferably between 0 ° C and 150 ° C, optionally using a suitable catalyst, for example bis (tri-o-tolylphosphine) palladium (II) chloride , Tris (dibenzylidene
  • the coupling reaction can also be carried out without the addition of solvent in bulk by melting the compounds of the general formulas III and IV at temperatures between room temperature and 250 ° C., optionally in the presence of one of the bases mentioned above and / or optionally using one of the catalysts mentioned above, be performed.
  • R 1 and R 2 are defined as mentioned at the outset, Y represents a methine group, X and Z each represent a nitrogen atom and L represents a leaving group such as a halogen atom, for example a chlorine or bromine atom,
  • R 1 has one of the meanings mentioned for R 1 or represents an optionally protected carboxy group which can subsequently be converted into the radicals defined initially for R 1 , R 2 is defined as mentioned at the beginning and.
  • X 1 represents a hydroxy or C 4 alkoxy group or a halogen atom
  • R 1 and R 2 are defined as mentioned above, with a halogenating agent, for example with thionyl chloride, thionyl bromide or oxalyl chloride.
  • a halogenating agent for example with thionyl chloride, thionyl bromide or oxalyl chloride.
  • the cyclization is carried out, for example, in a high-boiling solvent such as chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or without further solvent in the presence of excess formamide at temperatures between 100 and 200 ° C., preferably between 130 and 170 ° C.
  • a high-boiling solvent such as chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or without further solvent in the presence of excess formamide at temperatures between 100 and 200 ° C., preferably between 130 and 170 ° C.
  • the subsequent reaction with a halogenating agent for example with thionyl chloride, thionyl bromide or oxalyl chloride, is advantageously carried out either without a solvent in the presence of dimethylformamide as a catalyst or by adding a solvent such as dimethylformamide, pyridine, 4- ( ⁇ /, ⁇ / -dimethylamino ) -pyridine, benzene, carbon tetrachloride, 1, 2-dichloroethane or chloroform at temperatures between 20 and 120 ° C.
  • a solvent such as dimethylformamide, pyridine, 4- ( ⁇ /, ⁇ / -dimethylamino ) -pyridine, benzene, carbon tetrachloride, 1, 2-dichloroethane or chloroform at temperatures between 20 and 120 ° C.
  • R 1 and R 2 are defined as mentioned at the outset, X and Y each represent a methine group, Z a nitrogen atom and
  • L represents a leaving group such as a halogen atom, for example a chlorine or bromine atom,
  • R 1 is defined as mentioned at the beginning or represents a bromine atom
  • R 2 is defined as mentioned at the beginning and
  • X 2 represents a hydroxy, d- ⁇ -alkoxycarbonyloxy or C 4 alkoxy group or a halogen atom, with sodium azide, subsequent cyclization of the resulting compound to a.
  • R 1 is defined as mentioned at the beginning or represents a bromine atom and R 2 is defined as mentioned at the beginning,
  • a halogenating agent for example with thionyl chloride, thionyl bromide or oxalyl chloride.
  • R 1 is a bromine atom, it can then be converted into the corresponding carboxylic acid by treatment with n-butyllithium and trapping the intermediate product with carbon dioxide.
  • reaction with sodium azide is carried out, for example, in acetone in the presence of triethylamine and ethyl chloroformate at temperatures between 0 ° C. and room temperature.
  • the rearrangement cyclization sequence is carried out, for example, in a high-boiling solvent such as diphenyl ether, chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or without further solvent in the presence of tributylamine at temperatures between 100 and 250 ° C., preferably between 200 and 250 ° C, performed.
  • a high-boiling solvent such as diphenyl ether, chlorobenzene, xylene, dimethylformamide, dimethyl sulfoxide, sulfolane or without further solvent in the presence of tributylamine at temperatures between 100 and 250 ° C., preferably between 200 and 250 ° C, performed.
  • R 1 and R 2 are defined as mentioned at the outset, X is a nitrogen atom Y and Z are each a methine group,
  • L represents a leaving group such as a halogen atom, for example a chlorine or bromine atom,
  • scheme 3 can be produced, for example, according to the following scheme 3: scheme 3:
  • 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, te / t-butyl, trityl, benzyl or tetrahydropyranyl group,
  • a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, te / t-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the Amino group also includes the phthalyl 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 residue is split off, for example by hydrogenolysis, 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 1 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 between -35 and -25 ° C.
  • a 2,4-dimethoxybenzyl residue is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a fe / t-butyl or ferf.-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 hydrazine or a primary amine such as methylamine, ethylamine or ⁇ -butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • An Al lyloxycarbonyl 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 (l) 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
  • the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Separate compounds of the general formula I with at least two asymmetric carbon atoms into their diastereomers on the basis of their physicochemical differences using methods known per se, for example by chromatography and / or fractional crystallization, if they are obtained in racemic form, they 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 obtained in this way, 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
  • Suitable optically active alcohols are, for example, (+) - or (-) - menthol, and 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 their pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this purpose 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 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 and their tautomers, their enantiomers, their diastereomers and their physiologically tolerable salts have valuable pharmacological properties, 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 which prolongs the aPTT time and on an inhibitory effect on related serine proteases such as, for. B. urokinase, factor VIIa, factor IX, factor XI and factor XII.
  • 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 (relative to the solvent control) by the test substance is determined at different concentrations of test substance and from this the IC 5 o calculated as the concentration which inhibits the factor Xa used by 50%.
  • pNA p-nitroaniline
  • Substrate S 2765 (Chromogenix), final concentration: 0.3 mM / l (1 KM) per reaction mixture
  • 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 prepared according to the invention are generally well tolerated.
  • the new compounds and their physiologically tolerable salts are suitable for prevention and
  • venous and arterial thrombotic diseases such as the prevention and 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, as well as prevention and treatment pulmonary embolism, disseminated intravascular coagulation, prophylaxis and treatment of coronary thrombosis. prophylaxis of stroke and prevention of occlusion of shunts.
  • the compounds according to the invention are used for ahtithrombotic support in thrombolytic treatment, such as, for example, with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase
  • C Prevention of long-term restenosis according to PT (C) A, for the prophylaxis and treatment of ischemic events in patients with all forms of coronary heart disease, for the prevention of metastasis and the growth of tumors and of inflammatory processes, for example in the treatment of pulmonary Fibrous, suitable for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin-dependent tissue adhesions and / or scar tissue formation as well as for promoting wound healing processes.
  • C PT
  • the new compounds and their physiologically tolerable salts can be used therapeutically in combination with acetylsalicylic acid, with platelet aggregation inhibitors such as fibrinogen receptor antagonists (eg abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the coagulation system and their recombinant analogs, for example C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, ticiopidine), with P 2 T receptor antagonists (e.g. Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (e.g. Terbogrel).
  • fibrinogen receptor antagonists eg abciximab, eptifibatide, tirofiban, roxifiban
  • physiological activators and inhibitors of the coagulation system and their recombinant analogs for example C,
  • the dosage required to achieve a corresponding effect is expediently 0.01 to 3 mg / kg, preferably 0.03 to 1.0 mg / kg for intravenous administration, and 0.03 to 30 mg / kg, preferably 0.1 to 10 mg / kg, each 1 to for oral administration 4 times a day.
  • the compounds of the 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, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate 3, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water / ethanol, water / - glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as
  • HPLC-MS data was generated on the following system: Waters ZMD, Alliance 2690 HPLC, Waters 2700 Autosampier, Waters 996 diode array detector
  • the mobile phase used was: A: water with 0.1% trifluoroacetic acid; B: acetonitrile with 0.1% trifluoroacetic acid
  • the following gradient was used: time in min% A% B flow rate in ml / min
  • Ethanol 4: 1 is eluted.
  • Example 2h Prepared analogously to Example 2h from 4-benzyloxy-3 - ⁇ [7-methoxy-6- (pyrrolidin-1-yI-carbonyl) -isoquinolin-1-yl] amino-methyl ⁇ -benzonitrile and hydrochloric acid / ammonium carbonate in ethanol and subsequent reaction analogous to Example 2i with palladium on activated carbon and hydrogen in methanol.
  • Ethyl 4-yl] amino ⁇ -propionate are suspended in 2 ml of water and stirred with 0.65 ml of 1N sodium hydroxide solution for 4.5 h. The mixture is then adjusted to pH 3 with 1 N HCl, the solvent is distilled off, methanol is added and the mixture is filtered. Diethyl ether is added to the filtrate, the precipitate which has separated out is filtered off with suction and dried in a drying gun.
  • 0.300 g (0.628 mmol) of 4-benzyloxy-3 - ⁇ [6-methyl-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl ⁇ -benzonitrile are dissolved in 15 ml of methanol and successively 0.125 g (1.52 mmol) sodium acetate in 0.25 ml water and 0.106 g (1.52 mmol) hydroxylamine hydrochloride in 0.25 ml water and heated to boiling. After 2 hours, 0.2 g of sodium acetate and 0.18 g of hydroxylamine hydrochloride are again added and the mixture is heated to boiling for a further 3 hours.
  • N- (n-hexyloxycarbonyl) benzamidine Prepared analogously to Example 24 from 4-benzyloxy-3 - ⁇ [6-chloro-7- (pyrrolidin-1-yl-carbonyl) -quinazolin-4-yl] aminomethyl ⁇ benzamidine , 0- (n-Hexyl) -0 '- (p-nitrophenyl) carbonate and triethylamine in dichloromethane. Yield: 67%
  • Example 8h Prepared analogously to Example 8h from 4-chloro-7- (3-tert-butoxycarbonylamino-piperidin-1-yl-carbonyl) -quinazoline, 3-aminomethyl-benzamidine and N, N-diisopropylethylamine in dimethylformamide at room temperature. Subsequently, to remove Boc, after removing the solvent in vacuo, the residue is treated with a mixture of dichloromethane / trifluoroacetic acid / distilled water 30: 63: 7 for 2 days. Volatile components are then removed in vacuo. HPLC-MS results: retention time: 2.31 min
  • Example 8h Prepared analogously to Example 8h from 4-chloro-7- (2-tert-butoxycarbonylaminomethyl-piperidin-1-yl-carbonyl) -quinazoline, 3-aminomethyl-benzamidine and diisopropylethyl-amine in dimethylformamide at room temperature and subsequent Boc elimination with trifluoroacetic acid analogous to example 39.
  • 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 gelatine capsules on a capsule filling machine.
  • This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.
  • Suppositories with 100 mg of active ingredient 1 suppository contains:
  • 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

L'invention concerne de nouveaux composés bicycliques aromatiques de formule (I), dans laquelle Ar, X, Y, et Z ainsi que R<1> à R<3> sont tels que spécifiés dans la revendication 1. L'invention concerne également leurs tautomères, leurs énantiomères, leurs diastéréomères, leurs mélanges, leurs promédicaments et leurs sels, ainsi que leur production et leur utilisation en tant médicaments. Les composés de formule (I) présentent des propriétés pharmacologiques importantes, en particulier une action antithrombotique et une action d'inhibition du facteur Xa.
PCT/EP2004/002282 2003-03-10 2004-03-05 Nouveaux composes bicycliques aromatiques, leur production et leur utilisation en tant que medicaments Ceased WO2004080970A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes
WO2005014533A3 (fr) * 2003-08-08 2005-04-07 Transtech Pharma Inc Composes aryle et heteroaryle, compositions et procedes d'utilisation
US7122580B2 (en) 2002-08-09 2006-10-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE602006016566D1 (de) * 2005-01-10 2010-10-14 Bristol Myers Squibb Co Als antikoagulanzien verwendbare phenylglycinamid-derivate

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037075A1 (fr) * 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998037075A1 (fr) * 1997-02-18 1998-08-27 Boehringer Ingelheim Pharma Kg Heterocycles bicycliques disubstitues, production et utilisation comme medicaments

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7122580B2 (en) 2002-08-09 2006-10-17 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
WO2005014532A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions et procedes associes
WO2005014534A1 (fr) * 2003-08-08 2005-02-17 Transtech Pharma, Inc. Composes aryle et heteroaryle, compositions, et methodes d'utilisation
WO2005014533A3 (fr) * 2003-08-08 2005-04-07 Transtech Pharma Inc Composes aryle et heteroaryle, compositions et procedes d'utilisation
US7208601B2 (en) 2003-08-08 2007-04-24 Mjalli Adnan M M Aryl and heteroaryl compounds, compositions, and methods of use
US7459472B2 (en) 2003-08-08 2008-12-02 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use
US7501538B2 (en) 2003-08-08 2009-03-10 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions and methods of use
US7544699B2 (en) 2003-08-08 2009-06-09 Transtech Pharma, Inc. Aryl and heteroaryl compounds, compositions, and methods of use

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