Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions

CGRP antagonists of general formula

• wherein
• A denotes an oxygen or sulphur atom, a phenylsulphonylimino or cyanimino group,
• X denotes an oxygen or sulphur atom, an imino group optionally substituted by a C1-6-alkyl group or a methylene group optionally substituted by a C1-6-alkyl group,
• U denotes a C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl group wherein each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,
• V denotes a chlorine or bromine atom, an amino, methylamino or hydroxy group,
• W denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a difluoro- or trifluoromethyl group,
• R1 denotes a saturated, mono- or diunsaturated 5- to 7-membered aza, diaza, triaza, oxaza, thiaza, thiadiaza or S,S-dioxido-thiadiaza heterocyclic group,
• in which the abovementioned heterocycles are linked via a carbon or nitrogen atom,
• contain one or two carbonyl or thiocarbonyl groups adjacent to a nitrogen atom,
• may be substituted at one of the nitrogen atoms by an alkyl group,
• may be substituted at one or at two carbon atoms by an alkyl group, by a phenyl, phenylmethyl, naphthyl, biphenylyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl group, while the substituents may be identical or different, and
• while an olefinic double bond of one of the abovementioned unsaturated heterocycles may be fused to a phenyl, naphthyl, pyridine, diazine, 1,3-oxazole, thienyl, furan, thiazole, pyrrole, N-methylpyrrole or quinoline ring, to a 1H-quinolin-2-one ring optionally substituted at the nitrogen atom by an alkyl group or to an imidazole or N-methylimidazole ring or also two olefinic double bonds of one of the abovementioned unsaturated heterocycles may each be fused to a phenyl ring,
• while the phenyl, pyridinyl, diazinyl, furyl, thienyl, pyrrolyl, 1,3-oxazolyl, 1,3-thiazolyl, isoxazolyl, pyrazolyl, 1-methylpyrazolyl, imidazolyl or 1-methylimidazolyl groups contained in R1 as well as benzo-, thieno-, pyrido- and diazino-fused heterocycles in the carbon skeleton may additionally be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy, nitro, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylsulphonylamino, phenyl, difluoromethyl, trifluoromethyl, alkoxycarbonyl, carboxy, hydroxy, amino, alkylamino, dialkylamino, acetyl, acetylamino, propionylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, (4-morpholinyl)carbonyl, (1-pyrro-lidinyl)carbonyl, (1-piperidinyl)carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, methylenedioxy, aminocarbonylamino, alkanoyl, cyano, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while the substituents may be identical or different,
• R2 denotes the hydrogen atom,
• a phenylmethyl group or a C2-7-alkyl group which may be substituted in the ω position by a cyclohexyl, phenyl, pyridinyl, diazinyl, hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, aminocarbonyl, aminocarbonylamino, acetylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-(1-piperidinyl)-1-piperidinyl, 4-morpholinyl, hexahydro-1H-1-azepinyl, [bis-(2-hydroxyethyl)]amino, 4-alkyl-1-piperazinyl or 4-(ω-hydroxy-C2-7-alkyl)-1-piperazinyl group,
• a phenyl or pyridinyl group,
• while the abovementioned heterocyclic groups and phenyl groups may additionally be mono- di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by methyl, alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, aminocarbonyl, cyano, methylsulphonyloxy, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl, trifluoromethylsulphonyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl or di-(C1-3-alkyl)-amino-C1-3-alkyl groups and the substituents may be identical or different,
• R3 denotes the hydrogen atom or a C1-3-alkyl group optionally substituted by a phenyl or pyridinyl group,
• while the C1-3-alkyl group may be linked to an alkyl group present in R2 or a phenyl or pyridyl ring present in R2 and the nitrogen atom to which they are bound, forming a ring, or
• R2 and R3 together with the enclosed nitrogen atom denote a group of general formula
• wherein
• Y1 denotes the carbon atom or, if R5 is a pair of free electrons, it may also denote the nitrogen atom,
• q and r, if Y1 denotes the carbon atom, represent the numbers 0, 1 or 2, or
• q and r, if Y1 denotes the nitrogen atom, represent the numbers 1 or 2,
• R4 denotes the hydrogen atom, an amino, alkylamino, cycloalkylamino, dialkyl-amino, N-(cycloalkyl)-alkylamino, dicycloalkylamino, hydroxy, alkyl, cycloalkyl, amino-C2-7-alkyl, alkylamino-C2-7-alkyl, dialkylamino-C2-7-alkyl, amino-iminomethyl, alkylcarbonyl, alkylsulphonyl, alkylcarbonylamino, alkylsulphonyl-amino, N-alkylcarbonyl-N-alkylamino, N-alkylsulphonyl-N-alkylamino, amino-carbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, cyclo-alkylaminocarbonylamino, dicycloalkylaminocarbonylamino, phenylamino-carbonylamino, aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylamino-carbonylalkyl, aminocarbonylaminoalkyl, alkoxycarbonyl, alkoxycarbonylalkyl or carboxyalkyl group,
• or, if Y1 does not denote the nitrogen atom, the carboxy, aminomethyl, alkylaminomethyl or dialkylaminomethyl group,
• a phenyl, phenyl-C1-3-alkyl, pyridinyl, diazinyl, 1-naphthyl, 2-naphthyl, pyridinylcarbonyl or phenylcarbonyl group which may each be mono-, di- or trisubstituted in the carbon skeleton by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy, methylsulphonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ω-(dialkylamino)alkanoyl, ω-(dialkylamino)alkyl, ω-(dialkylamino)hydroxyalkyl, ω-(carboxy)alkanoyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while the substituents may be identical or different,
• a saturated or mono- or polyunsaturated 4- to 10-membered azacycloalkyl group, a 5- to 1 0-membered oxaza-, thiaza, diaza- or triazacycloalkyl group, a 6- to 10-membered azabicyclo- or diazabicycloalkyl group, a 1-alkyl-4-piperidinylcarbonyl or 4-alkyl-1-piperazinylcarbonyl, a 1-alkyl-4-piperidinylamino, 1-alkyl-4-piperidinylaminocarbonyl or 1-alkyl-4-piperidinylaminosulphonyl group,
• while the abovementioned mono- and bicyclic heterocycles are bound via a nitrogen or carbon atom,
• a methylene group in the abovementioned mono- and bicyclic heterocycles may be replaced by a carbonyl or sulphonyl group,
• in the abovementioned mono- and bicyclic heterocycles any methylene group not directly bound to a nitrogen, oxygen or sulphur atom may be substituted by one or two fluorine atoms,
• the abovementioned mono- and bicyclic heterocycles as well as the 1-alkyl-4-piperidinylcarbonyl- and 4-alkyl-1-piperazinylcarbonyl group in the ring may be mono- or polysubstituted by a C1-7-alkyl group and/or
• monosubstituted by a benzyl, alkanoyl, dialkylamino, phenylcarbonyl, pyridinylcarbonyl, carboxy, carboxyalkanoyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, alkylsulphonyl, cycloalkyl or cycloalkylalkyl group, or substituted by a cycloalkylcarbonyl, azacycloalkylcarbonyl, diazacycloalkylcarbonyl or oxazacycloalkylcarbonyl group optionally alkyl-substituted in the ring,
• while the alicyclic moieties contained in these substituents each comprise 3 to 10 ring members and the heteroalicyclic moieties each comprise 4 to 10 ring members and
• the phenyl and pyridinyl groups contained in the abovementioned groups may in turn be mono-, di- or trisubstituted by fluorine, chlorine, bromine or iodine atoms, by alkyl, alkoxy, methylsulphonyloxy, difluoromethyl, trifluoromethyl, hydroxy, amino, acetylamino, aminocarbonyl, aminocarbonylamino, aminocarbonylaminomethyl, cyano, carboxy, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, alkanoyl, ω-dialkylamino)alkanoyl, ω-(carboxy)alkanoyl, difluoromethoxy, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulphinyl or trifluoromethylsulphonyl groups, while the substituents may be identical or different,
• R5 denotes a hydrogen atom,
• a C1-4-alkyl group, while an unbranched alkyl group may be substituted in the ω position by a phenyl, pyridinyl, diazinyl, amino, alkylamino, dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 4-morpholinyl or hexahydro-1H-1-azepinyl group,
• an alkoxycarbonyl, the cyano or aminocarbonyl group or also, if Y1 denotes a nitrogen atom, a pair of free electrons,
• or, if Y1 does not denote a nitrogen atom, also the fluorine atom, or
• R4 and R5 together, if Y1 denotes the carbon atom, denote a 4- to 7-membered cycloaliphatic ring in which one or two methylene groups may be replaced by an —NH— or —N(alkyl)-group and one or two additional methylene groups may be replaced by carbonyl groups,
• while a hydrogen atom bound to a nitrogen atom within the abovementioned group R4 may be replaced by a protecting group,
• R6 and R7, which may be identical or different, in each case denote a hydrogen atom, a C1-3-alkyl or dialkylamino group or also, if Y1 does not denote a nitrogen atom, the fluorine atom and
• R8 and R9, which may be identical or different, each denote a hydrogen atom or a C1-3-alkyl, carboxy or C1-3-alkoxycarbonyl group,
• while, unless otherwise stated, all the abovementioned alkyl and alkoxy groups as well as the alkyl groups present within the other groups specified comprise 1 to 7 carbon atoms and may be straight-chain or branched, while each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,
• all the abovementioned cycloalkyl groups as well as the cycloalkyl groups present within the other groups specified, unless otherwise stated, may comprise 3 to 10 carbon atoms, while each methylene group may be substituted by up to 2 fluorine atoms,
• all the abovementioned aromatic and heteroaromatic groups may additionally be mono- di- or trisubstituted by fluorine, chlorine or bromine atoms, by cyano or hydroxy groups and the substituents may be identical or different,
• the tautomers, diastereomers, enantiomers, hydrates, mixtures thereof and the salts thereof as well as the hydrates of the salts.