Patent EA-002348-B1 (EA)
Title: 1-aryl-2-acylamino-ethane compounds and their use as neurokinin especially neurokinin 1 antagonists
Inventor: GERSPACHER MARC
IPC: C07D235/28
Filed: 1996-02-09
Abstract: 1. A compound of formula I   wherein R1 is aryl or heteroaryl; R2 is hydrogen, C1-C7alkyl or aryl-C1-C7alkyl; R3 is hydrogen, C1-C7alkyl, aryl or heteroaryl; R4 is aryl or heteroaryl; X is straight chain C1-C7alkylene, C2-C7 alkenylene or C4-C7alkanedienylene; and Am is an unsubstituted or mono- or di-substituted amino group, a disubstituted amino group being understood as including also an amino group in which the amino nitrogen is bonded into a ring, or a salt thereof. 2. A compound of formula I according to claim 1, wherein Am is an amino group -NR5R6 wherein R5 is hydrogen, unsubstituted or substituted C1-C7alkyl, unsubstituted or substituted C1-C7alkenyl. unsubstituted or substituted C1-C7alkynyl. unsubstituted or substituted cycloalkyl, unsubstituted or substituted (aza, oxa or thia)-cycloalkyl, unsubstituted or substituted benzo-(aza, oxa or thia)-cycloalkyl, aryl, partially hydrated heteroaryl, heteroaryl or (unsubstituted or substituted lower alkyl, unsubstituted or substituted C1-C7alkenyl, aryl or heteroaryl)-sulfonyl; and R6 is hydrogen, unsubstituted or substituted C1-C7alkyl, unsubstituted or substituted C1-C7alkenyl, unsubstituted or substituted C1-C7alkynyl, aryl, heteroaryl or acyl; or - when the radicals R5 and R6 together with the amino nitrogen form a ring - Am may also be an aza-(cycloalkyl, cycloalkenyl, cycloalkynyl, partially hydrated heteroaryl or heteroaryl) radical, bonded via a ring nitrogen atom, which in addition to the amino nitrogen may contain further hetero atoms selected from nitrogen, oxygen and sulfur atoms and which is unsubstituted or substituted. 3. A compound of formula I according to claim 1, wherein R1 is phenyl or pyridyl each of which is unsubstituted or substituted by 1 or 2 substituents selected from the group C1-C7alkyl, trifluoromethyl, halogen, hydroxy, C1-C7alkoxy and nitro; R2 is hydrogen, C1-C7alkyl or phenyl- C1-C7alkyl wherein the phenyl group is unsubstituted or substituted by 1 or 2 substituents selected from the group C1-C7alkyl, trifluoromethyl, halogen, hydroxy and lower alkoxy; R3 is hydrogen, C1-C7alkyl, phenyl, naphthyl or indolyl, with phenyl, naphthyl and indolyl each being unsubstituted or substituted by 1 or 2 substituents selected from the group C1-C7alkyl, trifluoromethyl, halogen, hydroxy and C1-C7alkoxy; R4 is phenyl, naphthyl or indoiyl, each of those radicals being unsubstituted or substituted by 1 or 2 substituents selected from the group C1-C7alkyl, trifluoromethyl. halogen, hydroxy and C1-C7alkoxy; X is C1-C7alkylene, C2-C7alkenylene or C4-C7alkanedienylene; and Am is an amino group -NR5R6 wherein R5 is an aryl radical selected from the group phenyl and naphthyl, that aryl radical being unsubstituted or substituted by from 1 to 3 radicals selected from C1-C7alkyl, halo-C1-C7alkyl, cyctoalkyl, halogen, hydroxy, C1-C7alkoxy, amino, C1-C7alkylamino, di- C1-C7alkylamino, piperidino, morpholino. thiomorpholino, nitro, C1-C7alkanoyl, halo- C1-C7alkanoyl, carboxy, C1-C7alkoxycarbonyt, carbamoyl, C1-C7alkylcarbamoyl, di- C1-C7alkylcarbamoyl, cyano, N- C1-C7alkyl-N-phenyl- C1-C7alkylcarbamoyl; and (phenyl or pyridyl)- C1-C7alkylcarbamoyl wherein the phenyl or pyridyl group is unsubstituted or substituted by C1-C7alkyl, trifluoromethyl, hydroxy, lower alkoxy or halogen; aryl-C1-C7alkyl in which the aryl group is defined in the same manner as an aryl radical R5 and which is unsubstituted or substituted by hydroxy in the C1-C7alkyl moiety; a heteroaryl radical selected from the group pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benz-imidazolyl. benzotriazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzopyranyl, quinolinyl and isoquinolinyl, that heteroaryl radical being unsubstituted or substituted by from 1 to 3 radicals selected from C1-C7alkyl, halo- C1-C7alkyl, halogen, hydroxy, C1-C7alkoxy, amino, C1-C7alkylamino, di- C1-C7alkylamino, nitro, C1-C7alkanoyl, halo- C1-C7alkanoyl, carboxy, C1-C7alkoxycarbonyt, carbamoyl, C1-C7alkylcarbamoyl, di- C1-C7alkylcarbamoyl, cyano, phenyl, (C1-C7lalkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl and oxo; heteroaryl- C1-C7alkyl wherein the heteroaryl group is defined in the same manner as a heteroaryl radical R5; a partially hydrated heteroaryl radical selected from the group dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyt, dihydrofuranyl, dihydrothienyl, dihydrooxazolyl. dihydrothiazolyl, dihydropyridyl and dihydropyrimidinyl, that partially hydrated heteroaryl radical being unsubstituted or substituted by from 1 to 3 radicals selected from C1-C7alkyl, halo- C1-C7alkyl, halogen, hydroxy, C1-C7alkoxy, amino, C1-C7alkylamino, di- C1-C7alkylamino, nitro, C1-C7alkanoyl, halo- C1-C7alkanoyl, carboxy, C1-C7alkoxycarbonyl, carbamoyl, C1-C7alkylcarbamoyl, di- C1-C7alkytcarbamoyl, cyano, phenyl, (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl and oxo; partially hydrated heteroaryt- C1-C7alkyl wherein the partially hydrated heteroaryl group is defined in the same manner as a partially hydrated heteroaryl radical R5; C1-C7alkyl that is unsubstituted or substituted by from 1 to 3 radicals selected from carboxy, lower alkoxycarbonyl, carbamoyl, C1-C7alkylcarbamoyl, di- C1-C7alkylcarbamoyl, cyano, amino, C1-C7alkylamino, di- C1-C7alkytamino, piperidino, morpholino, thiomorpholino, hydroxy, C1-C7alkoxy, halogen, C1-C7alkanoyl and benzoyl; C3-C7alkenyl that is unsubstituted or substituted by carboxy or by C1-C7alkoxycarbonyl; C3-C7alkynyl that is unsubstituted or substituted by carboxy or by C1-C7alkoxycarbonyl; cycloalkyl that is unsubstituted or substituted by C1-C7alkyl, hydroxy, carboxy or by C1-C7alkoxycarbonyl; cycloalkyl- C1-C7alkyl wherein the cycloalkyl group is defined in the same manner as cycloalkyl R5; (aza, oxa or thia)-cydoalkyl that is unsubstituted or substituted by oxo, C1-C7alkyl, phenyl- C1-C7alkyl, (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl- C1-C7alkyl, carboxy or C1-C7alkoxycarbonyl; benzo-(aza, oxa or thia)-cycloalkyl that is unsubstituted or substituted by oxo in the cycloaltphatic ring and is unsubstituted or substituted by C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy in the benzo ring; C1-C7alkylsulfonyl; arylsulfonyl wherein the aryl group is defined in the same manner as an aryl radical R5; aryl- C1-C7alkylsulfonyl wherein the aryl group is defined in the same manner as an aryl radical R5; C1-C7alkenylsulfonyl; aryl- C1-C7alkenylsulfonyl wherein the aryl group is defined in the same manner as an aryl radical R5; pyridylsulfonyl that is unsubstituted or substituted by C1-C7alkyl. trifluoromethyl. halogen, hydroxy, C1-C7alkoxy, phenyl- C1-C7alkoxy, (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl- C1-C7alkoxy, phenyloxy or (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyloxy; R6 is hydrogen, C1-C7alkyl, hydroxy- C1-C7alkyl, (carboxy, C1-C7alkoxycarbonyl, carbamoyl, C1-C7alkylcarbamoyl, di- C1-C7alkytcarbamoyl or cyano)- C1-C7alkyl, C3-C7alkenyl, C3-C7alkynyl, C1-C7alkanoyl, halo- C1-C7alkanoyl. phenyl- C1-C7alkanoyl that is unsubstituted or substituted by C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy in the phenyl ring, or benzoyl that is unsubstituted or substituted by C1-C7alkyl. trifluoromethyl, halogen, hydroxy or C1-C7alkoxy; or wherein -NR5R6 is a cyclic amino group selected from azacycloalkan-1-yl that is unsubstituted or substituted by 1 or 2 substituents selected from C1-C7alkyl, hydroxy- C1-C7alkyl, cyano- C1-C7alkyl, C1-C7alkyl-(sulfinyl or sulfonyl)- C1-C7alkyl, phenyl- C1-C7alkyl-(sulfinyl or sulfonyl)- C1-C7alkyl, (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl- C1-C7alkyl-(sulfinyl or sulfonyl)- C1-C7alkyl, phenyl-(sulfinyt or sulfonyl)- C1-C7alkyl, (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl-(sulfinyl or sulfonyl)- C1-C7alkyl, di- C1-C7alkylamino, C1-C7alkanoylamino, hydroxy, C1-C7alkoxy, carboxy, C1-C7alkoxycarbonyl, carbamoyl, C1-C7alkylcarbamoyl, di- C1-C7alkylcarbamoyl, cyano, phenyl, (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl and spiro-indolone that is unsubstituted or substituted by C1-C7alkyl; diazacycloalkan-1-yl that is unsubstituted or substituted by phenyl, (C1-C7alkyl, trifluoromethyl, halogen, hydroxy or C1-C7alkoxy)-phenyl, pyrimidinyl, (phenyl, C1-C7alkyl-phenyl, trifluoromethyl-phenyl, halo-phenyl, hydroxy-phenyl or C1-C7alkoxy-phenyl)- C1-C7alkyl, (carboxy, C1-C7alkoxycarbonyl, carbamoyl, C1-C7alkylcarbamoyl, di- C1-C7alkylcarbamoyl or cyano)- C1-C7alkyl or by (azacydoalkan-1-yl)-carbonyl- C1-C7alkyl; morpholino; thiomorpholino; and azaheteroaryl-1-yl selected from the group pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, triazol-1-yl, tetrazol-1-yl, indol-1-yl, benzimidazol-1-yl and benzotriazol-1-yl, that azaheteroaryl-1-yl radical being unsubstituted or substituted by C1-C7alkyl, di- C1-C7alkyiamino- C1-C7alkyl, cyano- C1-C7alkyl, hydroxy, C1-C7alkoxy, phenyl- C1-C7alkyloxy, C1-C7alkylthio, C1-C7alkanoyl or by halogen; or a salt thereof. 4. A compound of formula I according to claim 1, wherein R1 is phenyl that is unsubstituted or substituted by 1 or 2 substituents selected from the group C1-C7alkyl, trifluoromethyl, halogen, hydroxy and C1-C7alkoxy; R2 is hydrogen, C1-C7alkyl or phenyl- C1-C7alkyl wherein the phenyl group is unsubstituted or substituted by 1 or 2 substituents selected from the group C1-C7alkyl, trifluoromethyl, halogen, hydroxy and C1-C7alkoxy; R3 is hydrogen, C1-C7alkyl, phenyl, naphthyl or indolyl, with phenyl, naphthyl and indolyl each being unsubstituted or substituted by 1 or 2 substituents selected from the group C1-C7alkyl, trifluoromethyl, halogen, hydroxy and C1-C7alkoxy; R4 is phenyl, naphthyl or indolyl, each of those radicals b