Patent EA-000620-B1 (EA)
Title: Compounds having effects on serotonin-related systems
Inventor: AUDIA JAMES E
IPC: C07D237/30
Filed: 1996-01-11
Abstract: 1. A compound of the formula   wherein r is 0-4; s is 0-1; D is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl, imidazolyl, pyrazinyl, pyridazinyl or pyrimidinyl group; wherein X is hydrogen, phenyl, hydroxy or methoxy; provided that X is hydrogen or phenyl when r is 0; R is   the dotted line is an optional double bond; R<1> is piperidinyl, piperazino-, morpholino- or pyrrolyl, substituted with 0-1 phenyl or benzyl group or 0-4 C1-C3 alkyl, C1-C3 alkoxy- or halo- groups; which phenyl or benzyl group is substituted with 0-2 C1-C3 alkyl, halo-, trifluoromethyl or C1-C3 alkoxy-groups; or R<1> is   n and m are independently 4-5, and the group of formula VI may be substituted with 0-1 oxo- group and 0-2 C1-C3 alkyl, C1-C3 alkoxy- or halo groups; or R<1> is C1-C4 alkyl, substituted with pyrrolyl, furyl, chienyl, pyridinyl, morpholinyl, piperidinyl, tetrahydropyrrolyl, piperazinyl, tetrahydrofuryl, benzazepinyl, dibenzazepinyl or quinolinyl, substituted with 0-4 C1-C3 alkyl, C1-C3 alkoxy- or halo- groups; R<2> is hydroxy-, hydrogen, cyano-, C1-C4 alkyl, or (phenyl or benzyl substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy- or halo-groups; or R<2> is amino- substituted with phenyl or benzyl, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy-, halo- or trifluoromethyl groups; or R<2> is absent when the dotted line is a double bond; R<3> is C1-C4 alkyl, substituted with 0-2 phenyl groups, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy- or halo-groups; or R<3> is C1-C4 alkyl substituted with hydroxyimino- or hydroxy-; or R<3> is phenoxy-, substituted with 0-1 methylenedioxy or substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy-, trifluoromethyl or halo-groups; or R<3> is dibenzocycloheptenyl, benzodioxolyl, benzodioxinyl or dibenzocyclohexenyl; or R<3> is phenyl, naphthyl, tetralinyl, tetrazolyl, benzimidazoiyl, indolyl, benzofuryl, benzothienyl, piperidino- or morpholino-, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy-, C4-C8 cycloalkylalkoxy-, halo-, nitro-, trifluoromethyl, difluoromethyl, hydroxy- or trifluoromethoxy- groups; or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl or piperazinonyl group, substituted with 0-2 C1-C3 alkyl, oxo-, C1-C3 alkoxy-, halo- or trifluoromethyl groups; provided that R<3> is not halo- or trifluoromethyl-substituted phenyl when R<2> is hydroxy-; or R<2> and R<3> combine to form C1-C4 alkylidene, substituted with 0-2 phenyl groups. substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy-, halo- or trifluoromethyl groups; R<5> is C1-C6 alkyl or C1-C4 acyl; or R<5> is C1-C3 alkyl substituted with benzodioxinyl or benzodioxolyl, substituted on the phenyl ring with 0-2 C1-C3 alkyl. C1-C3 alkoxy- or halo-groups; or R<5> is pyridinyl, pyrimidinyl, indolyl, benzofuryl, benzothienyl, pyrazinyl, quinolinyl, isoquinolinyl, pyridazinyl or quinazolinyl, substituted with 0-2 C1-C3 alkyl, trifiuoromethyl, C1-C3 alkoxy- or halo-groups; or R<5> is   B is oxygen or sulfur; Y is a residue which combines with the atoms to which it is attached to complete a triazolyl, imidazolyl, thiazolyl or pyrrolyl ring; A is a residue which combines with the nitrogen atom to which it is attached to complete a) an azabicyclo (octyl, nonyl or decyl) group; b)   c)   or   d)   M is a residue which combines with the carbon atom to which it is attached to complete an indanyl, indenyl, pyrrolidinyl, tetralinyl, benzopyranyl, dihydroindolyl, naphthodihydrofuranyl, benzodihydrothienyl, benzodihydrofuranyl, benzodihydropyranyl, naphthodihydrothienyl or naphthodihydropyrrolyl group wherein the spiro junction is not to an aromatic ring, substituted with 0-2 C1-C3 alkyl, oxo-, C1-C3 alkoxy-, pyrrolidinyl- or piperidinyl- C1-C3 alkoxy-, C1-C2 alkylenedioxy-, phenoxy-, benzyloxy-, phenyl or halo- groups; p represents 0-2; R<6> and R<7> independently represent phenyl groups, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy- or halo-groups; or R<6> and R<7> combine with the atom to which they are attached to complete a fluorenyl or dihydroanthracenyl group; or R<6> and R<7> represent hydrogen, provided that p must not be 1; q represents 0-2; Q represents a residue which combines with the atoms to which it is attached to complete a phenyl or naphthyl group, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy- or halo-groups; R<8> is hydrogen or C1-C3 alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 of the formula   wherein r is 0-3; X is hydroxy-; R is   the dotted line is an optional double bond; R<2> is hydroxy- or hydrogen, or is absent when the dotted line is a double bond; R<3> is C1-C4 alkyl, substituted with 1-2 phenyl groups, substituted with 0-2 halo- groups; or R<3> is dibenzocycloheptenyl or benzodioxinyl; or R<3> is phenyl, benzothienyl, naphthyl, indolyl or piperidino, substituted with 0-2 C1-C3 alkoxy-, hydroxy-, cyano-, C1-C3 alkyl, C4-C8 cycloalkylalkoxy-, halo-, nitro-, trifluoromethyl or trifluoromethoxy groups; or R<2> and R<3> combine to form C1-C4 alkylidene, substituted with 1-2 phenyl groups. substituted with 0-2 halo-groups; provided that R<3> is not halo- or trifluoromethyl substituted phenyl when R<2> is hydroxy-; A is a residue which combines with the nitrogen atom to which it is attached to complete   M is a residue which combines with the carbon acorn to which it is attached to complete a benzopyranyl, naphthodihydrofuranyl, benzodihydrothienyl, or benzodihydrofuranyl group, wherein the spiro junction is not to an aromatic ring, substituted with 0-2 C1-C3 alkoxy-, benzyloxy-, phenyl or halo- groups; or a pharmaceutically acceptable salt thereof. 3. A compound of Claim 1 wherein X is hydroxy-, and D completes a pyrrolyl group. 4. A compound of Claim 1 wherein r is 1-3. 5. A compound of Claim 4 wherein s is 0. 6. A compound of Claim 3 wherein R is of formula III. 7. A compound of Claim 6 wherein R<2> is hydrogen or hydroxy-. 8. A compound of Claim 7 wherein R<3> is benzodioxolyl or benzodioxinyl; or R<3> is phenyl, naphthyl, indolyl or benzothienyl, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy-, C4-C8 cycloalkylalkoxy-, halo-, nitro-, trifluoromethyl, difluoromethyl, hydroxy- or trifluoromethoxy- groups; or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl or piperazinonyl group, substituted with 0-2 C1-C3 alkyl, oxo-, C1-C3 alkoxy-, halo- or trifluoromethyl groups. 9. A compound of Claim 8 wherein R<3> is phenyl or naphthyl,-, nitro-, trifluoromethyl, difluoromethyl, hydroxy- or trifluoromethoxy groups; or substituted with 0-1 phenyl, piperidinonyl. hexahydropyridazinonyl or piperazinonyl group, substituted with 0-2 C1-C3 alkyl, oxo-, C1-C3 alkoxy-, halo- or trifluoromethyl groups. 10. A compound of Claim 8 wherein R<3> is indolyl or benzothienyl, substituted with 0-2 C1-C3 alkyl, C1-C3 alkoxy-, C4-C8 cycloalkylalkoxy-, halo-, nitro-, trifluoromethyl, difluoromethyl, hydroxy- or trifluoromethoxy groups; or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl or piperazinonyl group, substituted with 0-2 C1-C3 alkyl, oxo-, C1-C3 alkoxy-, halo- or trifluoromethyl groups. 11. A compound of Claim 10 wherein R<3> is benzothienyl substituted with 1-2 C1-C3 alkoxy-, C1-C3 alkyl, C4-C8 cycloalkylalkoxy-, halo-, nitro-, trifluoromethyl or trifluoromethoxy groups. 12. A compound of Claim 10 wherein R<3> is indolyl substituted with 1-2 C1-C3 alkoxy-, C1-C3 alkyl, C4-C8 cycloalkylalkoxy-, halo-, nitro-, trifluoromethyl or trifluoromethoxy groups. 13. A compound of Claim 1 wherein R is of formula V and A is of formula VIII. 14. A compound of Claim 13 wherein M completes a benzopyranyl, benzodihydropyranyl, naphthodihydrofuranyl, benzodihydrofuranyl, indanyl, indenyl or tetralinyl group, substituted with 0-2 C1-C3 alkyl, oxo-, C1-C3 alkoxy-, pyrrolidinyl- or piperidinyl-C1-C3 alkoxy-, C1-C2 alkylenedioxy-, phenoxy-, benzyloxy-, phenyl or halo groups. 15. A compound of Claim 14 wherein the group completed by M is substituted with 0-2 alkyl, alkoxy-, oxo-, phenyl, halo-, phenoxy- or benzyloxy groups. 16. A compound of Claim 15 wherein M completes a benzopyranyl, benzodihydropyranyl, naphthodihydrofuranyl or benzodihydrofuranyl group, substituted with 0-2 oxo-, alkoxy- or phenoxy- groups. 17. A compound of Claim 14 wherein M completes an indenyl, tetralinyl, benzodihydrofuranyl or naphthodihydrofuranyl group, substituted with 0-2 C1-C3 alkyl, oxo-, C1-C3 alkoxy-, pyrrolidinyl- or piperidinyl- C1-C3 alkoxy-, C1-C2 alkylenedioxy-, phenoxy-, benzyloxy-, phenyl or halo groups. 18. A compound of Claim 17 wherein the group completed by M is substituted with 0-2 alkyl, oxo-, alkoxy-, phenyl, halo-, phenoxy- or benzyloxy groups. 19. A compound of Claim 18 wherein the group completed by M is substituted with 0-2 oxo-, alkoxy- or phenoxy- groups. 20. A compound of Claim 1 which is (2S)-(-)-1-(4-indolyloxy)-3-(4-(3,4-methylenedioxy)phenyl)piperidin-l-yl)-2-propanol, (2S)-(-)-1-(4-indolyloxy)-3-(spiro [1H-indene-1,4'-piperidin]-1'-yl)-2-propanol or (2S)-(-)-1-(4-indolyloxy)-3-(5-methoxyspiro[benzodihydrofuran-1(3H},4'-piperidin]-1'-yl)-2-propanol or a pharmaceutically acceptable salt thereof. 21. A compound of Claim 1 which is (2S)-(-)-1-(4-indolyloxy)-3-(4-(3,4-ethylenedioxylphenyl)piperidin-1-yl)-2-propanol, (2S)-(-)-1-(4-indolyloxy)-3-(3,4-dihydro-2-oxospiro[naphthalene-l(2H), 4'-piperidin]-1'-yl)-2-propanol or (2S)-(-)-1-(4-indolyloxy)-3-(4-methoxyspiro-[benzodihydrofuran-1(3H), 4'-piperidin]-3-one-l'-yl)-2-propanol or a pharmaceutically acceptable salt thereof. 22. A compound of Claim 1 which is (2S)-(-)-1-(4-indolyloxy)-3-(4-methoxyspiro[benzodihydrofuran-1(3H), 4'-piperidin]-1'-yl)-2-propanol, 1-(4-indolyloxy)-3- (4-methoxyspiro[benzodihydrofuran-1(3H),4'-piperidin]-1' -y) propane or (2S)-(-)-1-(4-indolyloxy)-3-(5-methylspiro[benzodihydrofuran-1(3H), 4'-piperidin]-1'-yl)-2-propanol or a pharmaceutically acceptable salt thereof. 23. A compound of Claim 2 which is (2S)-(-)-1-(4-indolyloxy)-3-(4-(2-naphthyl)piperidin-1-yl)-2-prop