Patent EA-003703-B1 (EA)
Title: Arylpiperazines having activity at the serotonin 1a receptor
Inventor: GODFREY ALEXANDER GLENN
IPC: C07D401/04
Filed: 1998-12-08
Abstract: 1. A compound of the formula wherein Ar' is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<1> is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio; R<2> is phenyl, naphthyl or (C3-C12)cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<3> is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; X is -(C=O)-, -CHOH- or -CH2-; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 2. A compound of Claim 1 wherein Ar' is phenyl or pyridine. 3. A compound of Claim 2 wherein Ar' is phenyl substituted with (C1-C6)alkoxy. 4. A compound of Claim 3 wherein R<2> is phenyl or (C3-C12)cycloalkyl. 5. A compound of Claim 4 wherein R<1> is hydrogen. 6. A compound of Claim 5 wherein X is -C=O. 7. A method of antagonizing the serotonin 1A receptor which comprises administering to a patient in need of such treatment an effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 8. A method of alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine which comprises the administration to a patient in need of such treatment of an effective amount of a compound of the formula wherein Ar' is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<1> is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio; R<2> is phenyl, naphthyl or (C3-C12)cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<3> is selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; X is -(C=O)-, -CHOH or -CH2-; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 9. A method of Claim 8 wherein the compound is 1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)propyl]piperazine; 1-(2-pyridyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine; 1-(2-ethoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)propyl]piperazine hydrochloride; 1-(2-methoxyphenyl)-4-[3-(benzoyl)-3-(phenyl)butyl]piperazine oxalate; 1-(2-methoxyphenyl)-4-[3-(cycloheptanecarbonyl)-3-(phenyl)propyl]piperazine hydrochloride; 1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazine hydrochloride; and 1-(2-methoxyphenyl)-4-[4-(cyclohexyl)-4-(hydroxy)-3-(phenyl)butyl]piperazine oxalate. 10. A method of treating anxiety comprising administering to a patient in need of such treatment an effective amount of a compound of the formula wherein Ar' is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<1> is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio; R<2> is phenyl, naphthyl or (C3-C12)cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<3> is selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; X is -(C=O)-, -CHOH- or -CH2-; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 11. A method of treating depression, hypertension, cognitive disorders, psychosis, sleep disorders, gastric motility disorders, sexual dysfunction, brain trauma, memory loss, eating disorders, obesity, substance abuse, obsessive-compulsive disease, panic disorder or migraine, comprising administering to a patient in need of such treatment an effective amount of a compound of the formula wherein Ar' is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<1> is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio; R<2> is phenyl, naphthyl or (C3-C12)cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<3> is selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; X is -(C=O)-, -CHOH- or -CH2-; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 12. A method for potentiating the action of a serotonin reuptake inhibitor in increasing the availability of serotonin, norepinephrin and dopamine in the brain, comprising administering to a patient in need of such treatment a serotonin reuptake inhibitor in combination with an effective amount of a compound of the formula wherein Ar' is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<1> is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio; R<2> is phenyl, naphthyl or (C3-C12)cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<3> is selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; X is -(C=O)-, -CHOH- or -CH2-; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1. 14. A method of Claim 8 wherein an effective amount of a serotonin reuptake inhibitor is administered. 15. A method of Claim 14 wherein the serotonin reuptake inhibitor is fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine or paroxetine. 16. A method of assisting a patient in ceasing or reducing their use of tobacco or nicotine comprising administering to a patient an effective amount of a compound of the formula wherein Ar' is a mono or bicyclic aryl or heteroaryl radical substituted with one to three substituents selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<1> is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio; R<2> is phenyl, naphthyl or (C3-C12)cycloalkyl substituted with one or two substituents selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; R<3> is selected from the group consisting of hydrogen (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkylhalo, (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl or halo; X is -(C=O)-, -CHOH- or -CH2-; or a pharmaceutically acceptable salt, racemate, optical isomer or solvate thereof. 17. A compound of the formula: or the pharmaceutically acceptable salts thereof. 18. A compound which is (+)-1-(2-methoxyphenyl)-4-[3-cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine and the pharmaceutically acceptable salts thereof. 19. A compound according to claim 18 wherein the pharmaceutically acceptable salt is a dihydrochloride salt. 20. A compound according to claim 18 wherein the pharmaceutically acceptable salt is an oxalate salt. 21. A compound according to claim 18 wherein the pharmaceutically acceptable salt is a maleate salt. 22. A compound according to claim 18 wherein the pharmaceutically acceptable salt is a phosphate salt. 23. A compound which is (+) -1-(2-methoxyphenyl)-4-[3-(cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine monohydrochloride. 24. A method of alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine which comprises the administration to a patient in need of such treatment of an effective amount of a compound of the formula: or the pharmaceutically acceptable salts thereof. 25. A method of alleviating the symptoms caused by withdrawal or partial withdrawal from the use of tobacco or of nicotine which comprises the administration to a patient in need of such treatment of an effective amount of (+)-1-(2-methoxyphenyl)-4-[3-cyclohexanecarbonyl)-3-(phenyl)butyl]piperazine or the pharmaceutically accepta