Source: http://www.google.es/patents/US6511987?hl=es&dq=flatulence
Timestamp: 2013-05-23 00:01:40
Document Index: 46311302

Matched Legal Cases: ['art 1', 'art 2', 'art 3', 'art 4', 'art 5', 'art 6', 'art 7', 'art 8', 'art 9', 'art 4', 'art 9', 'art 1', 'art 10', 'art 2', 'art 8', 'art 10', 'art 1']

Patente US6511987 - Bicyclic and tricyclic heteroaromatic compounds - Google PatentesB�squeda Im�genes Maps Play YouTube Noticias Gmail Drive M�s » B�squeda avanzada de patentes | Historial web | Iniciar sesi�n B�squeda avanzada de patentesPatentesDisclosed are compounds of the formula: and the pharmaceutically acceptable salts thereof, wherein W, Q, X, X1, Y and Z are as defined herein. These compounds bind with high selectivity and/or high affinity to the benzodiazepine site of GABAA receptors and are therefore useful in the treatment of central...http://www.google.es/patents/US6511987?utm_source=gb-gplus-sharePatente US6511987 - Bicyclic and tricyclic heteroaromatic compounds N�mero de publicaci�nUS6511987 B1Tipo de publicaci�nConcesi�n N�mero de solicitud09/709,887 Fecha de publicaci�n28 Ene 2003 Fecha de presentaci�n10 Nov 2000 Fecha de prioridad12 Nov 1999Tambi�n publicado comoCA2388593A1CN1390217AEP1228069A2EP1228069B1US7053093US7326709US20030181455US20060217384US20080146546WO2001034603A2WO2001034603A3 InventoresJun YuanPamela AlbaughKenneth ShawAlan Hutchinson Cesionario originalNeurogen Corporation Clasificaci�n de EE.UU.514/292546/85514/255.5546/86514/256544/405544/333546/87 Clasificaci�n internacionalA61P25/28A61K31/4545A61K31/437A61K31/541A61P25/22A61P25/20A61K31/496A61K31/55A61P25/00A61K31/5377A61P25/24A61P43/00C07D471/04C07D519/00C07D487/04C07D217/26C07D237/30 Clasificaci�n cooperativaC07D487/04G01N2333/70571C07D519/00C07D471/04C07D237/30C07D217/26 Clasificaci�n europeaC07D 519/00C07D 217/26C07D 237/30C07D 471/04C07D 487/04ReferenciasCitas de patentes (8) Citada por (3)Enlaces externosUSPTO Cesi�n de USPTO EspacenetBicyclic and tricyclic heteroaromatic compoundsUS 6511987 B1 Resumen Disclosed are compounds of the formula: and the pharmaceutically acceptable salts thereof, wherein W, Q, X, X1, Y and Z are as defined herein. These compounds bind with high selectivity and/or high affinity to the benzodiazepine site of GABAA receptors and are therefore useful in the treatment of central nervous system (CNS) diseases and as probes for the localization of GABAA receptors in tissue samples. Also disclosed are intermediates useful in the preparation of these compounds.
R1 is hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �NH(C1-C6alkyl), �N(C1-C6alkyl) (C1-C6alkyl), or H2N(C1-C6alkylene); X1 is CH or a carbon atom substituted with C1-C6 alkyl; R2 represents 0 to 4 groups independently chosen at each occurrence from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �NH(C1-C6alkyl), �N(C1-C6alkyl) (C1-C6alkyl), or H2N(C1-C6alkylene); W is aryl or heteroaryl, each of which is optionally substituted with one or more groups RA, wherein each RA is independently i) halogen, hydroxy, cyano, nitro, amino, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl) (C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C1-8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2(C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON(C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), or �SO2(C1-C8 alkyl); ii) aryl or heteroaryl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �NH(C1-C6alkyl), �N(C1-C6alkyl) (C1-C6alkyl), or H2N(C1-C6alkylene); iii) C1-C8alkyl, C2-C8alkenyl, C2-C8 alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl(C1-C3 alkyl), C3-C8cycloalkenyl, each of which is unsubstituted or substituted by one or more substituents independently selected from hydroxy, oxo, halogen, C1-C6alkoxy, �CONH2, �CONHC1-C6alkyl, �CON(C1-C6alkyl) (C1-C6alkyl), �COOH, and �CO2C1-C6alkyl; or iv) NR4R5, wherein R4, R5 and the nitrogen to which they are attached form a monocyclic or bicyclic ring optionally containing one or more of oxo, O, S, SO, SO2, or NR6 wherein R6 is hydrogen, C1-C6alkyl, or Ar�(C1-C6alkyl) where Ar is aryl or heteroaryl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, and amino(C1-C6)alkyl; and Q is selected Formulas III, IV and V: wherein: J is N or C1-C8 alkylene; and R9 and R10 are independently hydrogen, C1-C8 alkyl, or Ar1, wherein Ar1 is aryl or heteroaryl, each of which may be substituted with one or two of RB, where each RB independently carries the definition of RA; or R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring optionally containing one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl, or Ar1�(C1-C8 alkyl); wherein Ar1 is optionally substituted with one or two of RB, where each RB independently carries the definition of RA; and wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl; R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring which is optionally substituted with one or more of halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �NH(C1-C6alkyl), �N(C1-C6alkyl) (C1-C6alkyl), or H2N(C1-C6alkylene); and n is 1, 2, 3, or 4; and W′
(i) independently carries the same definition as W; (ii) represents �OR where R is C1-C8 alkyl or aryl(C1-C6)alkyl; or (iii) is M5 where M5 is hydroxy, C1-C8 alkyl, aryl(C1-C6)alkyl or �N(C1-C4 alkyl) (C1-C4 alkoxy). 2. A compound according to claim 1 of the formula wherein each R1, Q, and X1 are defined as in claim 1,
R2 represents 0 to 2 groups independently chosen at each occurrence from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �NH(C1-C6alkyl), �N(C1-C6alkyl) (C1-C6alkyl), or H2N(C1-C6alkylene); and W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, amino, C1-C8alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl) (C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C1-8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2(C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON (C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), �SO2(C1-C8 alkyl) and phenyl. 3. A compound according to claim 2 wherein W is phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyrimidyl, imidazolyl, isoxazolyl, furanyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
halogen, hydroxy, cyano, nitro, amino, C1-C8alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl) (C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C1-8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2(C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON(C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), �SO2(C1-C8 alkyl) and phenyl. 4. A compound according to claim 3, wherein
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy; Q is selected from the group consisting of Formulas III, IV and V: wherein: J is N or C1-C8 alkylene; and R9 and R10 are independently hydrogen, C1-C8 alkyl; or R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl; R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6alkyl; and n is 1, 2, 3, or 4; W′ phenyl, pyridyl, or naphthyl; and W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy. 5. A compound according to claim 3, wherein R1 is hydrogen or C1-C6 alkyl.
W is phenyl, naphthyl, thienyl, pyridyl, pyrazinyl, pyrimidyl, imidazolyl, isoxazolyl, furanyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, amino, C1-C8alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl) (C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C1-8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2(C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON(C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), �SO2(C1-C8 alkyl) and phenyl. 7. A compound according to claim 6, wherein
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy; Q is selected from the group consisting of Formulas III, IV and V wherein: J is N or C1-C8 alkylene; and R9 and R10 are independently hydrogen, C1-C8 alkyl; or R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl; R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6alkyl; and n is 1, 2, 3, or 4; W′ phenyl, pyridyl, or naphthyl; and W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy. 8. A compound according to claim 2, wherein where R1 is hydrogen or C1-C6 alkyl.
9. A compound according to claim 3, wherein R1 is hydrogen or C1-C6 alkyl.
10. A compound according to claim 9, wherein R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V wherein: J is N or C1-C8 alkylene; and R9 and R10 are independently hydrogen, C1-C8 alkyl; or R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl; R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and n is 1, 2, 3, or 4; W′ phenyl, pyridyl, or naphthyl; and W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy. 11. A compound according to claim 1, which is:
1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]piperidine. 12. A compound according to claim 1, which is:
1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]pyrrolidine. 13. A compound according to claim 1, which is:
(R)-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-2-hydroxymethyl-pyrrolidine. 14. A compound according to claim 1, which is:
4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]morpholine. 15. A compound according to claim 1, which is:
cis-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-2,6-dimethylpiperidine. 16. A compound according to claim 1, which is:
4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-thiomorpholine. 17. A compound according to claim 1, which is:
1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-4-methylpiperazine. 18. A compound according to claim 1, which is:
cis-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-3,5-dimethylpiperazine. 19. A compound according to claim 1, which is:
1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-N,N-dimethylamine. 20. A compound according to claim 1, which is:
1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-N,N-diethylamine. 21. A compound according to claim 1, which is:
1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine. 22. A compound according to claim 1, which is:
(R)-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine. 23. A compound according to claim 1, which is:
1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine. 24. A compound according to claim 1, which is:
1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine. 25. A compound according to claim 1, which is:
(R)-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine. 26. A compound according to claim 1, which is:
1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine. 27. A compound according to claim 1, which is:
1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine. 28. A compound according to claim 1, which is:
(R)-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethylpyrrolidine. 29. A compound according to claim 1, which is:
1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine. 30. A compound according to claim 1, which is:
4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-1,1-dioxido-thiomorpholine. 31. A compound according to claim 1, which is: cis-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3,5-dimethyl-piperazine.
32. A compound according to claim 1, which is: cis-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}}-3,5-dimethyl-piperazine.
33. A compound according to claim 1, which is: cis-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-}}-3,5-dimethyl-piperazine.
34. A compound according to claim 1, which is: 1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine.
35. A compound according to claim 1, which is:
1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-4-methyl piperidine. 36. A compound according to claim 1, which is:
(R)-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methyl-piperazine. 37. A compound according to claim 1, which is:
(S-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methyl-piperazine. 38. A compound according to claim 1, which is:
4-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}morpholine. 39. A compound according to claim 1, which is:
1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine. 40. A compound according to claim 1, which is:
cis-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2,5-dimethylpiperazine. 41. A compound according to claim 1, which is:
1-{[3-(4-Methylisoxazol-3-yl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine. 42. A compound according to claim 1, which is:
4-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}morpholine. 43. A compound according to claim 1, which is:
(R)-1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine. 44. A compound according to claim 1, which is:
1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine. 45. A compound according to claim 1, which is:
(S)-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-3-methylpiperazine. 46. A compound according to claim 1, which is:
S)-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methylpiperazine. 47. A compound according to claim 1, which is:
(S)-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methylpiperazine. 48. A compound according to claim 1, which is:
S-1-{[3-(4-Methoxyphenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-homopiperazine. 49. A compound according to claim 1 of the formula wherein
W is phenyl, isoxazolyl, thienyl, pyridyl, or quinolyl, each of which is optionally substituted with one, two, or three of V1, V2 and V3, where V1, V2, and V3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl); R2 represents 0 to 2 groups independently chosen from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), and �N(C1-C8 alkyl) (C1-C8 alkyl); R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl); and R9 and R10 are independently hydrogen or C1-C8 alkyl; or R9 and R10 together represent a C4-C6 straight chain alkylene group which together with the nitrogen atom to which R9 and R10 are attached form a 5- to 7-membered ring optionally containing one or two double bonds, O and/or N�R8 where R8 is hydrogen, C1-C8 alkyl, or HAr�(C1-C8)alkyl, where HAr is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted with one or two halogen, hydroxy, hydroxy(C1-C6)alkyl, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl). 50. A compound according to claim 1 of the formula wherein
W is phenyl, isoxazolyl, thienyl, pyridyl, or quinolyl, each of which is optionally substituted with one, two, or three of V1, V2 and V3, where V1, V2, and V3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl); R2 represents up to 2 groups independently chosen from hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl); R1 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl; and W′ represents (i) phenyl optionally substituted with one, two, or three of T1, T2 and T3, where T1, T2, and T3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl); (ii) �OR where R is C1-C8 alkyl or aryl(C1-C6)alkyl; or (iii) M5 where M5 is hydroxy, C1-C8 alkyl, aryl(C1-C6)alkyl or �N(C1-C4 alkyl) (C1-C4 alkoxy). 51. A pharmaceutical composition comprising a compound according to claim 1 combined with at least one pharmaceutically acceptable carrier or excipient.
52. A method for the treatment of anxiety, depression, a sleep disorder, or cognitive impairment said method comprising administering to a patient in need of such treatment an effective amount of a compound of claim 1.
53. A method for localizing GABAA receptors in a tissue sample comprising:
contacting with the sample a detectably-labeled compound of claim 1 under conditions that permit binding of the compound to GABAA receptors, washing the sample to remove unbound compound, and detecting the bound compound. 54. A method of inhibiting the binding of a benzodiazepine compound to a GABAA receptor, said method comprising contacting a compound of claim 1 with cells expressing the GABAA receptor, in the presence of the benzodiazepine, wherein the compound is present at a concentration sufficient to inhibit the binding of the benzodiazepine compound to the GABAA receptor in vitro.
55. A method for altering the signal-transducing activity of GABAA receptors, said method comprising exposing cells expressing the GABAA receptors to a compound according to claim 1 at a concentration sufficient to inhibit RO15-1788 binding to cells expressing a cloned human GABAA receptor in vitro.
56. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 51 in a container and instructions for using the composition to treat a patient suffering from anxiety, depression, a sleep disorder, attention deficit disorder, Alzheimer's dementia, or cognitive impairment.
57. A compound according to claim 1 wherein in a assay of GABAA receptor binding that determines the displacement of 3H-Flumazenil from rat cortical tissue in 0.05 M Tris HCl buffer at 4� C. the compound exhibits an Ki of 1 micromolar or less.
58. A compound according to claim 1 wherein in a assay of GABAA receptor binding that determines the displacement of 3H-Flumazenil from rat cortical tissue in 0.05 M Tris HCl buffer at 4� C. the compound exhibits an Ki of 100 nanomolar or less.
59. A compound according to claim 1 wherein in a assay of GABAA receptor binding that determines the displacement of 3H-Flumazenil from rat cortical tissue in 0.05 M Tris HCl buffer at 4� C. the compound exhibits an Ki of 10 nanomolar or less.
This application claims the benefit of Provisional application Ser. No. 60/165,054, filed Nov. 12, 1999.
FIELD OF THE INVENTION This invention relates to heterocyclic derivatives that bind to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in the treatment of central nervous system (CNS) diseases. This invention also relates to the use of these heterocyclic compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABAA receptors in tissue sections.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2π subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2α, 2β, and 1γ subunits (Pritchett & Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are α1β2γ2, α2β3γ2, α3β3γ2, and α5β3γ2 (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).
SUMMARY OF THE INVENTION This invention provides heterocyclic derivatives, particularly imidazoquinoline and 1,2,4-triazoloquinoline derivatives, that bind to the benzodiazepine site of the GABAA receptor, including human GABAA receptors. Preferably, these compounds also bind with high affinity to such receptors. More preferably, these compounds bind with high selectivity to such receptors.
The invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula 1.
The invention further provides methods of treating patients suffering from CNS disorders with a therapeutically effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) and livestock animals suffering from CNS disorders with a therapeutically effective amount of a compound of the invention is contemplated by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering a therapeutically effective amount of a compound of the invention with another CNS active compound.
Additionally this invention provides for the use of the compounds of the invention as probes for the localization of GABAA receptors in tissue samples, in particular, tissue sections.
The invention also provides intermediate compounds that are useful in the preparation of compounds of Formula 1.
A broad aspect of the invention is directed to compounds of Formula 1: And the pharmaceutically acceptable salts thereof, wherein:
X represents N or CR1, wherein
R1 is hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, or amino(C1-C6)alkyl;
X1 represents N, CH, or C1-C6alkyl;
Y and Z are independently hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, or amino(C1-C6)alkyl; or
Y and Z together form an arylene ring or a C3-C8 cycloalkylene ring, each of which is optionally substituted with up to four groups R2 independently chosen at each occurrence from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, and amino(C1-C6) alkyl;
W is aryl or heteroaryl, each of which is optionally substituted with one or more groups RA, wherein each RA is independently
i) halogen, hydroxy, cyano, nitro, amino, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl)(C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C1-8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2(C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON(C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), or �SO2(C1-C8 alkyl);
ii) aryl or heteroaryl, each of which is optionally substituted with one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, and amino (C1-C6) alkyl;
iii) C1-C8alkyl, C2-C8alkenyl, C2-C8 alkynyl, C3-C8cycloalkyl, C3-C8cycloalkyl (C1-C3 alkyl), C3-C8cycloalkenyl, each of which is unsubstituted or substituted by one or more substituents independently selected from hydroxy, oxo, halogen, C1-C6alkoxy, �CONH2, �CONHC1-C6alkyl, �CON(C1-C6alkyl) (C1-C6alkyl), �COOH, and �CO2C1-C6alkyl; or
iv) NR4R5, wherein R4, R5 and the nitrogen to which they are attached form a monocyclic or bicyclic ring optionally containing one or more of oxo, O, S, SO, SO2, or NR6 wherein R6 is hydrogen, C1-C6alkyl, or Ar�(C1-C6alkyl) where
Ar is aryl or heteroaryl, each of which is optionally substituted by one or two groups independently selected from halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, and amino(C1-C6)alkyl; and
Q is selected Formulas III, IV and V: wherein:
J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-C8 alkyl, or Ar1, wherein Ar1 is aryl or heteroaryl, each of which may be substituted with one or two of RB, where each RB independently carries the definition of RA; or
R9, R10 and the atom to which they are attached form a 4-to 8-membered monocyclic or bicyclic ring optionally containing one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl, or Ar1�(C1-C8 alkyl); wherein Ar1 is optionally substituted with one or two of RB, where each RB independently carries the definition of RA; and wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6) alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6) alkanoyl; and
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C8 alkoxy; or
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring which is optionally substituted with one or more of halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, or amino(C1-C6)alkyl; and
(i) independently carries the same definition as W;
(ii) represents �OR where R is C1-C8 alkyl or aryl(C1-C6)alkyl; or
(iii) is M5 where M5 is hydroxy, C1-C8 alkyl, aryl(C1-C6)alkyl or �N((C1-C4 alkyl) (C1-C4 alkoxy).
DETAILED DESCRIPTION OF THE INVENTION For compounds of Formula I (above) preferred aryl and heteroaryl groups representing the variable W include, but are not limited to the groups W1 defined as follows: W1: phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is optionally substituted by one or more groups independently chosen at each occurrence from
halogen, hydroxy, cyano, nitro, amino, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl) (C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C1-8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2(C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON(C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), �SO2(C1-C8 alkyl), and phenyl.
Especially preferred groups representing the variable W includes the groups W2, wherein W2 represents phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is optionally substituted by one or more groups independently chosen at each occurrence from
A preferred arylene ring formed by Y and Z is benzo. Particularly preferred benzo rings are unsubstituted or substituted with one, two, or three, more preferably one or two, of R2 where each R2 is the same as or different than every other R2. Preferred benzo substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, �NO2, �CN, amino, �NH(C1-C6 alkyl), and �N(C1-C6 alkyl)2. Highly preferred benzo substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, �NH(C1-C6 alkyl), and �N(C1-C6 alkyl)2.
Preferred cycloalkylene rings formed by Y and Z are 5-, 6-, and 7-membered cycloalkylene rings. Particularly preferred are 5-, 6-, and 7-membered cycloalkylene rings are that are unsubstituted or are substituted with one, two, or three, preferably one or two, of R2 where each R2 is the same as or different than every other R2. Preferred cycloalkylene substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, �NO2, �CN, �SO2NH2, amino, �NH(C1-C6 alkyl), and �N(C1-C6 alkyl)2. Highly preferred cycloalkylene substituents are halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, amino, �NH(C1-C6 alkyl), and �N(C1-C6 alkyl)2.
A preferred group of compounds of the invention includes those represented by Formula A-3 wherein R2, Q, X1, X and W are as defined for Formula I and R2 is independently chosen at each occurrence.
Preferred compounds of Formula A-3 include compounds where
W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of:
halogen, hydroxy, cyano, nitro, amino, C1-C8alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl) (C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C1-8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2(C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON(C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), �SO2(C1-C8 alkyl) and phenyl.
Even more preferred compounds of Formula A-3 include those where
R2 is independently chosen at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V: wherein:
R9 and R10 are independently hydrogen, C1-C8 alkyl; or
R9, R10 and the atom to which they are attached form a 4-to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy (C1-C6) alkyl;
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6 alkyl; and
W′ phenyl, pyridyl, or naphthyl; and
W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is unsubstituted or substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.
Other preferred compounds of Formula A-3 include compounds where X1 is CR1 and R1 is hydrogen or C1-C6alkyl.
Preferred compounds of Formula A-3 also include compounds wherein X1 is CR1 and R1 is hydrogen or C1-C6alkyl, and W has the definition of W1 or more preferably W has the definition of W2.
Also preferred are compounds of Formula A-3 wherein X1 is CR1 and R1 is hydrogen or C1-C6alkyl;
R2 is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Q is selected from the group consisting of Formulas III, IV and V
R9 R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl(C1-C6)alkanoyl; and
Preferred W groups of Formula A-3 are those carrying k-2 substituents where k is the number of hydrogen atoms on the aryl or heteroaryl group defined by W. More preferably, the W groups carry k-3 substituents. The most preferred W groups are those carrying 1 or 2 substituents, and those substituents are most preferably hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- or di(C1-C6) alkylamino.
Another preferred group of compounds of the invention are those depicted by Formula A-6 wherein R2, Q, and X are defined as in Formula I, R2 is independently defined at each occurrence, and W is W1.
More preferred are compounds of Formula A-6 are those where R2, Q, and X are defined as in Formula I, and W is W2.
More preferred are compounds of Formula A-6 include those where
R2 are independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl;
R11 and R12 together with the atoms to which they are attached form a 5-8 membered monocyclic ring, which is optionally substituted with C1-C6alkyl; and
Preferred W groups of Formula A-6 are those carrying k-2 substituents where k is the number of hydrogen atoms on the aryl or heteroaryl group defined by W. More preferably, the W groups carry k-3 substituents. The most preferred W groups are those carrying 1 or 2 substituents, and those substituents are most preferably hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- or di(C1-C6)alkylamino.
Another preferred group of compounds of the invention is represented by Formula A-9, i.e., compound where both X and X1 are both CH, wherein R1, R2, and Q are as defined as in Formula 1, and W is W1.
More preferred are compounds of Formula A-9 include those wherein R2 and Q are as defined in Formula I, and W is W1.
Most preferred compounds of formula A-9 are those wherein
Q is selected from the group consisting of Formulas III, IV and V: J is N or C1-C8 alkylene; and
R9 and R10 are independently hydrogen, C1-CC8 alkyl; or
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C5 ) alkyl;
R11 is selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 alkanoyl, aryl(C1-C6)alkyl, and aryl (C1-C6) alkanoyl; and
Preferred W groups of Formula A-9 are those carrying k-2 substituents where k is the number of hydrogen atoms on the aryl or heteroaryl group defined by W. More preferably, the W groups carry k-3 substituents. The most preferred W groups are those carrying 1 or 2 substituents, and those substituents are most preferably hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- or di(C1-C6)alkylamino.
Still another preferred group of compounds is represented by Formula A-12. wherein
wherein R1, Q, and X are as defined in Formula I and p is 1, 2, 3, and 4; and W is W1.
More preferred compounds of Formula A-12 are those where
R2, Q, and X are as defined in Formula 1;
W is W2.
Even more preferred compounds of Formula 12 are those wherein
R2 is selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
Preferred compounds of the invention are also encompassed by Formula A-15 wherein R1, Q, and X are as defined in Formula 1; p is 1, 2, 3, or 4; and W is W1.
More compounds of Formula A-15 are those wherein
Even more preferred compounds of Formula A-15 are those where
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C6 alkyl or hydroxy(C1-C6 )alkyl;
Preferred compounds of the invention are also encompassed by Formula A-17, i.e., compounds where Y and Z are not joined to form an aryl ring. wherein X, X1, and Q are defined as in Formula I, and W is W1; and
Y and Z are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl.
More preferred compounds of Formula A-17 are those wherein X, X1, and Q are defined as in Formula I, and W is W2; and Y and Z are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, amino, C1-C6 alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, mono or di(C1-C6)alkylamino, amino(C1-C6)alkyl.
Even more preferred are compounds of Formula A-17 wherein
Other preferred compounds are represented by Formula A-18 W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which is optionally substituted with one, two, or three of V1, V2 and V3, where V1, V2, and V3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl);
R1 and R2 independently represent hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl);
X is nitrogen or CR111, where R111 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl); and
R9 and R10 are independently hydrogen or C1-C8 alkyl; or
NR9R10 represents a 5- to 7-membered ring optionally containing one or two double bonds, O and/or N�R8 where R8 is hydrogen, C1-C8 alkyl, or HAr�(C1-C8)alkyl, where HAr is phenyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted with one or two halogen, hydroxy, hydroxy(C1-C6)alkyl, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl).
More preferred compounds of Formula A-18 include those where X is nitrogen.
Still other more preferred compounds of Formula A-18 are those where X is CH or a carbon atom substituted with (C1-C6) alkyl.
Other preferred compounds are represented by Formula A-19 W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which is optionally substituted with one, two, or three of V1, V2 and V3, where V1, V2, and V3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl);
R1 and R2 independently represent hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N (C1-C8 alkyl) (C1-C8 alkyl);
W′ represents
(i) phenyl optionally substituted with one, two, or three of T1, T2 and T3, where T1, T2, and T3 independently represent halogen, hydroxy, C1-C6 alkyl, C1-C8 alkoxy, �NO2, �CN, amino, �NH(C1-C8 alkyl), or �N(C1-C8 alkyl) (C1-C8 alkyl);
(ii) �OR where R is C1-C8 alkyl or aryl(C1-C6)alkyl; or
(iii) M5 where M5 is hydroxy, C1-C8 alkyl, aryl(C1-C6)alkyl or �N(C1-C4 alkyl) (C1-C4 alkoxy).
More preferred compounds of Formula A-19 include those where X is nitrogen.
Still other more preferred compounds of Formula A-19 are those where X is CH or a carbon atom substituted with (C1-C6) alkyl.
Still other preferred compounds are represented by Formula A-20 wherein and Q are as defined in Formula I, and W is W1; and
Especially preferred definitiona of Y and Z for Formula A-20, are hydrogen, halogen, and C1-C6alkyl. More preferred compounds of Formula A-20, are those where W is W2.
Particularly preferred compounds of Formula A-20 are those wherein
Y and Z are independently chosen from hydrogen, halogen, and C1-C6alkyl, W is W2; and
R9, R10 and the atom to which they are attached form a 4- to 8-membered monocyclic or bicyclic ring, which may contain one or more double bonds or one or more of oxo, O, S, SO, SO2, or N�R8 wherein R8 is hydrogen, C1-C8 alkyl; wherein the monocyclic or bicyclic ring is optionally substituted with C1-C, alkyl or hydroxy(C1-C6)alkyl;
R12 is selected from the group consisting of hydrogen, C1-C8 alkyl, and C1-C6 alkoxy; or
For Formulas III, IV, and V Preferred R8 substituents on the hetero nitrogen (which is sometime present in the 4- to 8-membered monocyclic or bicyclic ring formed by R9 and R10) are methyl, ethyl, n-propyl and isopropyl.
Preferred JR9R10 groups include 1-piperidinyl optionally mono- or disubstituted with C1-C6 alkyl, preferably methyl or ethyl; 1-piperazinyl optionally mono- or disubstituted with C1-C6 alkyl, preferably methyl or ethyl; and morpholinyl optionally mono- or disubstituted with C1-C6 alkyl, preferably methyl or ethyl. Other preferred JR9R10 groups include pyrrolyl and imidazolinyl, each of which is optionally mono- or disubstituted with C1-C3 alkyl or hydroxy (C1-C6) alkyl, and preferably monosubstituted with methyl, ethyl, or hydroxymethyl.
Where the nature of the substituents permits, the groups represented by JR9R10 encompass various stereoisomers. While the invention encompasses racemic mixtures and mixtures of enantiomers in which one enantiomer is present in an enantiomeric excess, the preferred compounds of the invention are those where only a single, at least relatively pure, stereoisomer is present. Examples of preferred JR9R10 stereoisomers include the following: As used herein, monocyclic and bicyclic rings include both carbocyclic rings where J is, e.g., CH, and, for those rings formed by NR4R5 and NR4R10, nitrogen-containing carbocyclic ring systems of the type having at least one nitrogen, e.g., the nitrogen in NR4R5. Thus, in NR4R5 and NR9R10, the R4R5 and R9R10 groups together represent, for example, a C4-C6 straight chain alkylene group which together with the nitrogen atom to which, e.g., R9 and R10 are attached form a 5- to 7-membered ring system. This ring system may be further substituted with, e.g., C1-C6 alkyl or may contain one or two double bonds, O, and/or a substituted nitrogen as defined herein. In situations where J is, for example, CH, the resulting ring can contain hetero atoms such as oxygen or nitrogen giving rise to, e.g., a 4-piperidinyl group.
When J is a C1-C8 alkylene group, that group is attached at one terminus to the parent carbonyl and the groups R9 and R10 are attached at any position along the alkylene chain. For example, JR9R10 represents groups such as neopentyl, t-butyl, isopropyl, 2-ethylhexyl and n-octyl. Further, R9R10 may represent an alkylene group, e.g., a C5 alkylene group attached to the terminus of J where is n-propyl giving rise to a cyclohexylpropyl group.
Particularly preferred compounds of Formulas A-3, A-6, and A-9, A-12, A-15, A-17, and A-20 are those where Q represents either Formula III or Formula IV. In highly preferred embodiments, Q represents Formula III where
R9, R10 and the nitrogen atom to which they are attached represent mono- or di(C1-C6)alkylamino; or
R9, R10 and the nitrogen to which they are attached form a 5- or 6-membered ring.
The 5- and 6-membered rings are optionally substituted with C1-C6 alkyl or hydroxy(C1-C6)alkyl, preferably hydroxymethyl, and optionally contain one hetero atom selected from oxygen, sulfur, or nitrogen. The hetero sulfur atom may be oxidized to a sulfone or sulfoxide. The hetero nitrogen is optionally substituted with R8 where R8 represents hydrogen or C1-C8 alkyl.
Other particularly preferred compounds of the invention are those where W represents optionally substituted phenyl, isoxazolyl, or thienyl. Highly preferred compounds are those where the phenyl is unsubstituted or substituted with one or two of halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, or hydroxy. Other highly preferred compounds are those where W is isoxazolyl optionally substituted with C1-C6 alkyl, most preferably methyl, C1-C6 alkoxy, or halogen. The most preferred compounds are those where W is phenyl optionally substituted with one halogen, preferably chloro or fluoro, or one hydroxy. Even more preferably, the halogen or hydroxy group is in the ortho or para position of the phenyl ring.
The invention also provides intermediates of Formula A-69 wherein Y, Z, and X1 are defined as for Formula I, R is C1-C6alkyl, and RN is hydrogen, C1-C6 alkyl, or �C(O)W where W is as defined for Formula I.
Preferred intermediate compounds can be represented by Formula A-70 wherein X1 and R2 are as defined for Formula I, and R and RN are as defined in Formula A-69.
Another preferred class of intermediates is represented by Formula A-71 wherein X1, Y, and Z are defined as in Formula I, R is C1-C6alkyl and
W is phenyl, pyridyl, isoxazolyl, or thienyl, each of which is unsubstituted or substituted with one or more of halogen, hydroxy, cyano, nitro, amino, C1-C8alkyl, C1-C6alkoxy, trifluoromethyl, trifluoromethoxy, �SO2NH2, �SO2NH(C1-C8 alkyl), �SO2N(C1-8 alkyl) (C1-C8 alkyl), �NH(C1-C8 alkyl), �N(C1-C8 alkyl) (C8 alkyl), �N(C1-C8 alkyl)CO(C1-C8 alkyl), �N(C1-C8 alkyl)CO2((C1-C8 alkyl), �CONH2, �CONH(C1-C8 alkyl), �CON(C1-C8 alkyl) (C1-C8 alkyl), �CO2(C1-C8 alkyl), �S(C1-C8 alkyl), �SO(C1-C8 alkyl), �SO2(C1-C8 alkyl) and phenyl.
More preferred are intermediate compounds of Formula A-72 wherein X1 and R2 are as defined in Formula I, R is C1-C6alkyl, and W represents W2.
Even more preferred are intermediates of Formula A-73 wherein
R2, is independently selected at each occurrence from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;
W is W2; and
X1 is N or CH.
Another group of intermediate compounds useful in preparing compounds of the instant invention are those of Formula A-74 wherein Y, Z, X1, and W are as defined for Formula I, and R is C1-C6 alkyl.
More preferred intermediate compounds are represented by formula A-75 wherein X and R2 are as defined in Formula I, R2 is independently chosen at each occurrence, W is W2, and R is C1-C6alkyl.
Even more preferred are intermediates of Formula A-75 wherein
X is N or CR1; wherein R1 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy.
Still another group of intermediates that are useful in preparing compounds of the instant invention are those of Formula A-76 wherein Y, Z, X, X1, and W are as defined for Formula I, and M5 is hydroxy, C1-C8alkyl, aryl(C1-C6)alkyl, or �N(C1-C4alkyl) (C1-C4alkoxy).
A more preferred group of intermediates of Formula A-76 are those of Formula A-77 wherein X1, R2 and M5 are as defined for formula 76; and W is W2.
A preferred group of intermediates of Formula A-77 are those wherein
This invention relates to imidazoquinoline and triazoloquinoline derivatives and related compounds, preferred examples of which bind with high affinity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Preferred fused aryl substituted tetrahydroindazoles and related compounds that bind with high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors, are also included in this invention. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.
Cognition Impairment, e.g. cognition impairment, Alzheimer's disease, Parkinson's disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer, s dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al. , J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo[3,4-a]phthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, to the GABAA receptors which methods involve contacting a compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via an GABAA receptor binding assay, such as the assay described in Example 50. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.
The present invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAA receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 51.
Labeled derivatives the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
Definitions If the compounds of the present invention have asymmetric centers, then this invention includes all of the optical isomers and mixtures thereof.
In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention.
Compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be present as, for example, racemic mixtures, mixtures of diastereomers, and optically active forms including mixtures having one stereoisomer in enantiomeric excess and essentially pure stereoisomers, i.e., individual stereoisomers. In these latter situations, the single enantiomers can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malonic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
When any variable (e.g. C1-C6 alkyl, C1-C8 alkyl, R1-R8, W, X, Ar, G or Q) occurs more than one time in any formula herein, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term �alkyl� includes those alkyl groups of a designed number of carbon atoms. Alkyl groups may be straight, or branched. Examples of �alkyl� include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. Where the number of carbon atoms in the alkyl group is unspecified, the group is a C1-C6 alkyl groups.
The term �alkoxy� represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy. Where the number of carbon atoms in the alkoxy group is unspecified the group is C1-C6 alkoxy.
The term �aryl� refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, anthryl, phenanthryl, 1,2,3,4-tetrahydronaphthyl and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl.
The terms �halogen� or �halo� indicate fluorine, chlorine, bromine, and iodine. Preferred halo groups are fluoro, chloro, and bromo. Most preferred are fluoro and chloro.
The term �heterocycloalkyl� refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heterocycloalkyl ring may be optionally fused to or otherwise attached to other heterocycloalkyl rings and/or non-aromatic hydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-thiomorpholinyl, and pyrolidinyl.
The term �heteroaryl� refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.
The term �hydroxyalkyl� as used herein, refers to a hydroxy group, attached to the parent molecular moiety through an alkyl group, as defined above.
As used herein, the term �oxo� refers to a doubly bonded oxygen atom forming carbonyl group with the carbon atom to which the oxygen is attached. Thus, where a ring contains one or more oxo groups, it is intended that that ring contains a carbonyl group in at least one of the ring positions.
This invention relates to heterocyclic derivatives that bind to the benzodiazepine site of GABAA receptors, including human GABAA receptors. A compound may bind to such sites with high affinity but not high specificity or a compound may bind with high selectivity but not high affinity.
The present invention also encompasses the prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvates, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
Pharmaceutical Preparations The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Representative illustrations of the preparation of compounds of Formula 1 in the present invention are given in Schemes 1-3. In Scheme I, W, X1, X, and Y are as defined above for Formula 1 and R is C1-C6alkyl, MeOH is methanol, EtOAc is ethyl acetate, DMF is N,N-dimethylformamide, POCl3 is phosphorus oxychloride, and conc. is concentrated. Heat, as used herein, means elevated temperature, such as, for example, about 40 to about 250� C. In Scheme 2, X, X1, Y, Z, W, W′, J, R9 and R10 are as defined above for Formula 1, MeOH is methanol, BOP is benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate, TEA is triethylamine, DMF is N,N-dimethylformamide, THF is tetrahydrofuran. Heat, as used herein, means elevated temperature, such as, for example, about 40 to about 250� C. In Scheme 3, X1, Y, Z, W, X, n, R11 and R12 are as defined above for Formula 1, Me is methyl, Tol is toluene and heat as used herein, means elevated temperature, such as, for example, about 40 to about 250� C.
Those skilled in the art will recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations.
EXAMPLE 1 Preparation of 1-[(3-Phenylimidazo[5,1-a]isoguinolin-6-yl)carbonyl]piperidine (1) 4-[(Dimethylamino)methylene]-1H-2-benzopyran-1,3(4H)-dione
100 ml of anhydrous DMF in a 1 liter round-bottomed, three necked flask (fitted with a drying tube containing drierite, and a 125 ml dropping funnel) is cooled in an ice-salt bath, and 31 ml of POCl3 is subsequently added over a period of half an hour while stirring the DMF. The 125 ml dropping funnel is replaced with a 150 ml dropping funnel, and a solution of 54 g of homopthalic acid in 100 ml of DMF is added to the flask over a period of one hour at <10� C. The reaction mixture is then stirred at room temperature until a yellow paste was formed, and then poured into ice water. The solid is collected by filtration, washed with water and dried to give 54 g of the title compound as a yellow solid, m.p. 137-40� C.
(2) Methyl 1H-2-Benzopyran-1-oxo-4-carboxylate
Anhydrous HCl gas is continuously bubbled into a stirred solution of the product from part 1 (54 g) in 500 ml of methanol at slowly refluxing temperature for 6 hours. The reaction mixture is concentrated under vacuum. A NaHCO3 solution is added to the residue. The solid was collected by filtration, washed and dried to yield 29.4 g of the title compound as a solid, m.p. 88-90� C.
(3) Methyl 1,2-Dihydro-1-oxo-4-isoquinolinecarboxylate
A mixture of the product from part 2 (29 g) and ammonium acetate (50 g) in 100 ml of acetic acid is stirred at 80�C. overnight, and then cooled and poured into water. The solid is collected by filtration, washed with water and dried to yield the title compound (25 g) as a white solid, m.p. 258-60� C.
(4) Methyl 1-Chloroisoquinoline-4-carboxylate
A mixture of the product from part 3 (12.5 g) in 50 ml of POCl3 is stirred at 100� C. for about two hours then cooled and concentrated under vacuum. The residue is dissolved in 300 ml of CHCl3, and the resulting solution is washed with aqueous NaHCO3 and water, dried over Na2SO4, filtered and then concentrated to give the title compound, m.p. 53-55� C.
(5) Methyl 1-Isoquinolinecarbonitrile-4-carboxylate
A mixture of the product from part 4 (16 g) and potassium cyanide (5.4 g) in 50 ml of DMF was stirred at 90� C. for 4 hours. The mixture is cooled and poured into water. The solid is then collected by filtration, washed with water, and dried to give the title compound as a tan solid (11 g), m.p. 91-94� C.
(6) Methyl 1-Isoquinolinemethanamine-4-carboxylate dihydrochloride
A mixture of the product from part 5 (2 g) and 10% Pd on carbon (800 mg) in 50 ml of methanol containing 4 ml of conc. HCl is hydrogenated with a balloon of hydrogen for about half an hour. The mixture is filtered through celite and concentrated under vacuum to a solid. Recrystallization from EtOAc and methanol yields the title compound (1.8 g) as a white solid, m.p. 234-237� C. (dec).
(7) N-[(4-Methoxycarbonylisoquinolin-1-yl)methyl]benzamide
Benzoyl chloride (0.78 ml) is added dropwise to a stirred mixture of the product from part 6 (1.87 g) in 10 ml EtOAc and 10 ml of saturated aqueous NaHCO3 solution. After stirring for 15 minutes, the layers are separated, the organic layer is washed with water, dried, filtered and concentrated to a solid. The solid is washed with hexanes and dried to yield 1.97 g of the desired product as a white solid, m.p. 140-142� C.
(8) Methyl 3-Phenylimidazo[5,1-a]isoquinolin-6-carboxylate
A mixture of the product from part 7 (1.97 g) in 10 ml of POCl3 is stirred at 105� C. for two hours, then cooled and concentrated under vacuum. The residue is treated with EtOAc and washed with saturated aqueous NaHCO3 solution and water. The organic solution is dried over Na2SO4, filtered and then concentrated to afford a solid. Recrystallization from 2-propanol yields the title compound as a yellow solid (0.7 g).
(9) 3-Phenylimidazo[5,1-a]isoquinolin-6-carboxylic Acid
A slurry of the product from part 8 (488 mg) and NaOH (226 mg) in 15 ml of methanol and 10 ml of water is stirred at 60� C. until a solution forms. The methanol is then evaporated in vacuo, and the remaining mixture is diluted with water. After adjusting the pH to 5-6 with 1N HCl, the solid is collected by filtration, washed with water and dried to give the title compound (450 mg) as a yellow solid, m.p. 187-90� C.
(10) 1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-piperidine
A mixture of the product from part 9 (95 mg), BOP (220 mg), piperidine (56 mg) and TEA (67 mg) in 2 ml of DMF is stirred at room temperature for 18 hours. The mixture is added to aqueous NaHCO3 solution and extracted with EtOAc. The organic layer is washed with brine and water, dried (Na2SO4), filtered and concentrated to afford a foam. Purification on a silica gel column, eluting with 5% methanol in methylene chloride, gives the title compound. 1H NMR (CDCl3) δ 1.38-1.50 and 1.60-1.80 (6H, m), 3.18-3.36 (2H, m), 3.65-3.95 (2H, m), 7.40-7.60 (6H, m), 7.75 (2H, d), 7.95 (1H, s), 8.05 (1H, s), 8.10 (1H, d). The hydrochloride salt was prepared by treating the free base in EtOAc with a solution of hydrogen chloride in ether and collecting by filtration.
LC-MS data: HPLC: 1.93 min (HPLC method: Zorbax XDB-C18 column, 4.6�30 mm, 3.5 μm particle size, 3 min gradient from 0 to 100% B with 0.5 min hold at 100% B. Solvent A: 95% H2O-5%MeOH-0.05%TFA; Solvent B: 95%MeOH-5%H2O-0.05%TFA). MS (ES+): m/e 356 [M+H]+.
EXAMPLES 2-40 The following compounds are prepared using procedures analogous to those of Example 1. The compounds of these examples have the general structure shown below: where Q and W are defined in the following Table 1. LC-MS data are given as HPLC retention times (rt) and [M+H]+. The HPLC retention times of Table 1 are obtained by the method given in Example 1.
1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]- pyrrolidine
(R)-1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-2- hydroxymethyl- pyrrolidine
4-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]- morpholine
cis-1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-2,6- dimethylpiperidine
4-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-2,6- thiomorpholine
1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-4- methylpiperazine
cis-1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-3,5- dimethylpiperazine
1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-N,N- dimethylamine
1-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-N,N- diethylamine
1-{[3-(4-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}pyrrolidine
(R)-1-{[3-(4- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-2- hydroxymethyl- pyrrolidine
1-{[3-(4-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}piperidine
1-{[3-(2-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}pyrrolidine
(R)-1-{[3-(2- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl)-2- hydroxymethyl- pyrrolidine
1-{[3-(2-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}piperidine
1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}- pyrrolidine
(R)-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-2- hydroxymethyl- pyrrolidine
1-{[3-(Thien-3- yl)imidazo]5,1- a]isoquinolin-6- yl]carbonyl}- piperidine
4-[(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]- 1,1-dioxido- thiomorpholine
cis-1-{[3-(4- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-3,5- dimethyl-piperazine
cis-1-{[3-(2- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}}-3,5- dimethyl-piperazine
cis-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-}}-3,5- dimethyl-piperazine
1-{[3-(4-Chlorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}pyrrolidine
(R)-1-{[3-(4- Chlorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-2- hydroxymethyl- pyrrolidine
cis-1-{[3-(4- Chlorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-3,5- dimethyl-piperazine
1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-4-methyl piperidine
(R)-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-3-methyl- piperazine
(S)-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-3-methyl- piperazine
4-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}morpholine
1-{[3-(3-Fluorophenyl)- imidazo]5,1- a]isoquinolin-6- yl]carbonyl}pyrrolidine
cis-1-{[3-(Thien-3- yl)imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-2,5- dimethylpiperazine
1-{[3-(4- Methylisoxazol-3-yl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}pyrrolidine
4-{[3-(3-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}morpholine
(R)-1-{[3-(3- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-2- hydroxymethyl- pyrrolidine
1-{[3-(3-Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}piperidine
S-1-[3-(3- Phenylimidazo[5,1- a]isoquinolin-6- yl)carbonyl]-3- methylpiperazine
(S)-1-{[3-(2- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-3- methylpiperazine
(S)-1-{[3-(4- Fluorophenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}-3- methylpiperazine
(S)-1-{[3-(4- Methoxyphenyl)- imidazo[5,1- a]isoquinolin-6- yl]carbonyl}- homopiperazine
EXAMPLE 41 Preparation of 1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine (1) Methyl 3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-carboxylate
A mixture of methyl 1-Chloroisoquinoline-4-carboxylate, prepared essentially according to procedures described in Example 1, part 4, (293 mg) and benzoic hydrazide (192 mg) in 8 ml of DMF is stirred at 100� C. overnight. The mixture is cooled and poured into water. The solid is then collected by filtration and dried to give the title compound as a solid (258 mg). LC-MS data for the title compound: HPLC: 2.34 min. MS (ES+) m/e 304 [M+H]+. (The HPLC retention time is obtained by the method of Example 1).
(2) 3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-carboxylic Acid
This compound is prepared using the procedure described in Example 1, part 9 with the product of part 1 of this example being used as the starting material.
(3) 1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine
This compound is prepared essentially using the procedure described in Example 1, part 10 with the product of part 2 of this example being used as the starting material. Data for the title compound: 1H NMR (CDCl3) δ 1.38-2.00 (6H, m), 3.16-3.36 (2H, m), 3.65-3.95 (2H, m), 7.50-7.86 (8H, m), 8.05 (1H, s), 8.82 (1H, d).
LC-MS data: HPLC: 2.13 min. MS (ES+) m/e 357 [M+H]+. (The HPLC retention time is obtained by the method given in Example 1).
EXAMPLES 42-45 The following compounds are prepared by procedures analogous to those of Example 41. These compounds are represented by the general structure shown below: where Q and W are defined in Table 2. HPLC-MS data are given as HPLC retention times (Tr) and [M+H]+. The HPLC retention time is obtained by the method of Example 1.
[M + H]+ 42
1-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6- yl)carbonyl] pyrrolidine
(R)-1-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6- yl)carbonyl]-2- hydroxymethyl- pyrrolidine
4-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6- yl)carbonyl] morpholine
cis-1-[(3-Phenyl-1,2,4- triazolo[3,4- a]isoquinoline-6- yl)carbonyl]-3,5- dimethylpiperazine
EXAMPLE 46 Preparation of 3-Phenyl-6-(S-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole-3-yl-)-imidazo[5,1-a]isoquinoline A solution of trimethylaluminum in anhydrous toluene (1M, 2.5 ml) is added dropwise to a stirred solution of S-2-(aminomethyl) pyrrolidine (250 mg) in 10 ml of anhydrous toluene. The mixture is then slowly warmed to 80� C. and stirred for one hour. After cooling to room temperature, methyl 3-phenylimidazo[5,1-a]isoquinolin-6-carboxylate (prepared essentially according to procedures described in Example 1, part 8, 97 mg) was added in one portion. The reaction mixture is heated at reflux for 12 hours under nitrogen. After cooling, the solution is treated dropwise with 5 ml of water, diluted with 10 ml of methanol and 10 ml of methylene chloride, and refluxed for another 15 minutes. After filtration over celite and Na2SO4, and solvent evaporation, the residue is mixed with EtOAc and water. The organic layer is then separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified on a silica gel column, eluting with 5% methanol in methylene chloride to yield the titled compound. 1H NMR (CDCl3) δ 1.40-2.05 (4H, m), 3.00-3.20 (2H, m), 3.80-4.20 (3H, m), 7.40-7.62 (5H, m), 7.80 (2H, d), 7.95 (1H, s), 8.08 (1H, d), 8.35 (1H, d), 8.40 (1H, s). LC-MS data: HPLC: 1.51 min. MS (ES+) m/e 353 [M+H]+. The HPLC retention time was obtained by the method of Example 1.
EXAMPLE 47 Preparation of 1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine (1) 3-Phenyl-1,2,4-Triazolo[3,4-a]phthalazine-6-carboxylic Acid
A mixture of 6-Chloro-3-phenyl-1,2,4-Triazolo[3,4-a]phthalazine (2.0 g, prepared according to procedures described in Zh. Org. Khim. (1975), 11(7), 1570-2 and J. Med. Chem. (1988),31(6), 1115-23.) and copper cynaide (2.0 g) in 50 ml of DMSO is stirred at 140� C. overnight. The mixture is cooled, poured into water and extracted with methylene chloride. The organic layer is washed with water, dried over Na2SO4 and concentrated to give a tan solid which is then dissolved in 50 mL of methanol. The resulting solution is saturated with HCl gas and the mixture is stirred at room temperature overnight. 20 mL of water and 1 mL of 10 N NaOH solution are added, the resulting mixture is then heated under reflux for 4 hours. The methanol is then evaporated in vacuo, and the remaining mixture is diluted with water. After adjusting the pH to 4-5 with 1N HCl , the solid is collected by filtration, and dried to give the title compound as a solid.
(2) 1-[(3-Phenyl-1,2,4-triazolo[3,4-al]phthalazine-6-yl)carbonyl]piperidine
This compound is prepared essentially using the procedure described in Example 1, part 10 with the product of part 1 of this example being used as the starting material.
EXAMPLE 48 Preparation of Radiolabeled Probe Compounds of the Invention The compounds of the invention may be prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.
EXAMPLE 49 Receptor Autoradiography Receptor autoradiography (receptor mapping) is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example.
EXAMPLE 50 Binding Assay The high affinity and high selectivity of compounds of this invention for the benzodiazepine site of the GABAA receptor is demonstrated using the following binding assay. This assay is carried out essentially as described by Thomas and Tallman (J. Bio. Chem. 1981; 156:9838-9842, and J. Neurosci. 1983; 3:433-440).
Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) of Buffer A (0.05 M Tris HCl buffer, pH 7.4 at 4� C.). The tissue homogenate is centrifuged in the cold (4� C.) at 20,000�g for 20 minutes. The supernatant is decanted, the pellet rehomogenized in the same volume of buffer, and centrifuged again at 20,000�g. The supernatant of this centrifugation step is decanted and the pellet stored at −20 � C. overnight. The pellet is then thawed and resuspended in 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000�g and the supernatant decanted. This wash step is repeated once. The pellet is finally resuspended in 50 volumes of Buffer A.
Incubations contained 100 μl of tissue homogenate, 100 μl of radioligand, (0.5 nM 3H-Ro15-1788 [3H-Flumazenil], specific activity 80 Ci/mmol), and test compound or control (see below), and are brought to a total volume of 500 μl with Buffer A. Incubations are carried for 30 min at 4� C. and then rapidly filtered through Whatman GFB filters to separate free and bound ligand. Filters are washed twice with fresh Buffer A and counted in a liquid scintillation counter. Nonspecific binding (control) is determined by displacement of 3H Ro15-1788 (3H-Flumazenil) with 10 μM Diazepam (Research Biochemicals International, Natick, Mass.). Data are collected in triplicate, averaged, and percent inhibition of total specific binding (Total Specific Binding=Total−Nonspecific) is calculated for each compound.
A competition binding curve is obtained with up to 11 points spanning the compound concentration range from 10−12M to 10−5M obtained per curve by the method described above for determining percent inhibition. Ki values are calculated according the Cheng-Prussof equation. Each of the compounds shown and described in Examples 1 through 46, and tested in this assay was found to have a Ki of <1 μM.
EXAMPLE 51 Electrophysiology The following assay is used to determine if a compound of the invention act as an agonist, an antagonist, or an inverse agonist at the benzodiazepine site of the GABAA receptor.
Assays are carried out as described in White and Gurley (NeuroReport 6: 1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory (Receptors and Channels 3: 1-5, 1995) with modifications. Electrophysiological recordings are carried out using the two electrode voltage-clamp technique at a membrane holding potential of −70 mV. Xenopus Laevis oocytes are enzymatically isolated and injected with non-polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γ subunits, respectively. Of the nine combinations of α, β and γ subunits described in the White et al. publications, preferred combinations are α1β2γ2, α2β3γ2, α3β3 γ 2, and α5β3γ2. Preferably all of the subunit cRNAs in each combination are human clones or all are rat clones. The sequence of each of these cloned subunits is available from GENBANK, e.g., human α1, GENBANK accession no. X14766, human α2, GENBANK accession no. A28100; human α3, GENBANK accession no. A28102; human α5, GENBANK accession no. A28104; human β2, GENBANK accession no. M82919; human β3, GENBANK accession no. Z20136; human γ2, GENBANK accession no. X15376; rat α1, GENBANK accession no. L08490, rat α2, GENBANK accession no. L08491; rat α3, GENBANK accession no. L08492; rat α5, GENBANK accession no. L08494; rat β2, GENBANK accession no. X15467; rat β3, GENBANK accession no. X15468; and rat γ2, GENBANK accession no. L08497. For each subunit combination, sufficient message for each constituent subunit is injected to provide current amplitudes of >10 nA when 1 μM GABA is applied.
Compounds are evaluated against a GABA concentration that evokes <10% of the maximal evokable GABA current (e.g. 1 μM-9 μM). Each oocyte is exposed to increasing concentrations of compound in order to evaluate a concentration/effect relationship. Compound efficacy is calculated as a percent-change in current amplitude: 100* ((Ic/I)−1), where Ic is the GABA evoked current amplitude observed in the presence of test compound and I is the GABA evoked current amplitude observed in the absence of the test compound.
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