Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders
| Title: | Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
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| Patent Number: | 8,778,956 |
| Publication Date: | July 15, 2014 |
| Appl. No: | 12/327437 |
| Application Filed: | December 03, 2008 |
| Abstract: | The present invention is directed to novel hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives of the general formula [chemical expression included] wherein all variables are as defined herein, useful in the treatment of disorders and conditions mediated by the ORL-1 G-protein coupled receptor. More particularly, the compounds of the present invention are useful in the treatment of disorders and conditions such as anxiety, depression, panic, dementia, mania, bipolar disorder, substance abuse, neuropathic pain, acute pain, chronic pain, migraine, asthma, cough, psychosis, schizophrenia, epilepsy, hypertension, obesity, eating disorders, cravings, diabetes, cardiac arrhythmia, irritable bowel syndrome, Crohn's disease, urinary incontinence, adrenal disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), Alzheimer's disease, for improved cognition or memory and for mood stabilization. |
| Inventors: | Battista, Kathleen (Ewing, NJ, US); Bignan, Gilles (Bridgewater, NJ, US); Connolly, Peter J. (New Providence, NJ, US); Reitz, Allen B. (Lansdale, PA, US); Ross, Tina Morgan (Royerford, PA, US); Scott, Malcolm (Telford, PA, US); Middleton, Steven A. (Flemington, NJ, US); Orsini, Michael (Somerset, NJ, US) |
| Assignees: | Janssen Pharmaceutica NV (BE) |
| Claim: | 1. A method of treating a condition selected from the group consisting of anxiety, substance abuse, and epilepsy, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I) [chemical expression included] wherein R 0 is selected from the group consisting of [chemical expression included] each R A and R B is independently selected from the group consisting of hydrogen and C 1-4 alkyl; each R C and R D is independently selected from the group consisting of hydrogen, and C 1-4 alkyl; each R E is independently selected from the group consisting of hydrogen and C 1-4 alkyl; X is —NR 1 R 2 ; each R 1 and R 2 is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 alkoxycarbonyl, cycloalkyl, cycloalkyl-C 1-4 alkyl, partially unsaturated carbocylyl, partially unsaturated carbocyclyl-C 1-4 alkyl, aryl, arC 1-4 alkyl, arC 1-4 alkoxy, —C(O)—C 1-6 alkyl, —C(O)-aryl, —C(O)-arC 1-4 alkyl, —C(O)O-cycloalkyl, —C(O)O-aryl, —C(O)O-arC 1-4 alkyl and —C(O)O-(partially unsaturated carbocyclyl); wherein the C 1-8 alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl or arC 1-8 alkyl group, whether alone or part of a substituent group, is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, —C(O)—C 1-4 alkyl, C 1-4 alkoxycarbonyl, N(R E) 2 , N(R E) 2 —C 1-4 alkyl, N(R E)—C(O)C(CH 3) 3 , —C 1-4 alkyl-N(R E)—C(O)O—C 1-4 alkyl and N(R E)—C(O)O—C 1-4 alkyl, aryl, aryloxy, cycloalkyl, heteroaryl, aryl substituted heteroarylaminosulfonyl or C 1-6 alkylthio; R 3 is aryl; wherein the aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R E) 2 ; n is an integer from 0 to 2; R 4 is selected from the group consisting of hydroxy, C 1-4 alkyl and hydroxy substituted C 1-4 alkyl; m is an integer from 0 to 1; L 1 is selected from the group consisting of C 1-6 alkyl and C 3-6 alkenyl; wherein the double bond of the C 3-6 alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C 1-6 alkyl or C 3-6 alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 1-6 alkoxy; [chemical expression included] is selected from the group consisting of phenyl, naphthyl and acenaphthyl; p is an integer from 0 to 5; R 5 is selected from the group consisting of hydroxy, carboxy, halogen, C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, NR 1 R 2 , trifluoromethyl, trifluoromethoxy, C 1-4 alkoxycarbonyl, —SO—NR 1 R 2 , and —C(O)—NR 1 R 2 ; q is an integer from 0 to 1; R 6 is selected from the group consisting of -(L 2) 0-1 —R 7 ; L 2 is selected from the group consisting of —C 1-6 alkyl-, —C 2-4 alkenyl-, —C 2-6 alkynyl-, O—, —S—, —NH—, —N(C 1-4 alkyl)-, —C 1-6 alkyl-O—, —C 1-6 alkyl-S—, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —O—C 2-6 alkyl-O—, —S—C 2-6 alkyl-S—, —SO 2 —, —SO 2 NH—, —SO 2 N(C 1-4 alkyl)-, —NH—SO 2 —, —N(C 1-4 alkyl)-SO 2 -, —C(O)—O—and —O—C(O)—; R 7 is selected from the group consisting of aryl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from hydroxy, carboxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, N(R E) 2 , trifluoromethyl, trifluoromethoxy, C 1-4 alkoxycarbonyl, —SO 2 —N(R E) 2 and —C(O)—N(R E) 2 ; or a pharmaceutically acceptable salt thereof. |
| Claim: | 2. The method of claim 1 wherein: R 0 is selected from the group consisting of [chemical expression included] each R C and R D is independently selected from hydrogen and C 1-4 alkyl; X is —NR 1 R 2 ; R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, aryl, arC 1-4 alkyl, arC 1-4 alkyloxy, cycloalkyl-alkyl and C(O)—C 1-4 alkyl; wherein the C 1-4 alkyl, aryl, arC 1-4 alkyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, N(R E) 2 , N(R E) 2 —C 1-4 alkyl, N(R E)—C(O)OC(CH 3) 3 , nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C 1-4 alkylthio; R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, cycloalkyl, cycloalkyl-C 1-4 alkyl, aryl, arC 1-4 alkyl, arC 1-4 alkyloxy, partially unsaturated carbocyclyl, partially unsaturated carbocyclyl-C 1-4 alkyl, —C(O)—C 1-4 alkyl, —C(O)-aryl, —C(O)—arC 1-4 alkyl, —C(O)O-cycloalkyl and —C(OO)—C 1-4 alkyl; wherein the C 1-4 alkyl, aryl, arC 1-4 alkyl, partially unsaturated carbocyclyl or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, N(R E) 2 , N(R E) 2 C 1-4 alkyl, (CH 3) 3 COC(O)—N(R E)—C 1-4 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl substituted heteroaryl-aminosulfonyl, —C(O)—C 1-4 alkyl or C 1-4 alkylthio; R 3 is aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R E) 2 ; n is an integer from 0 to 1; L 1 is C 1-4 alkyl; wherein the C 1-4 alkyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C 1-4 alkyl, fluorinated C 1-4 alkyl or C 1-4 alkoxy; R 5 is selected from the group consisting of hydroxy, carboxy, halogen, C 1-4 alkyl, C 1-4 alkoxy, nitro, cyano, N(R E) 2 , trifluoromethyl, trifluoromethoxy, C 1-4 alkoxycarbonyl, —SO—N(R E) 2 , —SO 2 — N(R E) 2 and —C(O)— N(R E) 2 ; or a pharmaceutically acceptable salt thereof. |
| Claim: | 3. The method of claim 1 wherein: R 0 is selected from the group consisting of [chemical expression included] each R A , R B , R C and R D is hydrogen; X is —NR 1 R 2 ; R 1 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxycarbonyl, arC 1-4 alkyl and C(O)—C 1-4 alkyl; wherein the C 1-4 alkyl or aryl group, whether alone or part of a substituent group, is optionally substituted with one to two substituents independently selected from carboxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, N(R E) 2 or N(R E)—C(O)OC(CH 3) 3 ; R is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 alkoxy, cycloalkyl, aryl, arC 1-4 alkyl, arC 1-4 alkyloxy, partially unsaturated carbocyclyl, partially unsaturated carbocyclyl-C 1-4 alkyl, cycloalkyl-C 1-4 alkyl, —C(O)arC 1-4 alkyl, —C(OO)-cycloalkyl and C(O)O—C 1-4 alkyl; wherein the C 1-4 alkyl, aryl, arC 1-4 alkyl, partially unsaturated carbocyclyl-or cycloalkyl group, whether alone or part of a substituent group, is optionally substituted with one to three substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, N(R E) 2 , N(R E) 2 -C 1-4 alkyl, (CH 3) 3 CO—C(O)—N(R E)—C 1-4 alkyl, nitro, trifluoromethyl, trifluoromethoxy, phenyl, phenoxy, heteroaryl, cycloalkyl, 1-phenyl-pyrazol-2-yl-aminosulfonyl or C 1-4 alkylthio; R 3 is aryl; wherein the aryl group is optionally substituted with one or more substituents independently selected from halogen; n is 0; L 1 is C 1-4 alkyl; R 5 is selected from the group consisting of halogen, C 1-4 alkyl and trifluoromethyl; or a pharmaceutically acceptable salt thereof. |
| Claim: | 4. The method of claim 2 wherein: R 0 selected from the group consisting of —CH 2 —CH(OH)—CH 2 —X and —CH 2 —CH 2 —CH(OH)—CH 2 —X; X is —NR 1 R 2 ; R 1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, amino-n-propyl, dimethylaminoethyl, benzyl, phenylethyl, 4-methyl-benzyl, [chemical expression included] 2-(3,4-dimethoxy-phenyl)ethyl, 3-methyl-phenyl, ethoxy-carbonyl-methyl, 2-amino-2-methoxycarbonyl-ethyl, t-butoxycarbonyl and [chemical expression included] R 2 is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, carboxy-methyl, ethoxycarbonylmethyl, 2,2,2,-triluoroethyl, ethoxy, dimethylaminoethyl, t-butoxycarbonylamino-ethyl, n-butyl, t-butyl, n-propyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl, di(n-butyl)amino-n-propyl, t-butoxycarbonylamino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, t-butoxycarbonyl, cyclopropyl, phenyl, 4-fluorophenyl, 4-methyiphenyl, 3,4-dimethoxyphenyl, 2-aminophenyl, 4-biphenyl, 2-ethoxyphenyl, 4-((1-phenyl-pyrazol-2-yl)-aminosulfonyl)-phenyl, 4-cyclohexyiphenyl, 4-(aminoethyl)phenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl, —CH(CH 3)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl), 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonylbenzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)benzyl, 4-(dimethylamino)benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl, 1-phenyl-2-(t-butoxycarbonyl)ethyl, —C(O)—C(OCH 3)(CF 3)-phenyl, —C(O)O-(2-isopropyl-5 [chemical expression included] methyl-cyclohexyl) 2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl, 2-phenoxy-ethyl and 2-phenyl-cyclopropyl; R 3 is selected from the group consisting of phenyl and 4-fluorophenyl; L 1 is selected from the group consisting of —CH 2 —, —CH(CH 3)— and —CH 2 CH 2 —; [chemical expression included] is selected from the group consisting of 1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl, phenyl, 1-naphthyl, 2-naphthyl and 1,2,3,4-tetrahydro -naphthyl; R 5 is selected from the group consisting of chloro, methyl, n-propyl and trifluoromethyl; or a pharmaceutically acceptable salt thereof. |
| Claim: | 5. The method of claim 4 , wherein: X is —NR 1 R 2 ; R 1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, phenylethyl, NH 2 [chemical expression included] 3-methyl-phenyl, 2-(3,4-dimethoxyphenyl)-ethyl, ethoxycarbonyl-methyl, dimethylamino-ethyl and 2-amino-2-methoxycarbonyl-ethyl; R 2 is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, 2,2,2-triluoroethyl, ethoxy, dimethylaminoethyl, n-butyl, t-butyl, n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 2-aminophenyl, 4-(t-butoxycarbonylamino-ethyl)-phenyl, 3,4-dimethoxyphenyl, 4-biphenyl, 2-ethoxyphenyl, 4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4- dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 4-carboxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, adamantanyl, 1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl, [chemical expression included] 2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl; L 1 is selected from the group consisting of —CH 2 — and CH 2 —CH 2 —; [chemical expression included] is selected from the group consisting of 1-acenaphthenyl, R-1-acenaphthenyl, S-1-acenaphthenyl, phenyl-and 1-naphthyl; p is an integer from 0 to 2; or a pharmaceutically acceptable salt thereof. |
| Claim: | 6. The method of claim 5 , wherein: R 1 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, t-butyl, dimethylaminoethyl, benzyl, phenylethyl, 2-(3,4-dimethoxyphenyl)-ethyl, dimethylamino-ethyl, ethoxycarbonyl-methyl, [chemical expression included] R 2 is selected from the group consisting of hydrogen, methyl, methoxy, ethyl, ethoxycarbonyl-methyl, ethoxy, dimethylaminoethyl, n-butyl, n-propyl, di(n-butyl)amino-n-propyl, 3-phenyl-n-propyl, 3-(2-pyridyl)-n-propyl, cyclopropyl, phenyl, 4-fluorophenyl, 4-methylphenyl, 2-aminophenyl, 3,4-dimethoxyphenyl, 4-(t-butoxycarbonylamino-ethyl) -phenyl, 4-biphenyl, 2-ethoxyphenyl, 4-(aminoethyl)-phenyl, benzyl, benzyloxy, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-iodobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4-trifluoromethoxybenzyl, 4-methoxycarbonyl-benzyl, 2,3-dimethoxybenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 2,4-difluorobenzyl, 2,5-difluorobenzyl, 3,4,5-trimethoxybenzyl, 2,4,6-trimethoxybenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 3,4-difluorobenzyl, 3,5-di(trifluoromethyl)-benzyl, 2-phenylethyl, 2-(4-bromophenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl, 2-(2-nitro-4,5-dimethoxy-phenyl)ethyl, 1-adamantanyl, 1-adamantanyl-methyl, 1-naphthyl, 1-naphthyl-methyl, [chemical expression included] 2S-hydroxy-S-cyclopentyl-methyl, 2S-hydroxy-S-cyclohexyl-methyl, 2S-hydroxy-S-cycloheptyl-methyl and 2-phenoxy-ethyl; p is an integer from 0 to 1; R 5 is selected from the group consisting of methyl, n-propyl and trifluoromethyl; or a pharmaceutically acceptable salt thereof. |
| Claim: | 7. The method of claim 4 , wherein: R 0 —CH 2 —CH(OH)—CH 2 —X; X is —NR 1 R 2 ; R 1 is selected from the group consisting of hydrogen, 2-(3,4-dimethoxyphenyl)-ethyl, 1-(3,4-dimethoxyphenyl)-n-ethyl and amino-n-propyl; R 2 is selected from the group consisting of hydrogen, methyl, n-butyl, 3-hydroxy-n-propyl, 3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl, t- butoxycarbonylamino-n-propyl, N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl, 4-methoxycarbonyl-benzyl and —CH(CH 3)-phenyl; R 3 is selected from the group consisting of phenyl and 4-fluorophenyl; L 1 is selected from the group consisting of —CH 2 — and —CH 2 CH 2 —; [chemical expression included] is selected from the group consisting 1-naphthyl, 1-acenaphthenyl, R-1- acenaphthenyl and S-1-acenaphthenyl; p is an integer from 0 to 1; R 5 methyl; or a pharmaceutically acceptable salt thereof. |
| Claim: | 8. The method of claim 7 , wherein: R 1 is selected from the group consisting of hydrogen, 1-(3,4-dimethoxyphenyl)-n-ethyl and amino-n-propyl; R 2 is selected from the group consisting of hydrogen, methyl, n-butyl, 3-hydroxy-n- propyl, 3-methoxy-n-propyl, methylamino-n-propyl, dimethylamino-n-propyl, N-methyl-N-t-butoxycarbonyl-amino-n-ethyl, 3-nitrobenzyl, 4-methoxycarbonyl-benzyl and —CH(CH 3)— phenyl; [chemical expression included] is selected from the group consisting 1-naphthyl, 1-acenaphthenyl, R-1-acenaphthenyl and S-1-acenaphthenyl; or a pharmaceutically acceptable salt thereof. |
| Claim: | 9. The method of claim 7 , wherein the compound is selected from the group consisting of: 8-(R) acenaphthen-1-yl-3-(3-amino-2-(S)-hydroxy-propyl)- 1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one; 8-(R) acenaphthen- 1-yl-3-(3-amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one; 8-(R)-Acenaphthen-1-yl-3-(3-dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one; 3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one; 3-(3-Dimethylamino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro [4.5]decan-4-one; 1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-hydroxy-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro [4.5]decan-4-one; 1-(4-Fluoro-phenyl)-3-[2-(R)-hydroxy-3-(3-methylamino-propylamino)-propyl]-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro [4.5]decan-4-one; 3-[3-(3-Dimethylamino-propylamino)-2-(R)-hydroxy-propyl]-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one and pharmaceutically acceptable salts thereof. |
| Claim: | 10. The method of claim 1 wherein the compound is a compound of the formula (I) [chemical expression included] wherein R 0 is selected from the group consisting of [chemical expression included] each R A and R B is independently selected from the group consisting of hydrogen and C 1-4 alkyl; each R C and R D is independently selected from the group consisting of hydrogen and C 1-4 alkyl; each R E is independently selected from the group consisting of hydrogen and C 1-4 alkyl; X is —NR 1 R 2 ; each R 1 and R 2 is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 alkoxy, cycloalkyl, cycloalkyl-C 1-4 alkyl, partially unsaturated carbocylyl, aryl, arC 1-4 alkyl, arC 1-4 alkoxy, —C(O)—C 1-6 alkyl, —C(O)-aryl and —C(O)-arC 1-4 alkyl; wherein the C 1-8 alkyl, cycloalkyl, partially unsaturated carbocyclyl, aryl or arC 1-8 alkyl group, whether alone or part of a substituent group, is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, —C(O)—C 1-4 alkyl, C 1-4 alkoxycarbonyl, N(R E) 2 , N(R E) 2 —C 1-4 alkyl, N(R E)—C(O)C(CH 3) 3 , aryl, aryloxy, cycloalkyl, heteroaryl, aryl substituted heteroarylaminosulfonyl or C 1-6 alkylthio; R 3 is aryl; wherein the aryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, C 1-4 alkyl, C 1-4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano or N(R E) 2 ; n is an integer from 0 to 2; R 4 is selected from the group consisting of hydroxy, C 1-4 alkyl and hydroxy substituted C 1-4 alkyl; m is an integer from 0 to 1; L 1 is selected from the group consisting of C 1-6 alkyl and C 3-6 alkenyl; wherein the double bond of the C 3-6 alkenyl group is at least one carbon atom removed from the attachment point to the N atom; and wherein the C 1-6 alkyl or C 3-6 alkenyl group is optionally substituted with one to two substituents independently selected from hydroxy, fluoro, C 1-6 alkyl, fluorinated C 1-6 alkyl or C 1-6 alkoxy; [chemical expression included] is selected from the group consisting of phenyl, naphthyl and acenaphthyl; p is an integer from 0 to 5; R 5 is selected from the group consisting of hydroxy, carboxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, NR 1 R 2 , trifluoromethyl, trifluoromethoxy, C 1-4 alkoxycarbonyl, —SO—NR 1 R 2 , —SO 2 —NR 1 R 2 and —C(O)—NR 1 R 2 ; q is an integer from 0 to 1; R6 is selected from the group consisting of -(L 2) 0-1 -R 7 ; L 2 is selected from the group consisting of —C 1-6 alkyl-, —C 2-4 alkenyl-, —C 2-6 alkynyl-, —O—, —S—, —NH—, —N(C 1-4 alkyl)-, —C 1-6 alkyl—O—, —C 1-6 alkyl-S—, —O—C 1-6 alkyl-, —S—C 1-6 alkyl-, —O—C 2-6 alkyl—O—, —S—C 2-6 alkyl-S—, —SO 2 -, —SO 2 NH—, —SO 2 N(C 1-4 alkyl)-, —NH—SO 2 —, —N(C 1-4 alkyl)- SO 2 —, —C(O)—O— and —O—C(O)—; R 7 is selected from the group consisting of aryl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, partially unsaturated carbocyclyl, cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from hydroxy, carboxy, halogen, C 1-6 alkyl, C 1-6 alkoxy, nitro, cyano, N(R E) 2 , trifluoromethyl, trifluoromethoxy, C 1-4 alkoxycarbonyl, —SO 2 —N(R E) 2 and —C(O)N(R E) 2 ; or a pharmaceutically acceptable salt thereof. |
| Claim: | 11. The method of claim 9 , wherein the compound is the sulphate salt of 3-(3-Amino-2-(R)-hydroxy-propyl)-1-(4-fluoro-phenyl)-8-(8-methyl-naphthalen-1-ylmethyl)-1,3,8-triaza-spiro[4.5]decan-4-one. |
| Claim: | 12. The method of claim 1 , wherein q=0. |
| Claim: | 13. The method of claim 10 , wherein q=0. |
| Claim: | 14. The method of claim 1 wherein the condition is anxiety. |
| Claim: | 15. The method of claim 1 wherein the condition is substance abuse. |
| Current U.S. Class: | 514/278 |
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| Primary Examiner: | Aulakh, Charanjit S |
| Attorney, Agent or Firm: | Mangini, Michele G. |
| Accession Number: | edspgr.08778956 |
| Database: | USPTO Patent Grants |
| Language: | English |
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