MXPA98001905A - The use of an antagonist of the nk-1 receptor in the preparation of a composition for gene therapy - Google Patents
The use of an antagonist of the nk-1 receptor in the preparation of a composition for gene therapyInfo
- Publication number
- MXPA98001905A MXPA98001905A MXPA/A/1998/001905A MX9801905A MXPA98001905A MX PA98001905 A MXPA98001905 A MX PA98001905A MX 9801905 A MX9801905 A MX 9801905A MX PA98001905 A MXPA98001905 A MX PA98001905A
- Authority
- MX
- Mexico
- Prior art keywords
- azabicyclo
- diphenylmethyl
- octane
- cis
- methoxy
- Prior art date
Links
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title claims abstract description 17
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title claims abstract description 17
- 238000001415 gene therapy Methods 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000000203 mixture Substances 0.000 title claims abstract description 6
- 230000003042 antagnostic Effects 0.000 title description 7
- 239000005557 antagonist Substances 0.000 title description 4
- 239000002464 receptor antagonist Substances 0.000 claims abstract description 13
- 208000007920 Neurogenic Inflammation Diseases 0.000 claims abstract description 11
- 230000003612 virological Effects 0.000 claims abstract description 5
- 241000124008 Mammalia Species 0.000 claims abstract description 4
- -1 2-methoxybenzylamino Chemical group 0.000 claims description 47
- 150000001875 compounds Chemical class 0.000 claims description 12
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- ZGBXROBHDHIQGY-UHFFFAOYSA-N 2,4-dimethyl-1,3-thiazole-5-sulfonic acid Chemical compound CC1=NC(C)=C(S(O)(=O)=O)S1 ZGBXROBHDHIQGY-UHFFFAOYSA-N 0.000 claims description 5
- IWNUVCPVRJASIF-CONSDPRKSA-N (2S,3S)-2-benzhydryl-N-(2-methoxy-5-propan-2-ylphenyl)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine Chemical compound COC1=CC=C(C(C)C)C=C1N[C@@H]1[C@@](C(C=2C=CC=CC=2)C=2C=CC=CC=2)(C)N2CCC1CC2 IWNUVCPVRJASIF-CONSDPRKSA-N 0.000 claims description 4
- YHPMRWZVIQTSFZ-UHFFFAOYSA-N 3,5-difluoro-2-(2-fluorophenyl)pyridine Chemical compound FC1=CC(F)=CN=C1C1=CC=CC=C1F YHPMRWZVIQTSFZ-UHFFFAOYSA-N 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000011081 inoculation Methods 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- JASMWYNKLTULAN-UHFFFAOYSA-N octan-3-amine Chemical compound CCCCCC(N)CC JASMWYNKLTULAN-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- YSEQNZOXHCKLOG-UHFFFAOYSA-N 2-methyloctanoic acid Chemical compound CCCCCCC(C)C(O)=O YSEQNZOXHCKLOG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000972 4,5-dimethylthiazol-2-yl group Chemical group [H]C([H])([H])C1=C(N=C(*)S1)C([H])([H])[H] 0.000 claims description 3
- 230000002950 deficient Effects 0.000 claims description 3
- 230000002068 genetic Effects 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- UWMCHDDHXMFKMA-UHFFFAOYSA-N (2,5-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(OC)C(CN)=C1 UWMCHDDHXMFKMA-UHFFFAOYSA-N 0.000 claims description 2
- CLEMOHZZIAAIFC-CONSDPRKSA-N (2S,3S)-2-benzhydryl-N-(2-methoxy-5-propylphenyl)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine Chemical compound CCCC1=CC=C(OC)C(N[C@@H]2[C@](N3CCC2CC3)(C)C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 CLEMOHZZIAAIFC-CONSDPRKSA-N 0.000 claims description 2
- ZXKQLZMZYWXUJC-CDZUIXILSA-N (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxyphenyl)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine Chemical compound COC1=CC=C(C(C)(C)C)C=C1N[C@@H]1[C@@](C(C=2C=CC=CC=2)C=2C=CC=CC=2)(C)N2CCC1CC2 ZXKQLZMZYWXUJC-CDZUIXILSA-N 0.000 claims description 2
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- PRXRQNXEYXMJCK-NSIYGSDQSA-N (2S,3S,4S,5R)-2-benzhydryl-3-[(2,5-dimethoxyphenyl)methylamino]-1-azabicyclo[2.2.2]octane-5-carboxylic acid Chemical compound C=1C=CC=CC=1C([C@@H]1N2CC[C@@]([C@H](C2)C(O)=O)([C@@H]1NCC=1C(=CC=C(OC)C=1)OC)[H])C1=CC=CC=C1 PRXRQNXEYXMJCK-NSIYGSDQSA-N 0.000 claims description 2
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- ZBFJTKASKIUJNF-PHXFNYRRSA-N (2S,3S,4S,5R)-2-benzhydryl-3-[(2-methoxy-5-methylsulfinylphenyl)methylamino]-1-azabicyclo[2.2.2]octane-5-carboxylic acid Chemical compound C=1C=CC=CC=1C([C@@H]1N2CC[C@@]([C@H](C2)C(O)=O)([C@@H]1NCC=1C(=CC=C(C=1)S(C)=O)OC)[H])C1=CC=CC=C1 ZBFJTKASKIUJNF-PHXFNYRRSA-N 0.000 claims description 2
- NNQJDQUAJJRYRV-NSIYGSDQSA-N (2S,3S,4S,5R)-2-benzhydryl-3-[(2-methoxy-5-methylsulfonylphenyl)methylamino]-1-azabicyclo[2.2.2]octane-5-carboxylic acid Chemical compound C=1C=CC=CC=1C([C@@H]1N2CC[C@@]([C@H](C2)C(O)=O)([C@@H]1NCC=1C(=CC=C(C=1)S(C)(=O)=O)OC)[H])C1=CC=CC=C1 NNQJDQUAJJRYRV-NSIYGSDQSA-N 0.000 claims description 2
- FQMDWRVWAZOFJF-QUNNAWRHSA-N (2S,3S,4S,5R)-2-benzhydryl-3-[(5-butan-2-yl-2-methoxyphenyl)methylamino]-1-azabicyclo[2.2.2]octane-5-carboxylic acid Chemical compound C=1C=CC=CC=1C([C@@H]1N2CC[C@@]([C@H](C2)C(O)=O)([C@@H]1NCC=1C(=CC=C(C=1)C(C)CC)OC)[H])C1=CC=CC=C1 FQMDWRVWAZOFJF-QUNNAWRHSA-N 0.000 claims description 2
- HANWCAQDYMDUKN-ATACATFBSA-N (2S,3S,4S,5R)-2-benzhydryl-3-[(5-ethyl-2-methoxyphenyl)methylamino]-1-azabicyclo[2.2.2]octane-5-carboxylic acid Chemical compound C=1C=CC=CC=1C([C@@H]1N2CC[C@@]([C@H](C2)C(O)=O)([C@@H]1NCC=1C(=CC=C(CC)C=1)OC)[H])C1=CC=CC=C1 HANWCAQDYMDUKN-ATACATFBSA-N 0.000 claims description 2
- LBYSHULELVFOGE-ATACATFBSA-N (2S,3S,4S,5R)-2-benzhydryl-3-[[5-(dimethylamino)-2-methoxyphenyl]methylamino]-1-azabicyclo[2.2.2]octane-5-carboxylic acid Chemical compound C=1C=CC=CC=1C([C@@H]1N2CC[C@@]([C@H](C2)C(O)=O)([C@@H]1NCC=1C(=CC=C(C=1)N(C)C)OC)[H])C1=CC=CC=C1 LBYSHULELVFOGE-ATACATFBSA-N 0.000 claims description 2
- WRBGYJZVJVSZCB-UHFFFAOYSA-N 1-methyl-2-phenylpiperidin-3-amine Chemical compound CN1CCCC(N)C1C1=CC=CC=C1 WRBGYJZVJVSZCB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- VYNRTZNOSYPDGE-ZCYQVOJMSA-N CC(C)C[N-]C1=CC=C(OC(C)C)C(CN[C@@H]2[C@@H](NCCC2)C=2C=CC=CC=2)=C1 Chemical compound CC(C)C[N-]C1=CC=C(OC(C)C)C(CN[C@@H]2[C@@H](NCCC2)C=2C=CC=CC=2)=C1 VYNRTZNOSYPDGE-ZCYQVOJMSA-N 0.000 claims description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
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- 150000003839 salts Chemical class 0.000 claims description 2
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Abstract
The present invention relates to the use of an NK-1 receptor antagonist (e.g., a substance P receptor antagonist) in the preparation of a composition for preventing or treating neurogenic inflammation associated with the use of viral vectors. in gene therapy in a mammal, including a human being
Description
THE USE OF AN ANTAGONIST OF THE NK-1 RECEPTOR IN THE PREPARATION OF A COMPOSITION FOR GENE THERAPY
The present invention relates to the use of NK-1 receptor antagonists (eg substance P receptor antagonists) to prevent or treat neurogenic inflammation associated with the use of viral vectors in gene therapy. The administration of vectors carrying gene constructs useful in gene therapy has been associated with the induction of a neurogenic inflammatory response. This neurogenic response is caused by the local release of substance P and other peptide neurotransmitters from the non-myelin C fibers that surround the microvessels of the respiratory tract. The present inventors believe that antagonists of the NK-1 receptor, through which substance P and other tachykinins induce their biological responses, will inhibit this inflammation and, therefore, will be of therapeutic utility. The control of the neurogenic inflammatory response, for example, in the respiratory tract after inhalation of an appropriate adenoviral vector, will allow the subsequent search of the gene therapy protocol.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a method for the prevention or treatment of neurogenic inflammation caused or enhanced by the administration of viral vectors in gene therapy in a mammal, including a human being, comprising the administration to said mammal of an amount of an NK-1 receptor antagonist that is effective in the prevention or treatment of said neurogenic inflammation. A more specific embodiment of this invention relates to the above method wherein the neurogenic inflammation that is prevented or treated is caused or enhanced by the administration of adenoviral vectors in gene therapy. Another, more specific embodiment of this invention relates to the above procedures, in which the neurogenic inflammation that is treated or treated is inflammation and pulmonary edema caused or enhanced by endotracheal inoculation with a rival vector that can be delivered to the patient. a genetic construct used in gene therapy. Another more specific embodiment of this invention relates to the embodiment described in the preceding paragraph, in which the gene construct comprises the gene that corrects the defective chlorine ion transplants in patients with cystic fibrosis.
Other more specific embodiments of this invention relate to the aforementioned methods in which the NK-1 receptor antagonist is selected from the group consisting of (2S, 3S) -3- (5-tert-butyl-2-methoxybenzyl) amino-2- (3-trifluoromethoxyphenyl) piperidine; (2S, 3S) -3- (2-isopropoxy-5-t rif luo rome toxibenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (2-ethoxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (2-methoxy-5-trif luorome toxibenzyl) amino-2-f enylpipe ridine; (2S, 3S) -3- (5-tert-butyl-2-t-ri-1-one-toxibenzyl) -amino-2-phenyl-piperazine; 2- (dipnylmethyl) -N- (2-methoxy-5-trifluoromethoxyphenyl) methyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -3- [5-chloro-2- (2, 2, 2-t rif luoroethoxy) -benzyl] ami no-2-phenypipiperidine; (2S, 3S) -3- (5-tert-butyl-2-t ri f 1 uorome toxibenzyl) ami no-2-f eni Ipiperidine; (2S, 3S) -3- (2-isopropoxy-5-t rif luo rome toxibenzyl) ami no-2-phenypipiperidine; (2S, 3S) -3- (2-difluoromethoxy-5-t ri f 1 uo rome toxibenzyl) ami no-2-f eni lpipericli na; (2S, 3S) -2-phenyl-3- [2- (2,2,2-trifluoroethoxybenzyl) -a inopiperidine;
(2S, 3S) -2-f enyl -3- (2-t rif luo rome toxibencil) ami no-pipe ridine; cis -3- (2-chlorobenzylamino) -2-f-enylpiperidine; cis -3- (2-trifluoromethylbenzylamino) -2-phenylpiperidine; cis-3- (2-methoxybenzyl lami) -2- (2-f luo rofyl) -piperidine; cis-3- (2-me toxibenci lamino) -2- (2-chlorofenyl) -piperidine; cis-3- (2-me toxibenci lami no) -2- (2-methylphenyl) -piperidine; cis-3- (2-me toxibenci lami no) -2- (3-methoxy phenyl) -piperidine; cis-3- (2-methoxybenzyl lami) -2- (3-f luo rofyl) -piperidine; cis-3- (2-me toxibenci lami no) -2- (3-chlorofenyl) -piperidine; cis -3- (2-methoxybenzylamino) -2- (3-methylphenyl) -pipe ridine; cis -3- (2-methoxybenzylamino) -2- (4-f luorofenyl) -piperidine; cis-3- (2-methoxybenzyl lamino) -2- (3-thienyl) pipe ridine; cis -3- (2-methoxybenzylamino) -2-phenylazacycloheptane; 3- (2-me toxibenci lami no) -4-met i 1-2-f eni Ipiperidi na; 3- (2-methoxybenzyllamino) -5-methyl-2-f eni Ipiperidine; (2S, 3S) -l- (5-ca rboetoxypent-1-yl) -3- (2-methoxybenzyl-ami no) -2-f eni Ipiperidine; (2S, 3S) -l- (6-hydroxy-hex-l-yl) -3- (2-methoxybenzyl-1-na) -2-f enylpiperidine; (2S, 3S) -l- (4-hydroxy-4-phenylbut-1-yl) -3- (2-methoxy-benzylamino) -2-phenylpiperidine; (2S, 3S) -l- (4-oxo-4-phenylbut-1-yl) -3- (2-methoxybenzylamino) -2-f-enylpipe-ridine; (2S, 3S) -l- (5,6-dihydroxy hex-l-yl) -3- (2-methoxybenzyl-amino) -2-f enylpiperidine; cis-3- (5-f luo ro-2-me toxibenci lamino) -2-f enylpipe ridine; (2S, 3S) -l- [4- (4-f luo rofyl) -4-oxobut-l-yl] -3- (2- e toxibencylami) -2-f eni Ipiperidine; (2S, 3S) -l- [4- (4-f luo rofenil) -4-hi roxibut-l-il] -3- (2-me toxibenci lami no) -2-f eni Ipiperidi na; cis -3- (2-methoxy-5-methylenebenzylamine) -2-phenylpiperidine; (2S, 3S) -l- (4-benzamidobut-1-yl) -3- (2-methoxybenzylamino) -2-f enylpiperidine; cis -3- (2-methoxynaphth-1-ylmethylamino) -2-phenypipiperidine; (2S, 3S) -3- (2-methoxybenzyllamino) -l- (5-N-methyl-carboxamidopent-1-yl) -2-f enylpiperidine; (2S, 3S) -l- (4-cyanobut-1-yl) -3- (2-me toxibenci lami) -2-phenylpiperidine; (2S, 3S) -l-C4- (2-naphthamido) but-l-yl] -3- (2-methoxybenzyl lane) -2-f eni Ipiperidine; (2S, 3S) -l- (5-benzamidopent-1-yl) -3- (2-metoxibenz 1 -ami no) -2-f eni Ipiperidine; (2S, 3S) - (l- (5-aminopent-l-yl) -3- (2-methoxybenzylamino) -2-f eni Ipiperidine; (2S, 3S) -3- (5-chloro-2-metoxibenzin) lami no) -2-phenypipiperidine; (2S, 3S) -3- (2, 5-dime toxibenci lamino) -2-phenypipiperidine; cis-3- (3, 5-di f luo ro-2-me oxibenci lami no) -2-phen Ipiperidine; cis-3- (4,5-di f luo ro-2-me toxibenci lami no) -2-pheni Ipiperidine; cis-3- (2,5-dimethoxybenzylamine) -l- [4- (4-fluorophenyl) -4-oxobut-l-yl] -2-phenypipiperidine; cis-3- (5-chloro-2-metoxibenzylamino) -! - (5,6- dihid roxihex-1 -i 1) -2-f eni Ipiperidine; cis-1- (5,6-dihydroxy hex-l-yl) -3- (2, 5-dime toxibenci lami) -2- Ipiperidine, cis-2-phenyl-3- [2-prop-2-yloxy) benzylamino] pipe ridine; cis-3- (2,5-dimethoxybenzyl) amino-2- (3-methoxy-phenyl) pyridine hydrochloride; cis -3- (5-chloro-2-methoxybenzyl) amino-2- (3-methoxy-phenyl) piperidine dihydrochloride; cis-3- (5-chloro-2-methoxybenzyl) amino-2- (3-chloro-phenyl) -piperidine dihydrochloride;
3- (2-methoxybenzylamino) -2,4-diphenylpiperidine; (2S, 3S) -3- (2-meoxybenzylamino) -2-phenylpiperidine; cis -3- (2-methoxybenzylamino) -2-phenylpyrrolidine; (2S, 3S) -3- (5-ethyl-2-methoxybenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (5-n-butyl-2-methoxybenzyl) amino-2-phenypiperidine; (2S, 3S) -3- (2-methoxy-5-n-propylbenzyl) amino-2-phenypiperidine; (2S, 3S) -3- (5-isopropyl-2-methoxybenzyl) amino-2-phenypiperidine; (2S.3S) -3- (5-s-Butyl-2-methoxybenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (5-t-Butyl-2-methoxybenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (2-methoxy-5-f nylbenzyl) amino-2-phenypiperidine; 2,4-Dimethylthiazole-5-sulfonic acid 4-methoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -methylamide; N- (4,5-Dimethylthiazol-2-yl) -N- [4-methoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-yl-aminomethyl) phenyl] -methanesulfonamide; C5 - [(4,5-Dimethylthiazol-2-yl) methylamino] -2-methoxybenzyl} - ((2S, 3S) -2-phenylpiperidin-3-yl) amine; . { 5- (4,5-Dimethylthiazol-2-ylamino) -2-methoxybenzyl} - ((2S, 3S) -2-phenylpiperidin-3-yl) amine;
me-l- [3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) -4- trifluoromethoxy-phenyl] -amide of 4,5-dimethylthiazole-2-sulfonic acid; 2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3 - ((2S, 3S) -2-phenylepiperidin-3-ylaminomethyl) phenyl] -methylamide; 2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3 - ((2S, 3S) -2-phenylepiperidin-3-ylaminomethyl) phenyl] -isopropylamide; 2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -isopropylamide; 2,4-Dimethylthiazole-5-sulfonic acid [4-methoxy-3- ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -isobutylamide; [4-isopropoxy-3- ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -isobutylamide of 2,4-dimethylthiazole-5-sulfonic acid; (2S, 3S) -N- (5-isopropyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-tert-butyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-methyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-ethyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S) -N- (5-isopropyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-sec-butyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-n-propyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -2-diphenylmethyl-3- (5-tert-butyl-2-methoxybenzyl) amino-1-azabicyclo [2.2.2] octane; (2S, 3S) -N- [5- (l-cyano-l-melethyl) -2-methoxybenzyl] -2-phenylpiperidin-3-amine; (2S, 3S) -3- (6-methoxy-1-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl) methyl-2-phenylpiperidin-3-amine; (2S, 3S) -2-phenyl-N- [5- (2,2,2-trifluoro-1- (rifluoromethyl) yl] -2-oxoxybenzylpiperidin-3-amine; (2S, 3S) -2-diphenylmethyl -N- [2-methoxy-5- (me ylsulfonyl) benzyl] -l-azabicyclo [2.2.2] octan-3-amine; (2S, 3S) -2-diphenylmethyl-N- (5-isopropeni1-2- ethoxybenzyl) -l-azabicyclo [2.2.2] octan-3-amine; (2S, 3S) -2-diphenylmethyl-N- [5- (l-hydroxy-l-methylethyl) -2-methoxybenzyl] -l-azabicyclo [2.2.2] octan-3-amine; (3R, 4S, 5S, 6S) -N, N-diethyl-5- (5-isopropyl-2-methoxy-benzylamino) -6-diphenylmethyl-1-azabicyclo [2.2 .2] octane-3-carboxamide; (3R, 4S, 5S, 6S) -N, N-diethyl-5- (2,5-dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3 -carboxamide; (3R, 4S, 5S, 6S) -5- (5-isopropyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-2-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid (3R, 4S, 5S, 6S) -5- (2 , 5-dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylbenzyl) mino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-ethyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-n-propylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-c-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-sec-butyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-N-methyl-methanesulfonylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylsulfinylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-trifluoro-ethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-c-carboxylic acid;
(3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylsulfonylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-dimethylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-isopropyl-2-ethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2,5-dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-ethyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-n-propylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-sec-butyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-N-methyl-methanesulfonylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylisulfinylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-trifluoromethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylsulfonylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; and (3R, 4S, 5S, 6S) -5- (5-dimethylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid;
DETAILED DESCRIPTION OF THE INVENTION
The following references refer, as a whole, to quinuclidine, piperidine, ethylenediamine, pyrrolidine and azanorbornane derivatives and to related compounds that exhibit activity as NK-1 receptor antagonists and that can be used, combined with one to four additional different active ingredients, as described above, in the pharmaceutical compositions and methods of this invention, and methods of preparing them; U.S. Patent 5,162,339, issued November 11, 1992; U.S. Patent 5,232,929, issued August 3, 1993; international patent application WO 92/20676, published November 26, 1993; international patent application WO 93/00331, published January 7, 1993; international patent application WO 92/21677, published on December 10, 1992; International Patent Application WO 93/00330, published January 7, 1993; International patent application WO 93/06099, published on April 1, 1993; International Patent Application WO 93/10073, published May 27, 1993; international patent application WO 92/06079, published on April 16, 1992; International Patent Application WO 92/12151, published July 23, 1992; International patent application WO 92/15585, published on September 17, 1992; International Patent Application WO 93/10073, published May 27, 1993; International patent application WO 93/19064, published September 30, 1993; International patent application WO 94/08997, published on April 28, 1994; international patent application WO 94/04496, published March 3, 1994; International Patent Application WO 94/13663, published June 23, 1994; International Patent Application WO 94/20500, published September 15, 1994; International Patent Application PCT / IB94 / 00221, which designates the United States and was filed on July 18, 1994; International patent application PCT / JP94 / 00781, which designates the United States and was filed on May 13, 1994; International Patent Application PCT / JP94 / 01092, which designates the United States and was filed on July 5, 1994; and international patent application PCT / JP94 / 01514, which designates the United States and the September 13, 1994. All previous international patent applications designate the United States as the state in which they will be processed. The above patents and patent applications are hereby incorporated by reference in their entirety. The specific NK-1 receptor antagonists listed in the Summary of the Invention can be prepared by methods described in the patents and patent applications listed above and in the scientific literature. Other N-1 receptor antagonists that can be used in the combination therapies of this invention are described in the following references: European patent application EP 499,313, published on August 19, 1992; European patent application EP 520,555, published on December 30, 1992; European patent application EP 522,808, published on January 13, 1993; European patent application EP 528,495, published on February 24, 1993; PCT patent application W0 93/14084, published July 22, 1993; PCT patent application W0 93/01169, published January 21, 1993; PCT patent application W0 93/01165, published January 21, 1993; PCT patent application W0 93/01159, published January 21, 1993; PCT patent application W0 92/20661, published on November 26, 1992; European patent application EP 517,589, published on December 12, 1992; European patent application EP 428,434, published May 22, 1991; European patent application EP 360,390, published on March 28, 1990; PCT patent application WO 95/04042, published February 9, 1995; PCT patent application WO 95/08549, published March 30, 1995; PCT patent application WO 95/19344, published July 20, 1995; PCT patent application WO 95/23810, published September 8, 1995 and PCT patent application WO 95/20575, published August 3, 1995. These publications are also incorporated herein by reference in their entirety. In general, in carrying out the methods of this invention, the NK-1 receptor antagonist will be administered to an adult human in an amount ranging from about 0.07 to about 21 mg per kg of body weight of the subject being treating by day, in single or divided doses, preferably from about 0.36 to about 4.3 mg / kg. However, variations may occur depending on the animal species being treated and their individual response to said medicament, as well as the type of pharmaceutical formulation chosen and the period and time interval in which said administration is carried out. In some cases, dosing levels below the lower limit of the previous range may be more appropriate, while in other cases even higher doses may be used without causing any harmful side effects, provided that said major aoses are first divided into several doses minors for administration throughout the day. Antagonists of the NK-1 receptor and its pharmaceutically acceptable salts that are employed in the methods of this invention will hereinafter also be referred to as "therapeutic agents". The therapeutic agents can be administered either orally or parenterally. The therapeutic agents can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes indicated above, and such administration can be carried out in single or divided doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide range of different dosage forms, i.e. these can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, tablets, troches, candies hard, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, the oral pharmaceutical compositions can be sweetened and / or flavored in a suitable manner. In general, the therapeutic compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing different excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, together with different disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. In addition, for the purposes of the preparation of tablets, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are very often useful. Solid compositions of a similar type can also be employed as fillers in gelatin capsules; also including the preferred materials to this respect lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring materials or dyes and, if desired, also emulsifying and / or suspending agents, together with diluents. as water, ethanol, propylene glycol, glycerol and the different combinations thereof. For parenteral administration, solutions of a therapeutic agent in sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions will be taped appropriately if necessary and the liquid diluent will first be isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is carried out in a simple manner by conventional pharmaceutical techniques well known to those skilled in the art. The activity of certain therapeutic agents as substance P receptor antagonists can be determined by their ability to inhibit the binding of substance P at their receptor sites in bovine caudal tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography. The substance P antagonizing activity of the compounds described herein can be evaluated using the standard assay procedure described by M.A. Cascieri et al. , referenced in Journal of Biological Chemistry, Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of individual compound needed to reduce by 50% the amount of substance P ligands radioactively labeled at their receptor sites in said isolated bovine tissues, thereby providing the characteristic ICso values for each compound rehearsed In this procedure, bovine caudal tissue is extracted from a -70QC freezer and homogenized in 50 volumes (w / v) of Tris buffer (ie, tri-ethanamine, which is 2-amino-2-hydroxymethyl-3, propanodiol) 50 M hydrochloride cooled on ice with a pH of 7.7. The homogenate is centrifuged at 30,000 x G for a period of 20 minutes. The pellet is resuspended in 50 volumes of Tris buffer, re-homogenized and then recentrifuged at 30,000 x G for another twenty minute period. The pellet is then resuspended in 40 volumes of ice-cold 50 M Tris buffer (pH 7.7) containing 2 mM calcium chloride, 2 mM magnesium chloride, 4 μg / ml bacitracin, 4 μg / ml of leupeptin, 2 μg of the iostatin and 200 μg / ml of bovine serum albumin. This stage completes the production of the tissue preparation. The radioligand binding procedure is then carried out in the following manner, namely, initiating the reaction by the addition of 100 μl of test compound to a concentration of 1 μM, followed by the addition of 100 μl of the radioactive ligand to a final concentration of 0.5 mM and finally by the addition of 800 μl of tissue preparation produced as described above. The final volume is thus 1.0 ml, and the reaction mixture is vortexed next and incubated at room temperature (about 20 ° C) for a period of 20 minutes. The tubes are then filtered using a cell harvester, and the glass fiber filters (Whatman GF / B) are washed four times with 50 mM Tris buffer (pH 7.7), the filters being previously soaked for a period of two hours. hours before the filtering procedure. The radioactivity in a Beta counter is then determined at a count efficiency of 53%, and IC50 values are calculated using standard statistical procedures. The following study was conducted in order to determine if the exaggerated inflammatory reaction associated with the endotracheal administration of Ad5CMVLacZ can be prevented by selective antagonism of the substance P receptor (NK-1). Fischer F344 male rat free of pathogens (220-287 g of weight, 12-14 weeks), under anesthesia with sodium pentobarbital, received a localized endotracheal inoculation with 100 μl of phosphate buffered saline (PBS) containing 3 x 10 * 2 particles / ml of Ad5CMVLacZ, a defective adenovirus type 5 vector. the El and E3 regions of the viral genome and containing the transformed LacZ gene under the control of the CMV promoter (cytomegalovirus) immediately early. A group of control rats was inoculated with sterile PBS. Five days after the inoculation, 2 groups of rats inoculated with the adenoviral vector were treated with a selective P (NK-1) receptor antagonist (2S, 3S) -2-phenyl-3- [(2-methoxyphenyl) ) methylamino] piperidine (compound A) (4 mg / kg, iv; n = 5), or with its inactive stereoisomer (2R, 3R) -2-pheny1-3-C (2-methoxyphenyl) methylamino] -piperidine (compound B) (4 mg / kg, i.v., n = 5). Two other groups of rats inoculated with vector (n = 6) or with PBS (n = 6) did not receive any previous treatment. Five minutes after the previous treatment, Evans blue dye (30 mg / kg, i.v.) was injected in all rats to measure the increase in vascular permeability associated with neurogenic inflammation. Capsaicin (75 mg / kg, i.v. for 2 minutes) was injected immediately after Evans blue to stimulate the sensory nerves of the airway mucosa. Five minutes after capsaicin, the rats were subjected to cardiac perfusion with 100 ml of PBS. The trachea and main bronchi were excised and incubated in formamide (18 hours at 50 ° C) to extract the extravasated tracer. The magnitude of evasion blue extravasation was determined by specific measurements of the optical density of the formamide extracts. Extravasation of Evans blue produced by capsaicin in rats inoculated with Ad5CMVLacZ was inhibited by compound A (33.5 ± 4.6 vs. 104.5 ± 5.9 mg / kg, mean ± standard deviation, p <0.001 ) but not for compound B (88.3 ± 5.8 ng / mg, p> 0.05). After compound A, the extravasation induced by capsaicin in rats inoculated with the vector was not different from that of rats inoculated with PBS (43.9 ± 4.9 ng / mg, p> 0.05). These results indicate that potentiation of neurogenic inflammation caused by exposure of the respiratory tract of the rat to Ad5CMVLacZ involves activation of the substance P receptor (N -1) and can be prevented by selective antagonism of this receptor.
Claims (5)
1. The use of an NK-1 receptor antagonist in the preparation of a composition for preventing or treating neurogenic inflammation caused or enhanced by the administration of viral vectors in gene therapy in a mammal.
2. The use according to claim 1, wherein the neurogenic inflammation that is prevented or treated is caused or enhanced by the administration of adenoviral vectors in gene therapy. The use according to claim 2, wherein the neurogenic inflammation that is prevented or treated is inflammation and pulmonary edema caused or enhanced by endotracheal inoculation with an adenoviral vector carrying a genetic construct. 4. The use according to claim 3, wherein the genetic construct comprises the gene that corrects the chloride ion transporter defective in patients with cystic fibrosis. The use according to claim 1, wherein the NK-1 receptor antagonist used is selected from the group consisting of: (2S, 3S) -3- (5-tert-butyl-2-methoxybenzl) amino-2 - (3-trifluoromethoxyphenyl) piperidine; (2S, 3S) -3- (2-isopropoxy -5- trif luo rome toxibenzyl) ami no-2-phenypipiperidine; (2S, 3S) -3- (2-ethoxy-5-t rifl uorome toxibenzyl) ami no-2-phenypipiperidine; (2S, 3S) -3- (2-me toxi -5- t ri f luo rome toxibenzyl) ami no-2-f eni Ipiperidine; (2S, 3S) -3- (5-tert-buty-1-2-trifluo-romethoxybenzyl) amino-2-f-enylpipe-ridine; 2- (di feni lmeti 1) -N- (2-me toxi -5-t rif luoromethoxy phenyl) methyl l-l-azabicyclo [2.2.2] octan-3-amine; (2S, 3S) -3- [5-chloro-2- (2, 2, 2-t rif luo roe toxi) -benz l] ami no-2-f enylpipe ridine; (2S, 3S) -3- (5-tert-butyl-2-t rifl uorome toxibenzyl) ami no-2-phenypipiperidine; (2S, 3S) -3- (2-isopropoxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (2-di f luoromethoxy -5- trifluo rome toxibenzyl) ami no-2-phenypipiperidine; (2S, 3S) -2-phenyl-3- [2- (2,2,2-trifluoroethoxybenzyl) -aminopiperidine; (2S, 3S) -2-f-enyl -3- (2-trifluoromethoxybenzyl) amino-piperidine; cis-3- (2-chlorobenzyl lami) -2-phenylpiperidine; cis -3- (2-trifluoromethylbenzylamino) -2-phenylpiperidine; cis-3- (2-me toxibenci lami no) -2- (2-f luo rof enyl) -pipe ridi na; cis-3- (2-methoxybenzyl lamino) -2- (2-chlorofenyl) -pipe ridine; cis -3- (2-methoxybenzylamino) -2- (2-methylphenyl) -piperidine; cis -3- (2-methoxybenzylamino) -2- (3-methoxyphenyl) -pipe ridine; cis -3- (2-methoxybenzylamino) -2- (3-fluorophenyl) -piperidine; cis-3- (2-methoxybenzyl lamino) -2- (3-chlorofenyl) -pipe ridine; cis-3- (2-methoxybenzyl lamino) -2-f enylpipe ridine; cis -3- (2-methoxybenzylamino) -2- (3-methylphenyl) -piperidine; cis -3- (2-methoxybenzylamino) -2- (4-f luo rofenyl) -pipe ridine; cis-3- (2-methoxybenzilari no) -2- (3-ienyl) pipe ridin; cis-3- (2-me toxibenci lami no) -2-f eni lazacyclohep ta; (2S, 3S) -3- (2-ethoxybenzylamine) -2-phenypipiperidine; 3- (2-methoxybenzyl lamino) -4-methyl -2-f eni Ipiperidine; 3- (2-methoxybenzyl-lamino) -5-methyl-2-phenylpiperidine; 3- (2-methoxybenzylamino) -6-methyl-2-f-enylpipe-ridine; (2S, 3S) -l- (5-carboethoxypent-1-yl) -3- (2-methoxybenzyl-amino) -2-phenypipiperidine; (2S, 3S) -l- (6-hydroxy-hex-l-yl) -3- (2-methoxybenzyl-amino) -2-phenypipiperidine; (2S.3S) -l- (4-hydroxy-4-phenylbut-1-yl) -3- (2-methoxy-benzylamino) -2-phenylpiperidine; (2S, 3S) -l- (4-oxo-4-phenylbut-1-yl) -3- (2-ethoxy-benzyl-no) -2-f-enylpipe-ridine; (2S, 3S) -l- (5,6-di id roxy hex-l-yl) -3- (2-me toxibenzyl-na) -2-f eni Ipiperidine; cis-3- (5-f luoro-2-me toxibenci lami no) -2-f enyl-pipe ridi na; (2S, 3S) -l- [4- (4-fluorophenyl) -4-oxobut-l-yl] -3- (2-methoxybenzylamino) -2-phenylpiperidine; (2S, 3S) -l- [4- (4-f luo rofyl) -4-hydroxybut-l-yl] -3- (2-metoxibenzylami) -2-phenylpiperidine; cis -3- (2-methoxy-5-methylbenzylamino) -2-phenypipiperidine; (2S, 3S) -l- (4-benzamidobut-l-yl) -3- (2-toxibenzyl-na) -2-f enylpiperidine; cis -3- (2-me toxy naph t-1-ylmethylamino) -2-phenylpiperidine; (2S, 3S) -3- (2-metoxibenzlamino) -l- (5-N-methyl-ca rboxamidopent-1-yl) -2-phenypipiperidine; (2S, 3S) -l- (4-cyanobut-l-yl) -3- (2- e toxibencylami) -2-f eni Ipiperidine; (2S, 3S) -l- [4- (2-naphthatened) but-1-yl] -3- (2-me toxy-benzylane) -2-f eni Ipiperidine; (2S, 3S) -l- (5-benzamidopent-1-yl) -3- (2-metoxibenzyl-na) -2-phenypipiperidine; (2S, 3S) - (1- (5-aminopent-1-yl) -3- (2-methoxybenzyl) -2-phenylpiperidine; (2S, 3S) -3- (5-chloro-2) -methoxybenzylamine) -2-f eni Ipiperidine; (2S, 3S) -3- (2,5-di-ethoxybenzyl-lane) -2-f-enylpipe-ridine; cis-3- (3, 5-di-fluor-2) - e toxibenci lami no) -2-f eni Ipiperidine; cis-3- (4,5-di-fluoro-2-methoxybenzylamino) -2-phenylpiperidine; cis -3- (2,5-dimethoxybenzylamine) -l- [ 4- (4-fluorophenyl) -4-oxobut-l-yl] -2-phenyl Ipiperidine; cis-3- (5-chloro-2-me toxibencylamino) -l- (5,6-di hydroxy hex) -l-il) -2-f eni Ipiperidine; cis-1- (5,6-dihydroxy hex-1-yl) -3- (2, 5-dimetoxy-benzy lami) -2-f eni Ipiperidine, cis-2-phenyl-3-C2-prop-2-yloxy) benzylamino] piperidine; cis -3- (2,5-dime toxibenzyl) ami no-2- (3-me toxy-phenyl) pyridine hydrochloride; cis -3- (5-chloro-2-methoxybenzyl) amino-2- (3-methoxy-phenyl) piperidine dihydrochloride; cis-3- (5-chloro-2- e toxibenci 1) ami no-2- (3-chloro-phenyl) pyridine dihydrochloride; 3- (2-methoxybenzylamino) -2,4-diphenylpiperidine; cis -3- (2-methoxybenzylamino) -2-phenylpirolidine; (2S, 3S) -3- (5-ethyl-2-methoxybenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (5-n-butyl-2-methoxybenzyl) ami no-2-phenypipiperidine; (2S, 3S) -3- (2-methoxy-5-n-propylbenzyl) amino-2-f-enylpipe-ridine; (2S, 3S) -3- (5-isopropyl-2-me toxyl benzyl) ami no-2-f eni Ipiperidine; (2S, 3S) -3- (5-s-butyl-2-metoxibenzyl) ami no-2-phenypipiperidine; (2S, 3S) -3- (5-t-Butyl-2-methoxybenzyl) amino-2-phenylpiperidine; (2S, 3S) -3- (2-methoxy-5-phenylbenzyl) amino-2-phenylpiperidine; 2,4-Dimethylthiazole-5-sulfonic acid [4-methoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -methylamide; N- (4,5-Dimethylthiazol-2-yl) -N- [4-methoxy-3 - ((2S, 3S) -2-f-en-1-piperidin-3-yl-aminomethyl) -phenyl] -methanesulfonamide; . { 5- [(4,5-Dimethylthiazol-2-yl) methylamino] -2-methoxybenzyl} - ((2S, 3S) -2-phenylpiperidin-3-yl) amine; . { 5- (4,5-dimethylthiazol-2-ylamino) -2-methoxybenzyl} - ((2S, 3S) -2-phenylpiperidin-3-yl) amine; 4,5-dimethylthiazole-2-sulfonic acid methyl- [3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) -4-trifluoromethoxyphenyl] -amide; 2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -methylamide; 2,4-dimethylthiazole-5-sulfonic acid [4-isopropoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -isopropylamide; 2,4-dimethylthiazole-5-sulfonic acid [4-methoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -isopropylamide; 2,4-dimethyl-1-ylazole-5-sulfonic acid [4-methoxy-3 - ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -isobutylamide; [4-isopropoxy-3- ((2S, 3S) -2-phenylpiperidin-3-ylaminomethyl) phenyl] -isobutylamide of 2,4-dimethylthiazole-5-sulfonic acid; (2S, 3S) -N- (5-isopropyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-tert-butyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-methy1-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-ethyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octan-3-a ina; (2S, 3S) -N- (5-isopropyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-sec-buty1-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -N- (5-n-propyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -2-diphenylmethi1-3- (5-tert-butyl-2-methoxybenzyl) amino-1-azabicyclo [2.2.2] octane; (2S, 3S) -N- [5- (l-cyano-1-methylethyl) -2-methoxybenzyl] -2-phenylpiperidin-3-amine; (2S, 3S) -3- (6-methoxy-l-methyl-2-oxo-l, 2,3,4-tetrahydroquinolin-7-yl) methyl-2-phenylpiperidin-3-amine; (2S, 3S) -2-phenyl-N- [5- (2,2,2-trifluoro-l- (trifluoromethyl) ethyl] -2-methoxybenzyl] piperidin-3-amine; (2S, 3S) -2- diphenylmethyl-N- [2-methoxy-5- (methylsulfonyl) benzyl] -l-azabicyclo [2.2.2] octane-3-amine; (2S, 3S) -2-diphenylmethyl-N- (5-isopropenyl-2-) methoxybenzyl) -l-azabicyclo [2.2.2] octan-3-amine; (2S, 3S) -2-diphenylmethi-N- [5- (l-hydroxy-1-methylethyl) -2-methoxybenzyl] -l-azabicyclo [2.2.2] octan-3-amine; (3R, 4S, 5S, 6S) -N, N-diethi-5- (5-isopropy1-2-methoxy-benzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide; (3R, 4S, 5S, 6S) -N, N-diethyl-5- (2,5-dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxamide; (3R, 4S, 5S, 6S) -5- (5-isopropyl-2-ethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-2-methyl-iobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2,5-dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-ethyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-n-propylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-sec-butyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-N-methy1-methanesulfonylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; acid (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylsulfinylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; acid (3R, 4S, 5S, 6S) -5- (2-methoxy-5-trifluoromethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylsulfonylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-dimethylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-3-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-isopropyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylthiobenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2,5-dimethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-ethyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-n-propylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-sec-butyl-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (5-N-methyl-methanesulfonylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylsulfinylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-trifluoromethoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-c-carboxylic acid; (3R, 4S, 5S, 6S) -5- (2-methoxy-5-methylsulfonylbenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; and (3R, 4S, 5S, 6S) -5- (5-dimethylamino-2-methoxybenzylamino) -6-diphenylmethyl-1-azabicyclo [2.2.2] octane-2-carboxylic acid; and the pharmaceutically acceptable salts of the above compounds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US005002 | 1987-01-20 | ||
| US006344 | 1995-11-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA98001905A true MXPA98001905A (en) | 1999-05-31 |
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