CA2654147A1 - Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia - Google Patents
Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia Download PDFInfo
- Publication number
- CA2654147A1 CA2654147A1 CA002654147A CA2654147A CA2654147A1 CA 2654147 A1 CA2654147 A1 CA 2654147A1 CA 002654147 A CA002654147 A CA 002654147A CA 2654147 A CA2654147 A CA 2654147A CA 2654147 A1 CA2654147 A1 CA 2654147A1
- Authority
- CA
- Canada
- Prior art keywords
- 3alkyl
- 3alkoxy
- 10aryl
- dihydro
- piperidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 208000002193 Pain Diseases 0.000 title claims abstract description 23
- 230000036407 pain Effects 0.000 title claims abstract description 15
- 238000011282 treatment Methods 0.000 title claims description 10
- 201000000980 schizophrenia Diseases 0.000 title claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 title claims description 7
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 title description 25
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 title description 25
- 239000000018 receptor agonist Substances 0.000 title description 3
- 229940044601 receptor agonist Drugs 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 213
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- -1 methoxy, ethoxy, isopropoxy Chemical group 0.000 claims description 119
- 229910052739 hydrogen Inorganic materials 0.000 claims description 106
- 239000001257 hydrogen Substances 0.000 claims description 103
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 71
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 68
- 150000002367 halogens Chemical class 0.000 claims description 64
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 50
- 239000000203 mixture Substances 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 47
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 43
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 36
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 35
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 18
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 241001465754 Metazoa Species 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- VKQFQFLXAGPJKI-INIZCTEOSA-N tert-butyl (3s)-3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC[C@@H]1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 VKQFQFLXAGPJKI-INIZCTEOSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- CYPTXTYYWOUWKO-UHFFFAOYSA-N ethyl 3-[4-(5-chloro-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C(NC3=CC(Cl)=CC=C32)=O)CC1 CYPTXTYYWOUWKO-UHFFFAOYSA-N 0.000 claims description 5
- DMQNYYUSRGZMNA-IBGZPJMESA-N 1-methyl-3-[1-[(3s)-1-[3-(2-oxopyrrolidin-1-yl)propanoyl]pyrrolidin-3-yl]piperidin-4-yl]benzimidazol-2-one Chemical compound C([C@@H](C1)N2CCC(CC2)N2C3=CC=CC=C3N(C2=O)C)CN1C(=O)CCN1CCCC1=O DMQNYYUSRGZMNA-IBGZPJMESA-N 0.000 claims description 4
- JNOJPZRLZGKCBU-LPHOPBHVSA-N 3-[1-[(3s)-1-[(2s)-oxolane-2-carbonyl]pyrrolidin-3-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C([C@H](CC1)N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)N1C(=O)[C@@H]1CCCO1 JNOJPZRLZGKCBU-LPHOPBHVSA-N 0.000 claims description 4
- JAUFMQYUBYKIEE-SFHVURJKSA-N 3-[1-[(3s)-1-[3-(2-oxopyrrolidin-1-yl)propanoyl]pyrrolidin-3-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C([C@H](CC1)N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)N1C(=O)CCN1CCCC1=O JAUFMQYUBYKIEE-SFHVURJKSA-N 0.000 claims description 4
- HXYQHTSHRKZZEB-HNNXBMFYSA-N ethyl (3s)-3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 HXYQHTSHRKZZEB-HNNXBMFYSA-N 0.000 claims description 4
- UGVSPMUTKNEWKD-HNNXBMFYSA-N ethyl (3s)-3-[4-[2-oxo-6-(trifluoromethyl)-3h-benzimidazol-1-yl]piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=C(C=C32)C(F)(F)F)=O)CC1 UGVSPMUTKNEWKD-HNNXBMFYSA-N 0.000 claims description 4
- CQQOKEJUCXUWAA-UHFFFAOYSA-N ethyl 3-[4-(benzotriazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C3=CC=CC=C3N=N2)CC1 CQQOKEJUCXUWAA-UHFFFAOYSA-N 0.000 claims description 4
- FFXWWOUMOYWKDS-HNNXBMFYSA-N (3s)-n-ethyl-3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxamide Chemical compound C1N(C(=O)NCC)CC[C@@H]1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 FFXWWOUMOYWKDS-HNNXBMFYSA-N 0.000 claims description 3
- WGYJSEHXGADBCK-KRWDZBQOSA-N 3-[1-[(3s)-1-(1-methylpyrrole-2-carbonyl)pyrrolidin-3-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound CN1C=CC=C1C(=O)N1C[C@@H](N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)CC1 WGYJSEHXGADBCK-KRWDZBQOSA-N 0.000 claims description 3
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- IUSSAHCWZNNGON-QGZVFWFLSA-N ethyl (3r)-3-[4-(2-oxo-3h-indol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@H]1N1CCC(N2C3=CC=CC=C3CC2=O)CC1 IUSSAHCWZNNGON-QGZVFWFLSA-N 0.000 claims description 3
- IUSSAHCWZNNGON-KRWDZBQOSA-N ethyl (3s)-3-[4-(2-oxo-3h-indol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C3=CC=CC=C3CC2=O)CC1 IUSSAHCWZNNGON-KRWDZBQOSA-N 0.000 claims description 3
- VZLHBYBRNIIHIM-SFHVURJKSA-N ethyl (3s)-3-[4-(5-tert-butyl-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC(=CC=C32)C(C)(C)C)=O)CC1 VZLHBYBRNIIHIM-SFHVURJKSA-N 0.000 claims description 3
- GYLCSQMJDPAASE-INIZCTEOSA-N ethyl (3s)-3-[4-(6-cyano-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=C(C=C32)C#N)=O)CC1 GYLCSQMJDPAASE-INIZCTEOSA-N 0.000 claims description 3
- KLSANCSSLVHPCB-HNNXBMFYSA-N ethyl (3s)-3-[4-(6-methoxy-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=C(OC)C=C32)=O)CC1 KLSANCSSLVHPCB-HNNXBMFYSA-N 0.000 claims description 3
- YAGJOXUJBFGVSM-INIZCTEOSA-N ethyl (3s)-3-[4-(6-methyl-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=C(C)C=C32)=O)CC1 YAGJOXUJBFGVSM-INIZCTEOSA-N 0.000 claims description 3
- JLTRGVJUXXGCKP-AWEZNQCLSA-N ethyl (3s)-3-[4-[2-oxo-5-(trifluoromethoxy)-3h-benzimidazol-1-yl]piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC(OC(F)(F)F)=CC=C32)=O)CC1 JLTRGVJUXXGCKP-AWEZNQCLSA-N 0.000 claims description 3
- PAECBHQHHWJQIY-UHFFFAOYSA-N ethyl 3-[3-(2-oxo-3h-benzimidazol-1-yl)-8-azabicyclo[3.2.1]octan-8-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1C2CCC1CC(N1C(NC3=CC=CC=C31)=O)C2 PAECBHQHHWJQIY-UHFFFAOYSA-N 0.000 claims description 3
- XPEKEIQTHMSNSQ-UHFFFAOYSA-N ethyl 3-[4-(2-oxo-1,3-dihydroindol-3-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(C2C3=CC=CC=C3NC2=O)CC1 XPEKEIQTHMSNSQ-UHFFFAOYSA-N 0.000 claims description 3
- GMQVAFMIQKCBCF-UHFFFAOYSA-N ethyl 3-[4-(4-fluoro-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C(NC3=C(F)C=CC=C32)=O)CC1 GMQVAFMIQKCBCF-UHFFFAOYSA-N 0.000 claims description 3
- FKXJGWBHRQUXAR-UHFFFAOYSA-N ethyl 3-[4-(6-fluoro-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C(NC3=CC=C(F)C=C32)=O)CC1 FKXJGWBHRQUXAR-UHFFFAOYSA-N 0.000 claims description 3
- IPTYTVSDURDKDT-UHFFFAOYSA-N ethyl 3-[4-(7-fluoro-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C(NC3=CC=CC(F)=C32)=O)CC1 IPTYTVSDURDKDT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- VKQFQFLXAGPJKI-UHFFFAOYSA-N tert-butyl 3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 VKQFQFLXAGPJKI-UHFFFAOYSA-N 0.000 claims description 3
- IESXAYQMUSOGKX-FQEVSTJZSA-N 1-[1-[(3s)-1-[3-(2-oxopyrrolidin-1-yl)propanoyl]pyrrolidin-3-yl]piperidin-4-yl]-3h-indol-2-one Chemical compound C([C@H](CC1)N2CCC(CC2)N2C3=CC=CC=C3CC2=O)N1C(=O)CCN1CCCC1=O IESXAYQMUSOGKX-FQEVSTJZSA-N 0.000 claims description 2
- WQMADGKABXWRPB-UHFFFAOYSA-N 3-[1-(1-butanoylpyrrolidin-3-yl)piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C1N(C(=O)CCC)CCC1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 WQMADGKABXWRPB-UHFFFAOYSA-N 0.000 claims description 2
- KIKVFRJEORTHAK-SFHVURJKSA-N 3-[1-[(3s)-1-(cyclopentanecarbonyl)pyrrolidin-3-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C([C@H](CC1)N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)N1C(=O)C1CCCC1 KIKVFRJEORTHAK-SFHVURJKSA-N 0.000 claims description 2
- XEUDQGUHTWLHKW-IBGZPJMESA-N 3-[1-[(3s)-1-[4-(2-oxopyrrolidin-1-yl)butanoyl]pyrrolidin-3-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C([C@H](CC1)N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)N1C(=O)CCCN1CCCC1=O XEUDQGUHTWLHKW-IBGZPJMESA-N 0.000 claims description 2
- VTIHIQFWUKTACE-UHFFFAOYSA-N 3-[1-[1-(3-methylbutanoyl)pyrrolidin-3-yl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C1N(C(=O)CC(C)C)CCC1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 VTIHIQFWUKTACE-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 230000036506 anxiety Effects 0.000 claims description 2
- HPTPNUOHRVVTRL-UHFFFAOYSA-N benzyl 3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1CC(N2CCC(CC2)N2C(NC3=CC=CC=C32)=O)CN1C(=O)OCC1=CC=CC=C1 HPTPNUOHRVVTRL-UHFFFAOYSA-N 0.000 claims description 2
- HXYQHTSHRKZZEB-OAHLLOKOSA-N ethyl (3r)-3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@H]1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 HXYQHTSHRKZZEB-OAHLLOKOSA-N 0.000 claims description 2
- FKXJGWBHRQUXAR-OAHLLOKOSA-N ethyl (3r)-3-[4-(6-fluoro-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@H]1N1CCC(N2C(NC3=CC=C(F)C=C32)=O)CC1 FKXJGWBHRQUXAR-OAHLLOKOSA-N 0.000 claims description 2
- KLSANCSSLVHPCB-OAHLLOKOSA-N ethyl (3r)-3-[4-(6-methoxy-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@H]1N1CCC(N2C(NC3=CC=C(OC)C=C32)=O)CC1 KLSANCSSLVHPCB-OAHLLOKOSA-N 0.000 claims description 2
- XDSVIIYVPJSYLP-HNNXBMFYSA-N ethyl (3s)-3-[4-(6-chloro-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=C(Cl)C=C32)=O)CC1 XDSVIIYVPJSYLP-HNNXBMFYSA-N 0.000 claims description 2
- CTPAUVOWCXPALF-SFHVURJKSA-N ethyl (3s)-3-[4-(6-tert-butyl-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=C(C=C32)C(C)(C)C)=O)CC1 CTPAUVOWCXPALF-SFHVURJKSA-N 0.000 claims description 2
- PFTRZIHWZPEYRB-AWEZNQCLSA-N ethyl (3s)-3-[4-[2-oxo-6-(trifluoromethoxy)-3h-benzimidazol-1-yl]piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC=C(OC(F)(F)F)C=C32)=O)CC1 PFTRZIHWZPEYRB-AWEZNQCLSA-N 0.000 claims description 2
- ZGAHODJNAYVICT-UHFFFAOYSA-N ethyl 3-[4-(2-oxo-1h-indol-3-ylidene)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N(CC1)CCC1=C1C2=CC=CC=C2NC1=O ZGAHODJNAYVICT-UHFFFAOYSA-N 0.000 claims description 2
- HXYQHTSHRKZZEB-UHFFFAOYSA-N ethyl 3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 HXYQHTSHRKZZEB-UHFFFAOYSA-N 0.000 claims description 2
- NYOBTKVKUSUAAB-UHFFFAOYSA-N ethyl 3-[4-(5-fluoro-2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C(NC3=CC(F)=CC=C32)=O)CC1 NYOBTKVKUSUAAB-UHFFFAOYSA-N 0.000 claims description 2
- PCODWIPXFMYUEX-AWEZNQCLSA-N methyl (3s)-3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC)CC[C@@H]1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 PCODWIPXFMYUEX-AWEZNQCLSA-N 0.000 claims description 2
- YLZWMWDJXKINHH-INIZCTEOSA-N methyl (3s)-3-[4-(2-oxo-3h-indol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC)CC[C@@H]1N1CCC(N2C3=CC=CC=C3CC2=O)CC1 YLZWMWDJXKINHH-INIZCTEOSA-N 0.000 claims description 2
- PMPQXBUJYSYMJF-UHFFFAOYSA-N n,n-dimethyl-3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxamide Chemical compound C1N(C(=O)N(C)C)CCC1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 PMPQXBUJYSYMJF-UHFFFAOYSA-N 0.000 claims description 2
- NQSNZGROEBDODY-INIZCTEOSA-N propan-2-yl (3s)-3-[4-(2-oxo-3h-benzimidazol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)C)CC[C@@H]1N1CCC(N2C(NC3=CC=CC=C32)=O)CC1 NQSNZGROEBDODY-INIZCTEOSA-N 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 43
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 4
- 208000020401 Depressive disease Diseases 0.000 claims 1
- YFSKVZKNXCMCIT-HNNXBMFYSA-N ethyl (3s)-3-[4-[2-oxo-5-(trifluoromethyl)-3h-benzimidazol-1-yl]piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1N1CCC(N2C(NC3=CC(=CC=C32)C(F)(F)F)=O)CC1 YFSKVZKNXCMCIT-HNNXBMFYSA-N 0.000 claims 1
- IUSSAHCWZNNGON-UHFFFAOYSA-N ethyl 3-[4-(2-oxo-3h-indol-1-yl)piperidin-1-yl]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1N1CCC(N2C3=CC=CC=C3CC2=O)CC1 IUSSAHCWZNNGON-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 52
- 238000005481 NMR spectroscopy Methods 0.000 description 44
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 125000000623 heterocyclic group Chemical group 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
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Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
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- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Landscapes
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US81220806P | 2006-06-09 | 2006-06-09 | |
| US60/812,208 | 2006-06-09 | ||
| PCT/SE2007/000556 WO2007142585A1 (en) | 2006-06-09 | 2007-06-08 | Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia |
Publications (1)
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| CA2654147A1 true CA2654147A1 (en) | 2007-12-13 |
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| CA002654147A Abandoned CA2654147A1 (en) | 2006-06-09 | 2007-06-08 | Muscarinic receptor agonists that are effective in the treatment of pain, alzheimer's disease and schizophrenia |
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| EP (1) | EP2035412A4 (enExample) |
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| MX (1) | MX2008015155A (enExample) |
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| UY (1) | UY30393A1 (enExample) |
| WO (1) | WO2007142585A1 (enExample) |
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| TW200813018A (en) * | 2006-06-09 | 2008-03-16 | Astrazeneca Ab | Novel compounds |
| KR20120102172A (ko) | 2007-08-31 | 2012-09-17 | 시오노기세이야쿠가부시키가이샤 | 치환-퀴녹살린-형 피페리딘 화합물 및 그의 용도 |
| US20090221567A1 (en) * | 2008-02-28 | 2009-09-03 | Astrazeneca Ab | Muscarinic receptor agonists, compositions, methods of treatment thereof, and processes for preparation thereof 177 |
| US20090221642A1 (en) * | 2008-03-03 | 2009-09-03 | Astrazeneca Ab | Muscarinic receptor agonists, compositions, methods of treatment thereof, and processes for preparation thereof-176 |
| BRPI0911031B8 (pt) | 2008-07-21 | 2021-05-25 | Purdue Pharma Lp | compostos de piperidina ligada do tipo quinoxalina substituídos e os usos destes |
| GB0817982D0 (en) * | 2008-10-01 | 2008-11-05 | Glaxo Group Ltd | Compounds |
| TW201211028A (en) * | 2010-08-10 | 2012-03-16 | Dainippon Sumitomo Pharma Co | Fused ring pyrrolidine derivatives |
| AU2012253757B2 (en) | 2011-05-06 | 2017-04-13 | Zafgen Inc. | Partially saturated tricyclic compounds and methods of making and using same |
| JP2015083543A (ja) * | 2012-02-14 | 2015-04-30 | 大日本住友製薬株式会社 | 新規縮環ピロリジン誘導体 |
| US20140171466A1 (en) * | 2012-08-14 | 2014-06-19 | Regents Of The University Of Minnesota | Pain management in sickle cell anemia |
| BR112015006029B1 (pt) * | 2012-09-18 | 2022-01-25 | Heptares Therapeutics Limited | Compostos aza bicíclicos como agonistas de receptor m1 muscarínicos, composição farmacêutica compreendendo ditos compostos e uso dos mesmos para tratar um distúrbio cognitivo ou distúrbio psicótico ou para tratar ou reduzir a gravidade de dores agudas, crônicas, neuropáticas ou inflamatórias |
| BR112015010196A2 (pt) | 2012-11-05 | 2017-07-11 | Zafgen Inc | métodos de tratar doença do fígado |
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| US5524326A (en) * | 1993-01-21 | 1996-06-11 | Markowitz; Eli | Interactive game between pet and owner |
| EP0786997A4 (en) * | 1994-10-27 | 1998-03-11 | Merck & Co Inc | MUSCARINE ANTAGONISTS |
| US5756508A (en) * | 1995-10-31 | 1998-05-26 | Merck & Co., Inc. | Muscarine antagonists |
| AU2307999A (en) * | 1997-12-23 | 1999-07-12 | Alcon Laboratories, Inc. | Muscarinic agents and use thereof to treat glaucoma, myopia and various other conditions |
| DE60013464T2 (de) * | 1999-10-13 | 2005-09-15 | Banyu Pharmaceutical Co., Ltd. | Substituierte imidazolin-derivate |
| US7164024B2 (en) * | 2001-04-20 | 2007-01-16 | Banyu Pharmaceutical Co., Ltd. | Benzimidazolone derivatives |
| WO2004089942A2 (en) * | 2001-10-02 | 2004-10-21 | Acadia Pharmaceuticals Inc. | Benzimidazolidinone derivatives as muscarinic agents |
| JP2005532361A (ja) * | 2002-06-17 | 2005-10-27 | メルク エンド カムパニー インコーポレーテッド | 高眼圧症の治療用の眼科用組成物 |
| WO2004069828A1 (ja) * | 2003-02-04 | 2004-08-19 | Mitsubishi Pharma Corporation | ピペリジン化合物およびその医薬用途 |
| PT1753748E (pt) * | 2004-05-12 | 2009-08-28 | Pfizer Prod Inc | Derivados de prolina e a sua utilização como inibidores de dipeptidil peptidase iv |
| JP2008501031A (ja) * | 2004-05-28 | 2008-01-17 | バーテックス ファーマシューティカルズ インコーポレイテッド | ムスカリン受容体のモジュレーター |
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| US8119661B2 (en) * | 2007-09-11 | 2012-02-21 | Astrazeneca Ab | Piperidine derivatives and their use as muscarinic receptor modulators |
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- 2007-06-08 AU AU2007256014A patent/AU2007256014B2/en not_active Expired - Fee Related
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2008
- 2008-11-20 IL IL195427A patent/IL195427A0/en unknown
- 2008-11-24 ZA ZA2008/09976A patent/ZA200809976B/en unknown
- 2008-12-12 EC EC2008008967A patent/ECSP088967A/es unknown
- 2008-12-16 NO NO20085271A patent/NO20085271L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| TW200815405A (en) | 2008-04-01 |
| MX2008015155A (es) | 2008-12-12 |
| AR061306A1 (es) | 2008-08-20 |
| UY30393A1 (es) | 2009-04-30 |
| AU2007256014B2 (en) | 2011-06-30 |
| RU2008147543A (ru) | 2010-07-20 |
| US20100173935A1 (en) | 2010-07-08 |
| JP2009539833A (ja) | 2009-11-19 |
| ZA200809976B (en) | 2011-04-28 |
| EP2035412A4 (en) | 2011-02-16 |
| IL195427A0 (en) | 2009-08-03 |
| EP2035412A1 (en) | 2009-03-18 |
| CN101501024A (zh) | 2009-08-05 |
| BRPI0712415A2 (pt) | 2012-09-04 |
| WO2007142585A1 (en) | 2007-12-13 |
| KR20090016636A (ko) | 2009-02-16 |
| ECSP088967A (es) | 2009-01-30 |
| AU2007256014A1 (en) | 2007-12-13 |
| NO20085271L (no) | 2009-01-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20130610 |
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| FZDE | Discontinued |
Effective date: 20130610 |