RU2423362C2 - Соединения 8-азабицикло[3.2.1]октана и их применение в качестве антагонистов рецепторов мю-опиоидов - Google Patents
Соединения 8-азабицикло[3.2.1]октана и их применение в качестве антагонистов рецепторов мю-опиоидов Download PDFInfo
- Publication number
- RU2423362C2 RU2423362C2 RU2008138875/04A RU2008138875A RU2423362C2 RU 2423362 C2 RU2423362 C2 RU 2423362C2 RU 2008138875/04 A RU2008138875/04 A RU 2008138875/04A RU 2008138875 A RU2008138875 A RU 2008138875A RU 2423362 C2 RU2423362 C2 RU 2423362C2
- Authority
- RU
- Russia
- Prior art keywords
- azabicyclo
- endo
- oct
- ethyl
- benzamide
- Prior art date
Links
- 102000051367 mu Opioid Receptors Human genes 0.000 title claims abstract description 38
- 108020001612 μ-opioid receptors Proteins 0.000 title claims abstract description 38
- 229940123257 Opioid receptor antagonist Drugs 0.000 title description 8
- DGGKXQQCVPAUEA-UHFFFAOYSA-N 8-azabicyclo[3.2.1]octane Chemical class C1CCC2CCC1N2 DGGKXQQCVPAUEA-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 315
- 238000000034 method Methods 0.000 claims abstract description 135
- 150000003839 salts Chemical class 0.000 claims abstract description 87
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 41
- 125000005843 halogen group Chemical group 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 34
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 28
- 230000000694 effects Effects 0.000 claims abstract description 28
- 201000010099 disease Diseases 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 241000124008 Mammalia Species 0.000 claims abstract description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000005605 benzo group Chemical group 0.000 claims abstract description 8
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- -1 4,4-difluorocyclohexyl Chemical group 0.000 claims description 289
- 238000002360 preparation method Methods 0.000 claims description 109
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 100
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 29
- 125000006239 protecting group Chemical group 0.000 claims description 29
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 15
- HDXNRKIRVTVLBE-GVWQBGCGSA-N N-[8-[2-[cyclohexylmethyl-[(2S)-2,3-dihydroxypropanoyl]amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound OC[C@H](O)C(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CC1CCCCC1 HDXNRKIRVTVLBE-GVWQBGCGSA-N 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 10
- 125000005466 alkylenyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 208000003243 intestinal obstruction Diseases 0.000 claims description 9
- 230000002980 postoperative effect Effects 0.000 claims description 9
- 208000030053 Opioid-Induced Constipation Diseases 0.000 claims description 7
- 150000007942 carboxylates Chemical class 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- NZJWHJVQOVJCJO-UHFFFAOYSA-N N-[8-[2-[(4,4-difluorocyclohexyl)methyl-(2-hydroxyacetyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CC1CCC(F)(F)CC1 NZJWHJVQOVJCJO-UHFFFAOYSA-N 0.000 claims description 5
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims description 3
- YAPIQOLYHCCXRT-UHFFFAOYSA-N N-[8-[2-[(2,6-difluorophenyl)methyl-(2-hydroxyacetyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1c(F)cccc1F YAPIQOLYHCCXRT-UHFFFAOYSA-N 0.000 claims description 3
- 230000003042 antagnostic effect Effects 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 230000003993 interaction Effects 0.000 claims description 3
- ZTVPWFIKODZEQY-DGGBHQDZSA-N C1CCC(CC1)CN(CCN2C3CCC2CC(C3)NC(=O)C4=CC=CC=C4)C(=O)[C@H](CCO)O Chemical compound C1CCC(CC1)CN(CCN2C3CCC2CC(C3)NC(=O)C4=CC=CC=C4)C(=O)[C@H](CCO)O ZTVPWFIKODZEQY-DGGBHQDZSA-N 0.000 claims description 2
- IQSXEQHSMMMFQX-DGGBHQDZSA-N CN[C@@H](CO)C(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4CCCCC4 Chemical compound CN[C@@H](CO)C(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4CCCCC4 IQSXEQHSMMMFQX-DGGBHQDZSA-N 0.000 claims description 2
- LSYFHWUZDYGKCZ-UHFFFAOYSA-N CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4=CC(=CC=C4)F Chemical compound CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4=CC(=CC=C4)F LSYFHWUZDYGKCZ-UHFFFAOYSA-N 0.000 claims description 2
- NDFUZVRJWZPHKN-UHFFFAOYSA-N CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4=CC=CC=C4 Chemical compound CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4=CC=CC=C4 NDFUZVRJWZPHKN-UHFFFAOYSA-N 0.000 claims description 2
- JVEHMUCXOPAZHB-UHFFFAOYSA-N CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4CCCC4 Chemical compound CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)C3=CC=CC=C3)CC4CCCC4 JVEHMUCXOPAZHB-UHFFFAOYSA-N 0.000 claims description 2
- XVGJQDYOONPLPQ-UHFFFAOYSA-N CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1c(F)cccc1F Chemical compound CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1c(F)cccc1F XVGJQDYOONPLPQ-UHFFFAOYSA-N 0.000 claims description 2
- NNTUZKPKNQGNMP-UHFFFAOYSA-N N-[8-[2-[(2,6-difluorophenyl)methyl-(2-hydroxy-2-methylpropanoyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound CC(C)(O)C(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1c(F)cccc1F NNTUZKPKNQGNMP-UHFFFAOYSA-N 0.000 claims description 2
- MKRGAECVVOTHEN-UHFFFAOYSA-N N-[8-[2-[(2,6-difluorophenyl)methyl-(2-methoxyacetyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound COCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1c(F)cccc1F MKRGAECVVOTHEN-UHFFFAOYSA-N 0.000 claims description 2
- SQASGGKYHBIKOQ-IIDKWZDJSA-N N-[8-[2-[(2,6-difluorophenyl)methyl-[(2S)-2-hydroxypropanoyl]amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)NC1CC2CCC(C1)N2CCN(C([C@H](C)O)=O)CC1=C(C=CC=C1F)F SQASGGKYHBIKOQ-IIDKWZDJSA-N 0.000 claims description 2
- HPGNJJWESNRNSN-UHFFFAOYSA-N N-[8-[2-[(2-cyanoacetyl)-[(2,6-difluorophenyl)methyl]amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound Fc1cccc(F)c1CN(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)C(=O)CC#N HPGNJJWESNRNSN-UHFFFAOYSA-N 0.000 claims description 2
- YKUFTYGOCOWDBT-UHFFFAOYSA-N N-[8-[2-[(2-methylsulfonylacetyl)-[[4-(trifluoromethyl)phenyl]methyl]amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1ccc(cc1)C(F)(F)F YKUFTYGOCOWDBT-UHFFFAOYSA-N 0.000 claims description 2
- XYMOFXBLUTWAHJ-UHFFFAOYSA-N N-[8-[2-[(4,4-difluorocyclohexyl)methyl-(2-methylsulfonylacetyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CC1CCC(F)(F)CC1 XYMOFXBLUTWAHJ-UHFFFAOYSA-N 0.000 claims description 2
- XDDRUGHQRPHUJW-IHIONMKXSA-N N-[8-[2-[(4,4-difluorocyclohexyl)methyl-[(2S)-2-hydroxypropanoyl]amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)NC1CC2CCC(C1)N2CCN(C([C@H](C)O)=O)CC1CCC(CC1)(F)F XDDRUGHQRPHUJW-IHIONMKXSA-N 0.000 claims description 2
- MILBMMHPLVWTPZ-UHFFFAOYSA-N N-[8-[2-[2-(4-fluorophenyl)ethyl-(2-methylsulfonylacetyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound CS(=O)(=O)CC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CCc1ccc(F)cc1 MILBMMHPLVWTPZ-UHFFFAOYSA-N 0.000 claims description 2
- VCKXPHMVGJYYKB-UHFFFAOYSA-N N-[8-[2-[benzyl(2,2-dimethylpropanoyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound CC(C)(C)C(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1ccccc1 VCKXPHMVGJYYKB-UHFFFAOYSA-N 0.000 claims description 2
- PJTAYNXYRUIXLT-UHFFFAOYSA-N N-[8-[2-[benzyl-(2-hydroxy-2-methylpropanoyl)amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound CC(C)(O)C(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)Cc1ccccc1 PJTAYNXYRUIXLT-UHFFFAOYSA-N 0.000 claims description 2
- MPNLHIWOZACTHC-GCYRPYEUSA-N N-[8-[2-[benzyl-[(2S)-2-hydroxypropanoyl]amino]ethyl]-8-azabicyclo[3.2.1]octan-3-yl]benzamide Chemical compound C(C1=CC=CC=C1)(=O)NC1CC2CCC(C1)N2CCN(C([C@H](C)O)=O)CC1=CC=CC=C1 MPNLHIWOZACTHC-GCYRPYEUSA-N 0.000 claims description 2
- MAAPQPBUFWMQHO-UHFFFAOYSA-N OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CC1CCC(F)CC1 Chemical compound OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CC1CCC(F)CC1 MAAPQPBUFWMQHO-UHFFFAOYSA-N 0.000 claims description 2
- DVPPUYBRLDUIGP-UHFFFAOYSA-N OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CCc1ccc(F)cc1 Chemical compound OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CCc1ccc(F)cc1 DVPPUYBRLDUIGP-UHFFFAOYSA-N 0.000 claims description 2
- DHHRMPRXFISGRH-JQYBMQJWSA-N O[C@H](CC1)CC[C@@H]1C(N(CCN(C(CC1)C2)C1CC2NC(C1=CC=CC=C1)=O)CC(C(F)=CC=C1)=C1F)=O Chemical compound O[C@H](CC1)CC[C@@H]1C(N(CCN(C(CC1)C2)C1CC2NC(C1=CC=CC=C1)=O)CC(C(F)=CC=C1)=C1F)=O DHHRMPRXFISGRH-JQYBMQJWSA-N 0.000 claims description 2
- NVJZBJONODRFLJ-BGDLSBHESA-N C(C1=CC=CC=C1)(=O)NC1CC2CCC(C1)N2CCN(C([C@H]([C@@H](C)O)O)=O)CC2=CC=CC=C2 Chemical compound C(C1=CC=CC=C1)(=O)NC1CC2CCC(C1)N2CCN(C([C@H]([C@@H](C)O)O)=O)CC2=CC=CC=C2 NVJZBJONODRFLJ-BGDLSBHESA-N 0.000 claims 1
- ZJBRDYHXVDEXLO-UHFFFAOYSA-N OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CC1C2CC3CC1CC(O)(C3)C2 Chemical compound OCC(=O)N(CCN1C2CCC1CC(C2)NC(=O)c1ccccc1)CC1C2CC3CC1CC(O)(C3)C2 ZJBRDYHXVDEXLO-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 14
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002623 mu opiate receptor antagonist Substances 0.000 abstract description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 5
- 229910003827 NRaRb Inorganic materials 0.000 abstract 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 2
- 230000001747 exhibiting effect Effects 0.000 abstract 1
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- 238000005481 NMR spectroscopy Methods 0.000 description 72
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 22
- 239000003153 chemical reaction reagent Substances 0.000 description 21
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- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 20
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 20
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 18
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 17
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Classifications
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- C07D451/02—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
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- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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| TWI409067B (zh) * | 2007-02-28 | 2013-09-21 | Theravance Inc | ８-氮雜雙環〔３．２．１〕辛烷化合物之結晶型 |
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| US8759527B2 (en) | 2010-08-25 | 2014-06-24 | Bayer Cropscience Ag | Heteroarylpiperidine and -piperazine derivatives as fungicides |
| EP2423210A1 (de) | 2010-08-25 | 2012-02-29 | Bayer CropScience AG | Heteroarylpiperidin- und -piperazinderivate als Fungizide |
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| JP5703009B2 (ja) * | 2010-12-16 | 2015-04-15 | 住友精化株式会社 | スルホン化合物、スルホン化合物の製造方法、および電気化学デバイス用電解液 |
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| WO2004089908A2 (en) * | 2003-04-14 | 2004-10-21 | Pfizer Products Inc. | 3-azabicyclo[3.2.1]octane derivatives |
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