CA2793725C - Carboxamide bioisosteres of opiates - Google Patents
Carboxamide bioisosteres of opiates Download PDFInfo
- Publication number
- CA2793725C CA2793725C CA2793725A CA2793725A CA2793725C CA 2793725 C CA2793725 C CA 2793725C CA 2793725 A CA2793725 A CA 2793725A CA 2793725 A CA2793725 A CA 2793725A CA 2793725 C CA2793725 C CA 2793725C
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- CA
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- Prior art keywords
- unsubstituted
- alkyl
- substituted
- hydrogen
- compound according
- 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.)
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- 229940127240 opiate Drugs 0.000 title description 6
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
- -1 ̈OH Chemical group 0.000 claims description 33
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 150000002431 hydrogen Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 108090000137 Opioid Receptors Proteins 0.000 claims description 19
- 102000003840 Opioid Receptors Human genes 0.000 claims description 19
- 230000027455 binding Effects 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 125000003107 substituted aryl group Chemical group 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 11
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 10
- 206010013663 drug dependence Diseases 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 5
- 229960003920 cocaine Drugs 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 239000012634 fragment Substances 0.000 claims description 5
- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims description 4
- 206010057852 Nicotine dependence Diseases 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- 208000025569 Tobacco Use disease Diseases 0.000 claims description 4
- 229960002069 diamorphine Drugs 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 201000008482 osteoarthritis Diseases 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 230000036407 pain Effects 0.000 claims description 4
- 208000011117 substance-related disease Diseases 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 3
- 208000007848 Alcoholism Diseases 0.000 claims description 3
- 208000022497 Cocaine-Related disease Diseases 0.000 claims description 3
- 208000003698 Heroin Dependence Diseases 0.000 claims description 3
- 208000004454 Hyperalgesia Diseases 0.000 claims description 3
- 208000035154 Hyperesthesia Diseases 0.000 claims description 3
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 3
- 201000006145 cocaine dependence Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims description 2
- 208000029197 Amphetamine-Related disease Diseases 0.000 claims description 2
- 208000017228 Gastrointestinal motility disease Diseases 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 208000004756 Respiratory Insufficiency Diseases 0.000 claims description 2
- 206010038678 Respiratory depression Diseases 0.000 claims description 2
- 229940025084 amphetamine Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
- 229960002715 nicotine Drugs 0.000 claims description 2
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims 2
- 206010010904 Convulsion Diseases 0.000 claims 1
- 206010011224 Cough Diseases 0.000 claims 1
- 206010012735 Diarrhoea Diseases 0.000 claims 1
- 208000008589 Obesity Diseases 0.000 claims 1
- 208000003251 Pruritus Diseases 0.000 claims 1
- 230000036461 convulsion Effects 0.000 claims 1
- 235000020824 obesity Nutrition 0.000 claims 1
- 230000000954 anitussive effect Effects 0.000 abstract description 5
- 239000003434 antitussive agent Substances 0.000 abstract description 5
- 229940124584 antitussives Drugs 0.000 abstract description 5
- 229940035676 analgesics Drugs 0.000 abstract description 4
- 239000000730 antalgic agent Substances 0.000 abstract description 4
- 229940125681 anticonvulsant agent Drugs 0.000 abstract description 4
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 238000002483 medication Methods 0.000 abstract description 3
- 206010012335 Dependence Diseases 0.000 abstract description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 229940125714 antidiarrheal agent Drugs 0.000 abstract description 2
- 239000003793 antidiarrheal agent Substances 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 description 40
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 16
- 125000003545 alkoxy group Chemical group 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 8
- 229960005181 morphine Drugs 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000003446 ligand Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 150000003839 salts Chemical group 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- WIYUZYBFCWCCQJ-IFKAHUTRSA-N Naltrindole Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C3=CC=CC=C3NC=25)O)CC1)O)CC1CC1 WIYUZYBFCWCCQJ-IFKAHUTRSA-N 0.000 description 5
- 150000003857 carboxamides Chemical class 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- YQYVFVRQLZMJKJ-JBBXEZCESA-N (+)-cyclazocine Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@@H]2[C@@H]1C)CN2CC1CC1 YQYVFVRQLZMJKJ-JBBXEZCESA-N 0.000 description 4
- HPZJMUBDEAMBFI-WTNAPCKOSA-N (D-Ala(2)-mephe(4)-gly-ol(5))enkephalin Chemical compound C([C@H](N)C(=O)N[C@H](C)C(=O)NCC(=O)N(C)[C@@H](CC=1C=CC=CC=1)C(=O)NCCO)C1=CC=C(O)C=C1 HPZJMUBDEAMBFI-WTNAPCKOSA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
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- 125000004122 cyclic group Chemical group 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
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- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- APSUXPSYBJVPPS-YAUKWVCOSA-N Norbinaltorphimine Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CC=2C=3C[C@]4(O)[C@]67CCN(CC8CC8)[C@@H]4CC=4C7=C(C(=CC=4)O)O[C@H]6C=3NC=25)O)CC1)O)CC1CC1 APSUXPSYBJVPPS-YAUKWVCOSA-N 0.000 description 3
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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 description 3
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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| SI3446565T1 (sl) | 2010-08-23 | 2024-03-29 | Alkermes Pharma Ireland Limited | Metode zdravljenja povečanja teže, povzročene z antipsihotiki |
| RS56181B1 (sr) * | 2011-06-29 | 2017-11-30 | Alkermes Inc | Periferno delujuća opioidna jedinjenja |
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| JP2016519161A (ja) * | 2013-05-24 | 2016-06-30 | アルカームス ファーマ アイルランド リミテッド | モルファン及びモルフィナン類似物及び使用の方法 |
| CN103992272B (zh) * | 2014-06-09 | 2016-05-11 | 安徽省逸欣铭医药科技有限公司 | 一种盐酸喷他佐辛酯、其制备方法及其用途 |
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| CN104248763A (zh) | 2005-03-07 | 2014-12-31 | 芝加哥大学 | 阿片样物质拮抗剂用于减少内皮细胞增殖和迁移的用途 |
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| EP2190819B1 (en) * | 2007-08-09 | 2016-05-25 | Rensselaer Polytechnic Institute | Quaternary opioid carboxamides |
| WO2010000020A1 (en) | 2008-06-30 | 2010-01-07 | Cathrx Ltd | A catheter |
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