WO2023284833A1 - Dérivé de pipéridine spirocyclique, composition pharmaceutique de celui-ci, procédé de préparation s'y rapportant et utilisation associée - Google Patents
Dérivé de pipéridine spirocyclique, composition pharmaceutique de celui-ci, procédé de préparation s'y rapportant et utilisation associée Download PDFInfo
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- WO2023284833A1 WO2023284833A1 PCT/CN2022/105774 CN2022105774W WO2023284833A1 WO 2023284833 A1 WO2023284833 A1 WO 2023284833A1 CN 2022105774 W CN2022105774 W CN 2022105774W WO 2023284833 A1 WO2023284833 A1 WO 2023284833A1
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- Prior art keywords
- substituted
- alkyl
- compound
- pain
- unsubstituted
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 150000003053 piperidines Chemical class 0.000 title abstract 2
- 208000002193 Pain Diseases 0.000 claims abstract description 35
- 102000005962 receptors Human genes 0.000 claims abstract description 25
- 108020003175 receptors Proteins 0.000 claims abstract description 25
- 230000036407 pain Effects 0.000 claims abstract description 20
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 16
- 208000007848 Alcoholism Diseases 0.000 claims abstract description 8
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 8
- 230000036506 anxiety Effects 0.000 claims abstract description 8
- 201000009032 substance abuse Diseases 0.000 claims abstract description 8
- 231100000736 substance abuse Toxicity 0.000 claims abstract description 8
- 201000006152 substance dependence Diseases 0.000 claims abstract description 8
- 102100025912 Melanopsin Human genes 0.000 claims abstract 4
- 150000001875 compounds Chemical class 0.000 claims description 133
- -1 3,4-difluorophenyl Chemical group 0.000 claims description 94
- 125000001072 heteroaryl group Chemical group 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 239000000651 prodrug Chemical class 0.000 claims description 40
- 229940002612 prodrug Drugs 0.000 claims description 40
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 38
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 36
- 239000012453 solvate Substances 0.000 claims description 36
- 239000002207 metabolite Chemical class 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 24
- 239000000460 chlorine Substances 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 20
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000003107 substituted aryl group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 241000534944 Thia Species 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 206010065390 Inflammatory pain Diseases 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 9
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 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 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 208000004998 Abdominal Pain Diseases 0.000 claims description 7
- 208000006820 Arthralgia Diseases 0.000 claims description 7
- 206010006002 Bone pain Diseases 0.000 claims description 7
- 208000000094 Chronic Pain Diseases 0.000 claims description 7
- 208000011231 Crohn disease Diseases 0.000 claims description 7
- 206010019233 Headaches Diseases 0.000 claims description 7
- 208000000112 Myalgia Diseases 0.000 claims description 7
- 208000004550 Postoperative Pain Diseases 0.000 claims description 7
- 208000005298 acute pain Diseases 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 231100000869 headache Toxicity 0.000 claims description 7
- 208000013465 muscle pain Diseases 0.000 claims description 7
- 208000004296 neuralgia Diseases 0.000 claims description 7
- 208000021722 neuropathic pain Diseases 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- 239000000556 agonist Substances 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 4
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 3
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 208000004371 toothache Diseases 0.000 claims description 3
- 230000009977 dual effect Effects 0.000 claims description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims 1
- 150000001924 cycloalkanes Chemical class 0.000 claims 1
- 239000003446 ligand Substances 0.000 abstract description 3
- 239000012071 phase Substances 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
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- 102100028647 Mu-type opioid receptor Human genes 0.000 description 14
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
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- JUXAVSAMVBLDKO-UHFFFAOYSA-N 1-(1-azabicyclo[2.2.2]octan-3-yl)-3-[3-(1h-indol-3-yl)-1-oxo-1-spiro[1,2-dihydroindene-3,4'-piperidine]-1'-ylpropan-2-yl]urea Chemical group C1N(CC2)CCC2C1NC(=O)NC(C(=O)N1CCC2(C3=CC=CC=C3CC2)CC1)CC1=CNC2=CC=CC=C12 JUXAVSAMVBLDKO-UHFFFAOYSA-N 0.000 description 9
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
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- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 5
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- 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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D471/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne un dérivé de pipéridine spirocyclique, une composition pharmaceutique de celui-ci, un procédé de préparation s'y rapportant et une utilisation associée, le dérivé étant tel que représenté dans la formule (A). Le dérivé peut être utilisé en tant que récepteur MOP, récepteur NOP, ou ligand sélectif bifonctionnel du récepteur MOP et récepteur KOP, et le dérivé et la composition pharmaceutique peuvent être utilisés pour le traitement de la douleur, de l'anxiété, de la dépression, de la dépendance à l'alcool ou de l'abus de substances ou de la dépendance à celles-ci.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202280049749.8A CN117642402A (zh) | 2021-07-14 | 2022-07-14 | 一种螺哌啶环衍生物及其药物组合物、制备方法和用途 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110797648 | 2021-07-14 | ||
| CN202110797648.6 | 2021-07-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023284833A1 true WO2023284833A1 (fr) | 2023-01-19 |
Family
ID=84919065
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2022/105774 WO2023284833A1 (fr) | 2021-07-14 | 2022-07-14 | Dérivé de pipéridine spirocyclique, composition pharmaceutique de celui-ci, procédé de préparation s'y rapportant et utilisation associée |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN117642402A (fr) |
| WO (1) | WO2023284833A1 (fr) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050153998A1 (en) * | 2003-08-19 | 2005-07-14 | Fumitaka Ito | Tetrahydroisoquinoline or isochroman compounds |
| WO2005092858A2 (fr) * | 2004-03-29 | 2005-10-06 | Pfizer Japan Inc. | Composes alpha-aryle ou heteroaryle methyle beta piperidino propanamide en tant qu'antagoniste du recepteur orl1 |
| WO2007057775A1 (fr) * | 2005-11-21 | 2007-05-24 | Pfizer Limited | Dérivés de spiropipéridine |
| CN101227903A (zh) * | 2005-06-02 | 2008-07-23 | 詹森药业有限公司 | 用作orl-1受体调节剂的新型3-螺环吲哚基衍生物 |
| CN101678011A (zh) * | 2007-05-16 | 2010-03-24 | 默克公司 | 螺氮茚酮化合物 |
| US20180155314A1 (en) * | 2015-12-02 | 2018-06-07 | Astraea Therapeutics, Llc | Piperdinyl nociceptin receptor compounds |
| CN108884096A (zh) * | 2016-02-08 | 2018-11-23 | 豪夫迈·罗氏有限公司 | 作为ddr1抑制剂的螺二氢吲哚酮 |
| CN108883103A (zh) * | 2015-12-02 | 2018-11-23 | 阿斯特来亚治疗有限责任公司 | 哌啶基痛敏肽受体化合物 |
-
2022
- 2022-07-14 WO PCT/CN2022/105774 patent/WO2023284833A1/fr unknown
- 2022-07-14 CN CN202280049749.8A patent/CN117642402A/zh active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050153998A1 (en) * | 2003-08-19 | 2005-07-14 | Fumitaka Ito | Tetrahydroisoquinoline or isochroman compounds |
| WO2005092858A2 (fr) * | 2004-03-29 | 2005-10-06 | Pfizer Japan Inc. | Composes alpha-aryle ou heteroaryle methyle beta piperidino propanamide en tant qu'antagoniste du recepteur orl1 |
| CN101227903A (zh) * | 2005-06-02 | 2008-07-23 | 詹森药业有限公司 | 用作orl-1受体调节剂的新型3-螺环吲哚基衍生物 |
| WO2007057775A1 (fr) * | 2005-11-21 | 2007-05-24 | Pfizer Limited | Dérivés de spiropipéridine |
| CN101678011A (zh) * | 2007-05-16 | 2010-03-24 | 默克公司 | 螺氮茚酮化合物 |
| US20180155314A1 (en) * | 2015-12-02 | 2018-06-07 | Astraea Therapeutics, Llc | Piperdinyl nociceptin receptor compounds |
| CN108883103A (zh) * | 2015-12-02 | 2018-11-23 | 阿斯特来亚治疗有限责任公司 | 哌啶基痛敏肽受体化合物 |
| CN108884096A (zh) * | 2016-02-08 | 2018-11-23 | 豪夫迈·罗氏有限公司 | 作为ddr1抑制剂的螺二氢吲哚酮 |
Non-Patent Citations (2)
| Title |
|---|
| BIGNAN, G.C. BATTISTA, K. CONNOLLY, P.J. ORSINI, M.J. LIU, J. MIDDLETON, S.A. REITZ, A.B.: "Preparation of 3-spirocyclic indolin-2-ones as ligands for the ORL-1 receptor", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 15, no. 22, 15 November 2005 (2005-11-15), Amsterdam NL , pages 5022 - 5026, XP005098219, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2005.08.009 * |
| DING HUIPING, KIGUCHI NORIKAZU, YASUDA DENNIS, DAGA PANKAJ R., POLGAR WILLMA E., LU JAMES J., CZOTY PAUL W., KISHIOKA SHIROH, ZAVE: "A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates", SCIENCE TRANSLATIONAL MEDICINE, vol. 10, no. 456, 29 August 2018 (2018-08-29), XP093024176, ISSN: 1946-6234, DOI: 10.1126/scitranslmed.aar3483 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117642402A (zh) | 2024-03-01 |
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