CN114391011A - 一种六氢化苯并吡唑衍生物及其制备 - Google Patents
一种六氢化苯并吡唑衍生物及其制备 Download PDFInfo
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- CN114391011A CN114391011A CN202080061781.9A CN202080061781A CN114391011A CN 114391011 A CN114391011 A CN 114391011A CN 202080061781 A CN202080061781 A CN 202080061781A CN 114391011 A CN114391011 A CN 114391011A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- FINXVBSODIQGSH-UHFFFAOYSA-N 2,3,3a,4,5,6-hexahydro-1h-indazole Chemical class C1CCC2CNNC2=C1 FINXVBSODIQGSH-UHFFFAOYSA-N 0.000 title claims description 5
- -1 hexahydrobenzene pyrazole compounds Chemical class 0.000 claims abstract description 189
- 239000000651 prodrug Substances 0.000 claims abstract description 45
- 229940002612 prodrug Drugs 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 239000012453 solvate Substances 0.000 claims abstract description 41
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 claims abstract description 9
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 claims abstract description 9
- 150000004677 hydrates Chemical class 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 229910052731 fluorine Inorganic materials 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 42
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 229910052801 chlorine Inorganic materials 0.000 claims description 33
- 125000001072 heteroaryl group Chemical group 0.000 claims description 29
- 208000002193 Pain Diseases 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 26
- 230000036407 pain Effects 0.000 claims description 25
- 125000004076 pyridyl group Chemical group 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 18
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 18
- 125000003003 spiro group Chemical group 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
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- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 208000004998 Abdominal Pain Diseases 0.000 claims description 10
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- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 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 10
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
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- 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 9
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 9
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 9
- 125000002757 morpholinyl group Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 230000001404 mediated effect Effects 0.000 claims description 8
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- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
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- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
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- 230000003647 oxidation Effects 0.000 claims description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 46
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
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- 239000000243 solution Substances 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
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- MGNMZBODBIBFHI-GFCCVEGCSA-N FC1(CCCC=2C(=NN(C1=2)C=1C=[N+](C=CN=1)[O-])C(N[C@H](CO)C(C)(C)C)=O)F Chemical compound FC1(CCCC=2C(=NN(C1=2)C=1C=[N+](C=CN=1)[O-])C(N[C@H](CO)C(C)(C)C)=O)F MGNMZBODBIBFHI-GFCCVEGCSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
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- 241000394635 Acetomicrobium mobile Species 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 13
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- ACSQLTBPYZSGBA-GMXVVIOVSA-N olorinab Chemical compound C([C@@H]1C[C@@H]1C=12)C=1C(C(=O)N[C@H](CO)C(C)(C)C)=NN2C1=C[N+]([O-])=CC=N1 ACSQLTBPYZSGBA-GMXVVIOVSA-N 0.000 description 9
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- WGNGKLNMDDONTN-UHFFFAOYSA-N 1-pyrazin-2-ylspiro[5,6-dihydro-4H-indazole-7,1'-cyclopropane]-3-carboxylic acid Chemical compound N1=C(C=NC=C1)N1N=C(C=2CCCC3(C1=2)CC3)C(=O)O WGNGKLNMDDONTN-UHFFFAOYSA-N 0.000 description 5
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- 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
Landscapes
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- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开一种式(I)所示的六氢化苯并吡唑类化合物及其立体异构体、药学上可接受的盐、溶剂化物、水合物、N‑氧化物、前药及其药物组合物、制备方法，以及在由大麻素CB2受体介导的疾病的预防和治疗中的用途。
Description
PCT国内申请，说明书已公开。
Claims (17)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2019108669191 | 2019-09-12 | ||
| CN201910866919 | 2019-09-12 | ||
| CN2019109720918 | 2019-10-14 | ||
| CN201910972091 | 2019-10-14 | ||
| CN2019112470956 | 2019-12-11 | ||
| CN201911247095 | 2019-12-11 | ||
| CN2020100095223 | 2020-01-07 | ||
| CN202010009522 | 2020-01-07 | ||
| CN2020102276702 | 2020-03-27 | ||
| CN202010227670 | 2020-03-27 | ||
| PCT/CN2020/114448 WO2021047581A1 (zh) | 2019-09-12 | 2020-09-10 | 一种六氢化苯并吡唑衍生物及其制备 |
Publications (1)
| Publication Number | Publication Date |
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| CN114391011A true CN114391011A (zh) | 2022-04-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202080061781.9A Pending CN114391011A (zh) | 2019-09-12 | 2020-09-10 | 一种六氢化苯并吡唑衍生物及其制备 |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN114391011A (zh) |
| TW (1) | TWI768465B (zh) |
| WO (1) | WO2021047581A1 (zh) |
Citations (5)
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| EP0307801A1 (en) * | 1987-09-11 | 1989-03-22 | Mitsubishi Kasei Corporation | Pyrazole derivative and insecticidal and miticidal composition containing the derivative as active ingredient |
| WO2006030124A1 (fr) * | 2004-09-13 | 2006-03-23 | Sanofi-Aventis | Derives de pyrazole condense, leur preparation et leur application en therapeutique. |
| CN1956964A (zh) * | 2004-03-24 | 2007-05-02 | 詹森药业有限公司 | 四氢－吲唑大麻素调节剂 |
| JP2011195543A (ja) * | 2010-03-23 | 2011-10-06 | Agro Kanesho Co Ltd | Ｎ−置換アルキルピラゾール−３−カルボキサミド誘導体およびこれを有効成分とする殺ダニ剤 |
| JP2012056871A (ja) * | 2010-09-08 | 2012-03-22 | Agro Kanesho Co Ltd | Ｎ−フェニルチオアルキルピラゾール−３−カルボキサミド誘導体および該誘導体を有効成分とする殺ダニ剤 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2908031A1 (fr) * | 2006-11-03 | 2008-05-09 | Elbeuviennes De Materiels Pour | Machine a laver la vaisselle a rampes de lavage a basse pression |
| AU2007315848A1 (en) * | 2006-11-03 | 2008-05-08 | Glenmark Pharmaceuticals S.A. | Bridged bicyclic indazoles as cannabinoid receptor ligands |
| CA2770866C (en) * | 2009-08-28 | 2017-10-10 | Arena Pharmaceuticals, Inc. | Cannabinoid receptor modulators |
| AU2012222149B2 (en) * | 2011-02-25 | 2017-06-29 | Arena Pharmaceuticals, Inc. | Cannabinoid receptor modulators |
| WO2012116277A1 (en) * | 2011-02-25 | 2012-08-30 | Arena Pharmaceuticals, Inc. | Cannabinoid receptor modulators |
| EA035989B1 (ru) * | 2011-02-25 | 2020-09-09 | Арена Фармасьютикалз, Инк. | Кристаллические формы и способы получения модуляторов каннабиноидного рецептора |
-
2020
- 2020-09-10 WO PCT/CN2020/114448 patent/WO2021047581A1/zh active Application Filing
- 2020-09-10 CN CN202080061781.9A patent/CN114391011A/zh active Pending
- 2020-09-10 TW TW109131082A patent/TWI768465B/zh active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0307801A1 (en) * | 1987-09-11 | 1989-03-22 | Mitsubishi Kasei Corporation | Pyrazole derivative and insecticidal and miticidal composition containing the derivative as active ingredient |
| CN1956964A (zh) * | 2004-03-24 | 2007-05-02 | 詹森药业有限公司 | 四氢－吲唑大麻素调节剂 |
| WO2006030124A1 (fr) * | 2004-09-13 | 2006-03-23 | Sanofi-Aventis | Derives de pyrazole condense, leur preparation et leur application en therapeutique. |
| JP2011195543A (ja) * | 2010-03-23 | 2011-10-06 | Agro Kanesho Co Ltd | Ｎ−置換アルキルピラゾール−３−カルボキサミド誘導体およびこれを有効成分とする殺ダニ剤 |
| JP2012056871A (ja) * | 2010-09-08 | 2012-03-22 | Agro Kanesho Co Ltd | Ｎ−フェニルチオアルキルピラゾール−３−カルボキサミド誘導体および該誘導体を有効成分とする殺ダニ剤 |
Non-Patent Citations (1)
| Title |
|---|
| JAY M. MATTHEWS 等: "Tetrahydroindazole derivatives as potent and peripherally selective cannabinoid-1 (CB1) receptor inverse agonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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| Publication number | Publication date |
|---|---|
| WO2021047581A1 (zh) | 2021-03-18 |
| TW202115031A (zh) | 2021-04-16 |
| TWI768465B (zh) | 2022-06-21 |
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