JP2018534270A5 - - Google Patents
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- JP2018534270A5 JP2018534270A5 JP2018517286A JP2018517286A JP2018534270A5 JP 2018534270 A5 JP2018534270 A5 JP 2018534270A5 JP 2018517286 A JP2018517286 A JP 2018517286A JP 2018517286 A JP2018517286 A JP 2018517286A JP 2018534270 A5 JP2018534270 A5 JP 2018534270A5
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- halo
- optionally substituted
- alkoxy
- aryl
- 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.)
- Withdrawn
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- 125000000217 alkyl group Chemical group 0.000 claims description 467
- 125000003545 alkoxy group Chemical group 0.000 claims description 181
- 125000003118 aryl group Chemical group 0.000 claims description 170
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 114
- 125000005843 halogen group Chemical group 0.000 claims description 112
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 108
- -1 nitro, amino Chemical group 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 90
- 239000001257 hydrogen Substances 0.000 claims description 80
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 78
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 74
- 125000000623 heterocyclic group Chemical group 0.000 claims description 71
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 69
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 65
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 64
- 150000001875 compounds Chemical class 0.000 claims description 64
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 63
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 62
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 54
- 235000010290 biphenyl Nutrition 0.000 claims description 54
- 239000004305 biphenyl Substances 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 54
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 40
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 38
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 32
- 125000006413 ring segment Chemical group 0.000 claims description 31
- 239000012453 solvate Substances 0.000 claims description 28
- 125000004429 atom Chemical group 0.000 claims description 19
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 16
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 14
- 125000002619 bicyclic group Chemical group 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 208000002193 Pain Diseases 0.000 claims description 10
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 claims description 4
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 206010058019 Cancer Pain Diseases 0.000 claims description 2
- 208000023890 Complex Regional Pain Syndromes Diseases 0.000 claims description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 2
- 201000009273 Endometriosis Diseases 0.000 claims description 2
- 208000001640 Fibromyalgia Diseases 0.000 claims description 2
- 208000010412 Glaucoma Diseases 0.000 claims description 2
- 206010019233 Headaches Diseases 0.000 claims description 2
- 208000019695 Migraine disease Diseases 0.000 claims description 2
- 208000019022 Mood disease Diseases 0.000 claims description 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 2
- 208000004550 Postoperative Pain Diseases 0.000 claims description 2
- 208000028017 Psychotic disease Diseases 0.000 claims description 2
- 208000008765 Sciatica Diseases 0.000 claims description 2
- 208000027520 Somatoform disease Diseases 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 231100000869 headache Toxicity 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 206010027599 migraine Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 208000027753 pain disease Diseases 0.000 claims description 2
- 230000001314 paroxysmal effect Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 230000001568 sexual effect Effects 0.000 claims description 2
- 230000001148 spastic effect Effects 0.000 claims description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 2
- 206010044652 trigeminal neuralgia Diseases 0.000 claims description 2
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 claims 2
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- 230000036571 hydration Effects 0.000 claims 1
- 238000006703 hydration reaction Methods 0.000 claims 1
- 238000003419 tautomerization reaction Methods 0.000 claims 1
- 0 CC(C(*)CN1C(N[C@@](CN(*)C(*)=O)C2=NC3=[N+])=[N+])([C@@]12N3O)O Chemical compound CC(C(*)CN1C(N[C@@](CN(*)C(*)=O)C2=NC3=[N+])=[N+])([C@@]12N3O)O 0.000 description 80
- KYEACNNYFNZCST-UHFFFAOYSA-N CN(C(CC1)=O)C1=O Chemical compound CN(C(CC1)=O)C1=O KYEACNNYFNZCST-UHFFFAOYSA-N 0.000 description 11
- KZNICNPSHKQLFF-UHFFFAOYSA-N O=C(CC1)NC1=O Chemical compound O=C(CC1)NC1=O KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 10
- TTZJVVZTHPDUIB-UHFFFAOYSA-O N=C(NCC1N2)N(CCC3(O)O)C13NC2=[NH2+] Chemical compound N=C(NCC1N2)N(CCC3(O)O)C13NC2=[NH2+] TTZJVVZTHPDUIB-UHFFFAOYSA-O 0.000 description 4
- GRWXJRHEMNQLLE-UHFFFAOYSA-N NC(c1c(CCCC2)c2ccc1)=O Chemical compound NC(c1c(CCCC2)c2ccc1)=O GRWXJRHEMNQLLE-UHFFFAOYSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- CIHJZKMEIJKCIE-VGZKRQLQSA-O N=C(NCC1N2)N(CC[C@H]3O)C13NC2=[NH2+] Chemical compound N=C(NCC1N2)N(CC[C@H]3O)C13NC2=[NH2+] CIHJZKMEIJKCIE-VGZKRQLQSA-O 0.000 description 3
- HXZZHYZJJLFSKL-UHFFFAOYSA-N NC(c1c(CCC2)c2ccc1)=O Chemical compound NC(c1c(CCC2)c2ccc1)=O HXZZHYZJJLFSKL-UHFFFAOYSA-N 0.000 description 3
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 description 3
- PGHYPCPNTBGZLQ-UHFFFAOYSA-N CN(C(C1C2CCCC1)=O)C2=O Chemical compound CN(C(C1C2CCCC1)=O)C2=O PGHYPCPNTBGZLQ-UHFFFAOYSA-N 0.000 description 2
- RHYBFKMFHLPQPH-UHFFFAOYSA-N CN(CC(N1)=O)C1=O Chemical compound CN(CC(N1)=O)C1=O RHYBFKMFHLPQPH-UHFFFAOYSA-N 0.000 description 2
- RFTORHYUCZJHDO-UHFFFAOYSA-N CN(CC(N1C)=O)C1=O Chemical compound CN(CC(N1C)=O)C1=O RFTORHYUCZJHDO-UHFFFAOYSA-N 0.000 description 2
- JHMBTUMIVBSJFS-UHFFFAOYSA-N CN(Cc1ccccc11)C1=O Chemical compound CN(Cc1ccccc11)C1=O JHMBTUMIVBSJFS-UHFFFAOYSA-N 0.000 description 2
- BBETZVGADODUNX-XIRUVYRFSA-O N=C(NCC1N2)N(C[C@@H](C3(O)O)OC(c4cc(C(F)(F)F)ccc4C(F)(F)F)=O)C13NC2=[NH2+] Chemical compound N=C(NCC1N2)N(C[C@@H](C3(O)O)OC(c4cc(C(F)(F)F)ccc4C(F)(F)F)=O)C13NC2=[NH2+] BBETZVGADODUNX-XIRUVYRFSA-O 0.000 description 2
- DXBQJUMPQKYUJH-MLGTYFKZSA-O N=C(N[C@@H](CN(C(CC1)=O)C1=O)C1N2)N(CCC3(O)O)C13NC2=[NH2+] Chemical compound N=C(N[C@@H](CN(C(CC1)=O)C1=O)C1N2)N(CCC3(O)O)C13NC2=[NH2+] DXBQJUMPQKYUJH-MLGTYFKZSA-O 0.000 description 2
- RPQXVSUAYFXFJA-HGRQIUPRSA-N saxitoxin Chemical class NC(=O)OC[C@@H]1N=C(N)N2CCC(O)(O)[C@@]22N=C(N)N[C@@H]12 RPQXVSUAYFXFJA-HGRQIUPRSA-N 0.000 description 2
- ZUKVOFZWPKIFJM-KOULWWPBSA-O C#C[C@@](C(C1)NC(c(cccc2O3)c2OC3(F)F)=O)([C@@](C(C(CN(C(CC2)=O)C2=O)N2)N3)(NC3=[NH2+])N1C2=N)O Chemical compound C#C[C@@](C(C1)NC(c(cccc2O3)c2OC3(F)F)=O)([C@@](C(C(CN(C(CC2)=O)C2=O)N2)N3)(NC3=[NH2+])N1C2=N)O ZUKVOFZWPKIFJM-KOULWWPBSA-O 0.000 description 1
- SSALFBQYYAZQKA-UHFFFAOYSA-O C#[O]CC(C(CN1)N2)(NC2=[NH2+])N(CCNC(c2cc(OC(F)(F)F)ccc2)=O)C1=N Chemical compound C#[O]CC(C(CN1)N2)(NC2=[NH2+])N(CCNC(c2cc(OC(F)(F)F)ccc2)=O)C1=N SSALFBQYYAZQKA-UHFFFAOYSA-O 0.000 description 1
- IAUWHMJFQSXYQQ-SDUBBSOGSA-O C#[O][C@H](CC1)C(C([C@H](CN(C(CC2)=O)C2=O)N2)N3)(NC3=[NH2+])N1C2=N Chemical compound C#[O][C@H](CC1)C(C([C@H](CN(C(CC2)=O)C2=O)N2)N3)(NC3=[NH2+])N1C2=N IAUWHMJFQSXYQQ-SDUBBSOGSA-O 0.000 description 1
- HEAFHLROVZMBSI-DSHYYTJWSA-O C#[O][C@H]([C@H](C1)OC(NCC(c2ccccc2)c2ccccc2)=O)C(C(C(CN(C(CC2)=O)C2=O)N2)N3)(NC3=[NH2+])N1C2=N Chemical compound C#[O][C@H]([C@H](C1)OC(NCC(c2ccccc2)c2ccccc2)=O)C(C(C(CN(C(CC2)=O)C2=O)N2)N3)(NC3=[NH2+])N1C2=N HEAFHLROVZMBSI-DSHYYTJWSA-O 0.000 description 1
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- AVCGCMDLFOTMQA-SMCLFLENSA-O CC(C)(CC(N1C[C@@H](C(C(C2(O)O)(N3)N4C[C@@H]2OC(c2ccccc2)=O)NC3=[NH2+])NC4=N)=O)C1=O Chemical compound CC(C)(CC(N1C[C@@H](C(C(C2(O)O)(N3)N4C[C@@H]2OC(c2ccccc2)=O)NC3=[NH2+])NC4=N)=O)C1=O AVCGCMDLFOTMQA-SMCLFLENSA-O 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562235412P | 2015-09-30 | 2015-09-30 | |
| US62/235,412 | 2015-09-30 | ||
| PCT/US2016/055050 WO2017059385A1 (en) | 2015-09-30 | 2016-09-30 | 11,13-modified saxitoxins for the treatment of pain |
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| WO2015157559A2 (en) | 2014-04-09 | 2015-10-15 | Siteone Therapeutics, Inc. | 10',11'-modified saxitoxins for the treatment of pain |
| CN110914276A (zh) | 2017-03-29 | 2020-03-24 | 赛特温治疗公司 | 用于治疗疼痛的11,13-修饰的石房蛤毒素类化合物 |
| BR112019020111A2 (pt) | 2017-03-29 | 2020-05-05 | Siteone Therapeutics Inc | saxitoxinas 11,13-modificadas para o tratamento de dor |
| WO2020072835A1 (en) * | 2018-10-03 | 2020-04-09 | Siteone Therapeutics, Inc. | 11,13-modified saxitoxins for the treatment of pain |
| SI4069691T1 (sl) | 2019-12-06 | 2025-02-28 | Vertex Pharmaceuticals Incorporated | Substituirani tetrahidrofurani kot modulatorji natrijevih kanalčkov |
| KR20230051252A (ko) * | 2020-08-14 | 2023-04-17 | 사이트원 테라퓨틱스, 인코포레이티드 | 통증의 치료를 위한 nav 1.7의 비수화 케톤 억제제 |
| EP4347031B1 (en) | 2021-06-04 | 2025-10-29 | Vertex Pharmaceuticals Incorporated | N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels |
| WO2022256679A1 (en) | 2021-06-04 | 2022-12-08 | Vertex Pharmaceuticals Incorporated | N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamide analogs as modulators of sodium channels |
| US20240285596A1 (en) | 2021-06-04 | 2024-08-29 | Vertex Pharmaceuticals Incorporated | Solid dosage forms and dosing regimens comprising (2r,3s,4s,5r)-4-[[3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carbonyl]amino]pyridine-2-carboxamide |
| JP2024520648A (ja) | 2021-06-04 | 2024-05-24 | 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 | ナトリウムチャネルの調節因子としての置換テトラヒドロフラン－２－カルボキサミド |
| CA3221960A1 (en) | 2021-06-04 | 2022-12-08 | Vertex Pharmaceuticals Incorporated | Hydroxy and (halo)alkoxy substituted tetrahydrofurans as modulators of sodium channels |
| CN117794918A (zh) | 2021-06-04 | 2024-03-29 | 沃泰克斯药物股份有限公司 | 经取代的四氢呋喃类似物作为钠通道调节剂 |
| CN113943243B (zh) * | 2021-10-14 | 2023-08-01 | 南开大学 | 一种用于同时鉴定和定量氨基酸的氟探针的制备与应用 |
| EP4511114A1 (en) | 2022-04-22 | 2025-02-26 | Vertex Pharmaceuticals Incorporated | Heteroaryl compounds for the treatment of pain |
| AU2023257313A1 (en) | 2022-04-22 | 2024-10-31 | Vertex Pharmaceuticals Incorporated | Heteroaryl compounds for the treatment of pain |
| CR20240513A (es) | 2022-04-22 | 2025-04-30 | Vertex Pharma | Compuestos de heteroarilo para el tratamiento del dolor |
| CN119487003A (zh) | 2022-04-22 | 2025-02-18 | 沃泰克斯药物股份有限公司 | 用于治疗疼痛的杂芳基化合物 |
| EP4630405A1 (en) | 2022-12-06 | 2025-10-15 | Vertex Pharmaceuticals Incorporated | Process for the synthesis of substituted tetrahydrofuran modulators of sodium channels |
| TW202535867A (zh) | 2023-10-23 | 2025-09-16 | 美商維泰克斯製藥公司 | 用於治療疼痛之鈉通道調節劑及其固體形式的製備方法 |
| WO2025090516A1 (en) | 2023-10-23 | 2025-05-01 | Vertex Pharmaceuticals Incorporated | Methods of preparing compounds for treating pain and solid forms thereof |
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-
2016
- 2016-09-30 JP JP2018517286A patent/JP2018534270A/ja not_active Withdrawn
- 2016-09-30 EP EP16785597.2A patent/EP3356370B1/en active Active
- 2016-09-30 US US15/283,187 patent/US10112953B2/en active Active
- 2016-09-30 CN CN201680068998.6A patent/CN108473503A/zh active Pending
- 2016-09-30 ES ES16785597T patent/ES2895155T3/es active Active
- 2016-09-30 AU AU2016329201A patent/AU2016329201A1/en not_active Abandoned
- 2016-09-30 WO PCT/US2016/055050 patent/WO2017059385A1/en not_active Ceased
- 2016-09-30 CA CA3000708A patent/CA3000708A1/en not_active Abandoned
-
2018
- 2018-03-29 IL IL258471A patent/IL258471A/en unknown
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