MD4069691T2 - Tetrahidrofurani substituiţi ca modulatori ai canalelor de sodiu - Google Patents

Info

Publication number

MD4069691T2

MD4069691T2 MDE20221109T MDE20221109T MD4069691T2 MD 4069691 T2 MD4069691 T2 MD 4069691T2 MD E20221109 T MDE20221109 T MD E20221109T MD E20221109 T MDE20221109 T MD E20221109T MD 4069691 T2 MD4069691 T2 MD 4069691T2

Authority

MD

Moldova

Prior art keywords

tetrahydrofuran

trifluoromethyl

dimethyl

carboxamide

phenyl

Prior art date

2019-12-06

Links

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• 108010052164 Sodium Channels Proteins 0.000 title abstract description 18
• 102000018674 Sodium Channels Human genes 0.000 title abstract description 17
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 609
• 150000003839 salts Chemical class 0.000 claims abstract description 405
• 208000002193 Pain Diseases 0.000 claims abstract description 282
• 230000036407 pain Effects 0.000 claims abstract description 240
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 107
• 238000000034 method Methods 0.000 claims abstract description 92
• -1 4-((2R,3S,4R,5S)-3-(4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide Chemical compound 0.000 claims description 1893
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 327
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 271
• 229910052757 nitrogen Inorganic materials 0.000 claims description 189
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 163
• IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 128
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 106
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 99
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 93
• 239000000203 mixture Substances 0.000 claims description 66
• 208000004296 neuralgia Diseases 0.000 claims description 62
• 239000003814 drug Substances 0.000 claims description 52
• 125000001475 halogen functional group Chemical group 0.000 claims description 49
• 208000021722 neuropathic pain Diseases 0.000 claims description 46
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
• 206010065390 Inflammatory pain Diseases 0.000 claims description 28
• 208000004550 Postoperative Pain Diseases 0.000 claims description 27
• 206010028391 Musculoskeletal Pain Diseases 0.000 claims description 26
• 208000009935 visceral pain Diseases 0.000 claims description 25
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
• 208000005298 acute pain Diseases 0.000 claims description 23
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 22
• 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 claims description 22
• 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 claims description 22
• 201000006417 multiple sclerosis Diseases 0.000 claims description 21
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 208000010261 Small Fiber Neuropathy Diseases 0.000 claims description 18
• 206010073928 Small fibre neuropathy Diseases 0.000 claims description 18
• 208000017692 primary erythermalgia Diseases 0.000 claims description 18
• 230000001575 pathological effect Effects 0.000 claims description 16
• 206010011224 Cough Diseases 0.000 claims description 15
• 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 15
• 230000000968 intestinal effect Effects 0.000 claims description 15
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
• 229940124597 therapeutic agent Drugs 0.000 claims description 14
• 208000000094 Chronic Pain Diseases 0.000 claims description 13
• 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 13
• 201000008482 osteoarthritis Diseases 0.000 claims description 13
• 206010021639 Incontinence Diseases 0.000 claims description 12
• 206010003119 arrhythmia Diseases 0.000 claims description 12
• 206010058019 Cancer Pain Diseases 0.000 claims description 11
• 230000002401 inhibitory effect Effects 0.000 claims description 11
• 208000010693 Charcot-Marie-Tooth Disease Diseases 0.000 claims description 9
• 238000011282 treatment Methods 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 8
• 239000003981 vehicle Substances 0.000 claims description 8
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 6
• GXHAENUAJYZNOA-UHFFFAOYSA-N oxolane-2-carboxamide Chemical compound NC(=O)C1CCCO1 GXHAENUAJYZNOA-UHFFFAOYSA-N 0.000 claims description 6
• ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 claims description 6
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
• LWMFVTNKELGHDB-WXRLOADJSA-N 4-[[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carbonyl]amino]-3-methylpyridine-2-carboxamide Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=C(C(=NC=C1)C(=O)N)C)OC LWMFVTNKELGHDB-WXRLOADJSA-N 0.000 claims description 4
• ADJYUTDHUPEPHU-LIWAJOSJSA-N 4-[[(2R,3S,4S,5R)-4-cyclopropyl-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)oxolane-2-carbonyl]amino]pyridine-2-carboxamide Chemical compound COC1=C(C=CC(F)=C1F)[C@H]1[C@@H](O[C@](C)([C@H]1C1CC1)C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(N)=O ADJYUTDHUPEPHU-LIWAJOSJSA-N 0.000 claims description 4
• QGPXJRWCPXXASO-LCIZUOBNSA-N COC1=C(F)C(F)=CC=C1[C@@H]1C[C@@](C)(O[C@H]1C(=O)NC1=CC=NC(=C1)C(N)=O)C(C)(F)F Chemical compound COC1=C(F)C(F)=CC=C1[C@@H]1C[C@@](C)(O[C@H]1C(=O)NC1=CC=NC(=C1)C(N)=O)C(C)(F)F QGPXJRWCPXXASO-LCIZUOBNSA-N 0.000 claims description 4
• QGPXJRWCPXXASO-ZINOCKGTSA-N COC1=C(F)C(F)=CC=C1[C@H]1C[C@](C)(O[C@@H]1C(=O)NC1=CC=NC(=C1)C(N)=O)C(C)(F)F Chemical compound COC1=C(F)C(F)=CC=C1[C@H]1C[C@](C)(O[C@@H]1C(=O)NC1=CC=NC(=C1)C(N)=O)C(C)(F)F QGPXJRWCPXXASO-ZINOCKGTSA-N 0.000 claims description 4
• CQXINKGVJMCJCT-HHTRBMLDSA-N FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=C(C(=NC=C1)C(=O)N)F)OC Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=C(C(=NC=C1)C(=O)N)F)OC CQXINKGVJMCJCT-HHTRBMLDSA-N 0.000 claims description 4
• ZJYBVDTWEGOOBO-TZDAZOALSA-N FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CC(=NC(=C1)C)C(=O)N)OC Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CC(=NC(=C1)C)C(=O)N)OC ZJYBVDTWEGOOBO-TZDAZOALSA-N 0.000 claims description 4
• PKLCDRHEWINUTD-TZDAZOALSA-N FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CC(=NC=C1C)C(=O)N)OC Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CC(=NC=C1C)C(=O)N)OC PKLCDRHEWINUTD-TZDAZOALSA-N 0.000 claims description 4
• QPURUMKJNZYDSU-PAFIKIDNSA-N FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CC=CC(=N1)C(=O)N)OC Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CC=CC(=N1)C(=O)N)OC QPURUMKJNZYDSU-PAFIKIDNSA-N 0.000 claims description 4
• ZWMRHKNSHIHPQW-CFKRIXOTSA-N FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CN=CC(=N1)C(=O)N)OC Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=CN=CC(=N1)C(=O)N)OC ZWMRHKNSHIHPQW-CFKRIXOTSA-N 0.000 claims description 4
• INIGXNMOJVWVTQ-PAFIKIDNSA-N FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=NC=CC(=C1)C(=O)N)OC Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC1=NC=CC(=C1)C(=O)N)OC INIGXNMOJVWVTQ-PAFIKIDNSA-N 0.000 claims description 4
• AEWBTHLLNJNUEP-PAFIKIDNSA-N FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC=1C=C(C=NC=1)C(=O)N)OC Chemical compound FC=1C(=C(C=CC=1F)[C@H]1[C@@H](O[C@]([C@H]1C)(C(F)(F)F)C)C(=O)NC=1C=C(C=NC=1)C(=O)N)OC AEWBTHLLNJNUEP-PAFIKIDNSA-N 0.000 claims description 4
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• XSQUJFKRXZMOKA-YOLASOTISA-N [2H]C=1C(=NC=CC=1NC(=O)[C@@H]1O[C@]([C@H]([C@H]1C1=C(C(=C(C=C1)F)F)OC)C)(C(F)(F)F)C)C(=O)N Chemical compound [2H]C=1C(=NC=CC=1NC(=O)[C@@H]1O[C@]([C@H]([C@H]1C1=C(C(=C(C=C1)F)F)OC)C)(C(F)(F)F)C)C(=O)N XSQUJFKRXZMOKA-YOLASOTISA-N 0.000 claims description 4
• MWVFLWXUZYQGEY-URKNILKWSA-N 4-[[(2R,3S,5R)-5-tert-butyl-3-(3,4-difluoro-2-methoxyphenyl)oxolane-2-carbonyl]amino]pyridine-2-carboxamide Chemical compound COC1=C(F)C(F)=CC=C1[C@@H]1C[C@@H](O[C@H]1C(=O)NC1=CC(=NC=C1)C(N)=O)C(C)(C)C MWVFLWXUZYQGEY-URKNILKWSA-N 0.000 claims description 3
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