JP7402857B2 - オピオイド受容体モジュレーター、およびそれに関連する生成物ならびに方法 - Google Patents
オピオイド受容体モジュレーター、およびそれに関連する生成物ならびに方法 Download PDFInfo
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- JP7402857B2 JP7402857B2 JP2021503713A JP2021503713A JP7402857B2 JP 7402857 B2 JP7402857 B2 JP 7402857B2 JP 2021503713 A JP2021503713 A JP 2021503713A JP 2021503713 A JP2021503713 A JP 2021503713A JP 7402857 B2 JP7402857 B2 JP 7402857B2
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- 238000000034 method Methods 0.000 title description 80
- 102000003840 Opioid Receptors Human genes 0.000 title description 12
- 108090000137 Opioid Receptors Proteins 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims description 381
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 131
- 150000003839 salts Chemical class 0.000 claims description 124
- 239000012453 solvate Substances 0.000 claims description 106
- 125000000623 heterocyclic group Chemical group 0.000 claims description 91
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 87
- -1 2,3-dihydroindolyl Chemical group 0.000 claims description 85
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 37
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 125000004191 (C1-C6) alkoxy 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 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000004043 oxo group Chemical group O=* 0.000 claims description 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 12
- 208000002193 Pain Diseases 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 150000004677 hydrates Chemical class 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 384
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 342
- 238000003786 synthesis reaction Methods 0.000 description 269
- 230000015572 biosynthetic process Effects 0.000 description 264
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 243
- 239000000243 solution Substances 0.000 description 185
- 235000019439 ethyl acetate Nutrition 0.000 description 165
- 238000005481 NMR spectroscopy Methods 0.000 description 163
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 144
- 239000000203 mixture Substances 0.000 description 140
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 125
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 123
- 239000011541 reaction mixture Substances 0.000 description 123
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 122
- 239000007787 solid Substances 0.000 description 104
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 98
- 238000006243 chemical reaction Methods 0.000 description 95
- 239000000047 product Substances 0.000 description 89
- 229960001866 silicon dioxide Drugs 0.000 description 83
- 239000000741 silica gel Substances 0.000 description 82
- 229910002027 silica gel Inorganic materials 0.000 description 82
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 69
- 239000011734 sodium Substances 0.000 description 69
- 239000012044 organic layer Substances 0.000 description 64
- 239000000460 chlorine Substances 0.000 description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
- 239000007858 starting material Substances 0.000 description 59
- 125000005843 halogen group Chemical group 0.000 description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 56
- 238000003818 flash chromatography Methods 0.000 description 55
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 51
- 239000012267 brine Substances 0.000 description 49
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 43
- 238000003756 stirring Methods 0.000 description 41
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 35
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 33
- 229910052757 nitrogen Inorganic materials 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 238000000746 purification Methods 0.000 description 30
- 125000004429 atom Chemical group 0.000 description 29
- 239000010410 layer Substances 0.000 description 29
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 29
- 238000001914 filtration Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 24
- 239000000706 filtrate Substances 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 24
- 239000000725 suspension Substances 0.000 description 24
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 229910021529 ammonia Inorganic materials 0.000 description 19
- 229910052740 iodine Inorganic materials 0.000 description 19
- 239000011630 iodine Substances 0.000 description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 18
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 18
- 239000012230 colorless oil Substances 0.000 description 18
- 239000000284 extract Substances 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- 239000000843 powder Substances 0.000 description 18
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
- 125000005842 heteroatom Chemical group 0.000 description 17
- 239000007864 aqueous solution Substances 0.000 description 16
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 16
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical class COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 16
- 108020001612 μ-opioid receptors Proteins 0.000 description 16
- DWYBBDHZIDBVJJ-JTQLQIEISA-N NC[C@H](CC1=CC(=C(C(=O)NC)C=C1)F)N(C)C Chemical compound NC[C@H](CC1=CC(=C(C(=O)NC)C=C1)F)N(C)C DWYBBDHZIDBVJJ-JTQLQIEISA-N 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 150000003857 carboxamides Chemical class 0.000 description 14
- 239000012043 crude product Substances 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 13
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- YQGDRMBKFXAICH-GXSJLCMTSA-N (1R,2S)-2-methyl-2-phenylcyclopropane-1-carboxylic acid Chemical compound C[C@@]1(C[C@H]1C(O)=O)c1ccccc1 YQGDRMBKFXAICH-GXSJLCMTSA-N 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 12
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 12
- UGZBFCCHLUWCQI-LURJTMIESA-N methyl (2r)-3-iodo-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound COC(=O)[C@H](CI)NC(=O)OC(C)(C)C UGZBFCCHLUWCQI-LURJTMIESA-N 0.000 description 12
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 108020001588 κ-opioid receptors Proteins 0.000 description 12
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 239000006260 foam Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- YQGDRMBKFXAICH-ONGXEEELSA-N (1R,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid Chemical compound C[C@]1(C[C@H]1C(O)=O)c1ccccc1 YQGDRMBKFXAICH-ONGXEEELSA-N 0.000 description 10
- WPXPVPPATVXIOO-NSHDSACASA-N 4-[(2S)-3-amino-2-(dimethylamino)propyl]benzamide Chemical compound NC[C@H](CC1=CC=C(C(=O)N)C=C1)N(C)C WPXPVPPATVXIOO-NSHDSACASA-N 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- GCBXAQLZTBLSGE-UHFFFAOYSA-N 1-phenylcyclopropane-1-carboxamide Chemical compound C=1C=CC=CC=1C1(C(=O)N)CC1 GCBXAQLZTBLSGE-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 8
- 239000005557 antagonist Substances 0.000 description 8
- 239000013058 crude material Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- 239000012258 stirred mixture Substances 0.000 description 8
- YQGDRMBKFXAICH-KOLCDFICSA-N (1S,2R)-2-methyl-2-phenylcyclopropane-1-carboxylic acid Chemical compound C[C@]1(C[C@@H]1C(O)=O)c1ccccc1 YQGDRMBKFXAICH-KOLCDFICSA-N 0.000 description 7
- LAVAXZCEGFOATB-XRIOVQLTSA-N 4-[(2S)-3-amino-2-(dimethylamino)propyl]phenol dihydrochloride Chemical compound Cl.Cl.CN(C)[C@H](CN)Cc1ccc(O)cc1 LAVAXZCEGFOATB-XRIOVQLTSA-N 0.000 description 7
- UTJXXISIWLUQQZ-IDMXKUIJSA-N Cl.Cl.FC=1C=C(C=CC=1)C[C@@H](CN)N(C)C Chemical compound Cl.Cl.FC=1C=C(C=CC=1)C[C@@H](CN)N(C)C UTJXXISIWLUQQZ-IDMXKUIJSA-N 0.000 description 7
- 206010012335 Dependence Diseases 0.000 description 7
- LXKCIPMTABVMTH-YJBOKZPZSA-N [(1S)-1-phenylethyl] N-[(2S)-2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)propyl]carbamate Chemical compound O=C(C1=CC(C)=C(C[C@@H](CNC(=O)O[C@H](C2=CC=CC=C2)C)N)C(C)=C1)N LXKCIPMTABVMTH-YJBOKZPZSA-N 0.000 description 7
- 125000001072 heteroaryl group Chemical group 0.000 description 7
- 208000015122 neurodegenerative disease Diseases 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 7
- 125000000168 pyrrolyl group Chemical group 0.000 description 7
- 239000012279 sodium borohydride Substances 0.000 description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 description 7
- XCAGGZDZMFNJCW-LBPRGKRZSA-N tert-butyl N-[(2S)-1-(4-carbamoylphenyl)-3-hydroxypropan-2-yl]carbamate Chemical compound O=C(C1=CC=C(C[C@@H](CO)NC(=O)OC(C)(C)C)C=C1)N XCAGGZDZMFNJCW-LBPRGKRZSA-N 0.000 description 7
- PNOVNGYAOGDVGS-ZDUSSCGKSA-N tert-butyl n-[(2s)-1-(4-cyanophenyl)-3-hydroxypropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](CO)CC1=CC=C(C#N)C=C1 PNOVNGYAOGDVGS-ZDUSSCGKSA-N 0.000 description 7
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 7
- POZGETMIPGBFGQ-UHFFFAOYSA-N 3-methylbut-1-en-2-ylbenzene Chemical compound CC(C)C(=C)C1=CC=CC=C1 POZGETMIPGBFGQ-UHFFFAOYSA-N 0.000 description 6
- AZFQKZKHNVUOCL-PZJWPPBQSA-N 4-[(2S)-2-amino-3-[[(S)-cyclopropyl(phenyl)methyl]carbamoylamino]propyl]-3,5-dimethylbenzamide Chemical compound O=C(C1=CC(C)=C(C[C@@H](CNC(=O)N[C@H](C2=CC=CC=C2)C2CC2)N)C(C)=C1)N AZFQKZKHNVUOCL-PZJWPPBQSA-N 0.000 description 6
- ULUUPZTYGCURBN-ZOWNYOTGSA-N Cl.N[C@@H](CC1=CC=C(C(=O)N)C=C1)CN1C(C2=CC=CC=C2C1=O)=O Chemical compound Cl.N[C@@H](CC1=CC=C(C(=O)N)C=C1)CN1C(C2=CC=CC=C2C1=O)=O ULUUPZTYGCURBN-ZOWNYOTGSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 239000003039 volatile agent Substances 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- NBAJLENORWYRLD-AAEUAGOBSA-N (1R,2R)-2-phenyl-2-propan-2-ylcyclopropane-1-carboxylic acid Chemical compound CC(C)[C@@]1(C[C@H]1C(O)=O)c1ccccc1 NBAJLENORWYRLD-AAEUAGOBSA-N 0.000 description 5
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- YNYXJJMHXPZFDD-JTQLQIEISA-N tert-butyl N-[(2S)-1-amino-3-(2-chloro-4-hydroxyphenyl)propan-2-yl]carbamate Chemical compound OC1=CC=C(C(Cl)=C1)C[C@@H](CN)NC(=O)OC(C)(C)C YNYXJJMHXPZFDD-JTQLQIEISA-N 0.000 description 1
- IHVVNHCSNVODGB-AWEZNQCLSA-N tert-butyl N-[(2S)-3-(4-bromophenyl)-2-(dimethylamino)propyl]carbamate Chemical compound CN(C)[C@H](CNC(=O)OC(C)(C)C)Cc1ccc(Br)cc1 IHVVNHCSNVODGB-AWEZNQCLSA-N 0.000 description 1
- FALMULXQLUOQQK-HNNXBMFYSA-N tert-butyl N-[(2S)-3-(4-cyanophenyl)-2-(dimethylamino)propyl]carbamate Chemical compound C1(=CC=C(C[C@@H](CNC(=O)OC(C)(C)C)N(C)C)C=C1)C#N FALMULXQLUOQQK-HNNXBMFYSA-N 0.000 description 1
- VGKNVRSIDINOPV-NSHDSACASA-N tert-butyl n-[(2s)-1-amino-3-(4-bromophenyl)-1-oxopropan-2-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H](C(N)=O)CC1=CC=C(Br)C=C1 VGKNVRSIDINOPV-NSHDSACASA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000001935 tetracenyl group Chemical group C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- AWDBHOZBRXWRKS-UHFFFAOYSA-N tetrapotassium;iron(6+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+6].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] AWDBHOZBRXWRKS-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 208000002271 trichotillomania Diseases 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000003960 triphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C3=CC=CC=C3C12)* 0.000 description 1
- 210000001177 vas deferen Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
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- 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
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/62—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
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- C07C233/00—Carboxylic acid amides
- C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- C07C237/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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- C07C237/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system of the same carbon skeleton
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/80—Acids; Esters in position 3
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- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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Description
環Aは炭素環または複素環であり;
環Bは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2である。
環Aは炭素環または複素環であり;
環Bは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2であり;
ただし、以下のことを条件とする:
Lが-(CR7 2)q-Q-(CR7 2)r-であるとき、
環Bが芳香族の単環の炭素環または複素環である場合、mは0ではなく、かつ、少なくとも1つのR5は-OH、ハロ、またはアルコキシではなく、あるいは、
環Bが芳香族の単環の炭素環または複素環であり、mが2-5である場合、少なくとも1つのR5はハロではなく、あるいは、
環Bが芳香族の多環式の炭素環または複素環である場合、R3とR4は両方ともHではなく、かつ、環Aはチオフェンではなく;
Lが環Cであるとき、
環Bがフェニルまたはピロリルであり、R3がH、(C1-C6)アルキルであるか、または1つのR5と一体となって5-7員の複素環を形成する場合、mは0ではなく、あるいは、
R3とR4が、それらが結合するNと一体となって、4-7員の複素環を形成し、1つのR6がハロであり、および、mが1である場合、R5はハロではなく;ならびに、
Lが単結合であるとき、
環Bがフェニルまたはピロリルであり、R3がHまたは(C1-C6)アルキルである場合、mは0ではなく、あるいは、
R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成する場合、m’は0ではなく、環Bがフェニルであり、
R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成し、および、m’が1である場合、R5はハロでもアルコキシでもなく、あるいは、
環Bが7員の炭素環であり、R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成し、および、m’が1である場合、R5は-OHではなく、あるいは、
環Bが単環の炭素環または複素環であり、およびR3とR4がそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであるか、または、R3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、mは0ではなく、あるいは、
環Bがフェニルであり、R3とR4がそれぞれHであるか、またはR3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、R5はハロではなく、あるいは、
環Aがイミダゾリルであり、環Bがフェニルである場合、nは0ではない。
環Bが芳香族の単環の炭素環または複素環である場合、mは0ではなく、かつ、少なくとも1つのR5は-OH、ハロ、またはアルコキシではなく、あるいは、
環Bが芳香族の単環の炭素環または複素環であり、mが2-5である場合、少なくとも1つのR5はハロではなく、あるいは、
環Bが芳香族の多環式の炭素環または複素環である場合、R3とR4は両方ともHではなく、かつ、環Aはチオフェンではない。
環Bがフェニルまたはピロリルであり、R3がH、(C1-C6)アルキルであるか、または1つのR5と一体となって5-7員の複素環を形成する場合、mは0ではなく、あるいは、
R3とR4が、それらが結合するNと一体となって、4-7員の複素環を形成し、1つのR6がハロであり、および、mが1である場合、R5はハロではない。
環Bがフェニルまたはピロリルであり、R3がHまたは(C1-C6)アルキルである場合、mは0ではなく、あるいは、
R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成する場合、m’は0ではなく、環Bがフェニルであり、
R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成し、および、m’が1である場合、R5はハロでもアルコキシでもなく、あるいは、
環Bが7員の炭素環であり、R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成し、および、m’が1である場合、R5は-OHではなく、あるいは、
環Bが単環の炭素環または複素環であり、およびR3とR4がそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであるか、または、R3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、mは0ではなく、あるいは、
環Bがフェニルであり、R3とR4がそれぞれHであるか、またはR3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、R5はハロではなく、あるいは、
環Aがイミダゾリルであり、環Bがフェニルである場合、nは0ではない。
ここで、
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
Q1、Q2、Q3、Q4、およびQ5はそれぞれ独立して、CまたはNであり;
Q1、Q2、Q3、Q4、およびQ5の0、1、または2つがNであり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2であり;
ただし、以下のことを条件とする:
Lが-(CR7 2)q-Q-(CR7 2)r-であるとき、
mは0ではなく、少なくとも1つのR5は-OH、ハロ、またはアルコキシではなく、あるいは、mが2-5である場合、少なくとも1つのR5はハロではなく;もしくは、
Lが環Cであるとき、
Q1、Q2、Q3、Q4、およびQ5がそれぞれ独立してCであり、R3がH、C1-C6アルキルであるか、または、1つのR5と一体となって5-7員の複素環を形成する場合、mは0ではなく、あるいは、
R3とR4が、それらが結合するNと一体となって、4-7員の複素環を形成し、1つのR6がハロであり、および、mが1である場合、R5はハロではなく;ならびに、
Lが単結合であるとき、
Q1、Q2、Q3、Q4、およびQ5がそれぞれ独立してCであり、R3がHまたは(C1-C6)アルキルである場合、mは0ではなく、あるいは、
R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成する場合、m’は0ではなく、
Q1、Q2、Q3、Q4、およびQ5がそれぞれ独立してCであり、R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成し、および、m’が1である場合、R5はハロでもアルコキシでもなく、あるいは、
R3とR4がそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであるか、または、R3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、mは0ではなく、あるいは、
Q1、Q2、Q3、Q4、およびQ5がそれぞれ独立してCであり、R3とR4がそれぞれHであるか、R3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、R5はハロではなく、あるいは、
環Aがイミダゾリルであり、Q1、Q2、Q3、Q4、およびQ5がそれぞれ独立してCである場合、nは0ではない。
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2であり;
ただし、以下のことを条件とする:
Lが-(CR7 2)q-Q-(CR7 2)r-であるとき、
mは0ではなく、少なくとも1つのR5は-OH、ハロ、またはアルコキシではなく、あるいは、
mが2-5である場合、少なくとも1つのR5はハロではなく;もしくは、
Lが環Cであるとき、
R3がH、(C1-C6)アルキルであるか、または1つのR5と一体となって5-7員の複素環を形成する場合、mは0ではなく、あるいは、
R3とR4が、それらが結合するNと一体となって、4-7員の複素環を形成し、1つのR6がハロであり、および、mが1である場合、R5はハロではなく;ならびに、
Lが単結合であるとき、
R3がHまたは(C1-C6)アルキルである場合、mは0ではなく、あるいは、
R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成する場合、m’は0ではなく、R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成し、および、m’が1である場合、R5はハロでもアルコキシでもなく、あるいは、
R3とR4がそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであるか、または、R3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、mは0ではなく、あるいは、
R3とR4がそれぞれHであるか、またはR3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、R5はハロではなく、あるいは、
環Aがイミダゾリルである場合、nは0ではない。
ここで、
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
m’は0-4であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2である。
ここで、
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
m’は0-4であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2である。
ここで、
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
m’は0-4であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2である。
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2であり;
ただし、以下のことを条件とする:
Lが-(CR7 2)q-Q-(CR7 2)r-であるとき、
mは0ではなく、少なくとも1つのR5は-OH、ハロ、またはアルコキシではなく、あるいは、
mが2-5である場合、少なくとも1つのR5はハロではなく;ならびに、
Lが環Cであるとき、
R3とR4が、それらが結合するNと一体となって、4-7員の複素環を形成し、1つのR6がハロであり、および、mが1である場合、R5はハロではなく;ならびに、
Lが単結合であるとき、
R3と1つのR5が、それらが結合している原子と一体となって、5-7員の複素環を形成する場合、m’は0ではなく、あるいは、環Bが単環の炭素環または複素環であり、およびR3とR4がそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであるか、または、R3とR4が、それらが結合しているNと一体となって、4-7員の複素環を形成する場合、mは0ではない。
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
m’は0-4であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2である。
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
Q1、Q4、およびQ5はそれぞれ独立して、CまたはNであり;
Q2とQ3はそれぞれCであり;
環Dは、Q2とQ3と一体となって縮合二環式環Bを形成する、5-6員の炭素環または複素環であり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2であり;
ただし、以下のことを条件とする:
Lが-(CR7 2)q-Q-(CR7 2)r-であるとき、
R3とR4は両方ともHではなく、環Aはチオフェンではない。
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
Q1、Q4、およびQ5はそれぞれ独立して、CまたはNであり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2である。
環Aは炭素環または複素環であり;
Lは、単結合、-(CR7 2)q-Q-(CR7 2)r-、または環Cであり;
Qは、-C(Ra)2-、-NRa-、または-O-であり;
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり;
RaはそれぞれHまたは(C1-C6)アルキルであり;
R1とR2はそれぞれ独立して、H、または、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり;
R3とR4はそれぞれ独立して、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり;
あるいは、R3とR4は、それらが結合しているNと一体となって、4-7員の複素環を形成し;
R5、R6、およびR7はそれぞれ独立して、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり;
あるいは、R3と1つのR5は、それらが結合している原子と一体となって、5-7員の複素環を形成し;
R8はHまたは(C1-C6)アルキルであり;
Q1、Q4、およびQ5はそれぞれ独立して、CまたはNであり;
mは0-5であり;
nは0-5であり;
qは0-5であり;
rは0-5であり;および、
tは0-2である。
実験部分に記載されていない合成のためのすべての試薬は、市販されているか、または周知の化合物であるか、または当業者によって周知の方法で周知の化合物から形成されてもよい。
以下の略語が実施例では使用されるが、その他の略語は当該技術分野において慣用的な意味を有する:
Boc:tertブトキシカルボニル保護基
DIAD:ジイソプロピルアゾジカルボキシレート
EDCl:1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミドハイドロクロライド
EtOH:エタノール
EtOC(O)Cl:エチルクロロホルメート
h:時間(s)
HOBt:ヒドロキシベンゾトリアゾール
KOtBu:カリウムt-ブトキシド
l:リットル
LCMS:液体クロマトグラフィー-質量分析法
M:モル
MeOH:メタノール
min:分
μl:マイクロリットル
ml:ミリリットル
N2:窒素
N2H4:ヒドラジン一水和物
NaBH4:水素化ホウ素ナトリウム
N2CHCO2Et:ジアゾ酢酸エチル
NMR:核磁気共鳴スペクトル測定法
Pd2(dba)3:トリス(ジベンジリデンアセトン)ジパラジウム(0);
PPh3:トリフェニルホスフィン
ppm:パーツ・パー・ミリオン
Rh2(OAc)4:酢酸ロジウム(II)二量体
rt:室温
Rt:保持時間
sat.:飽和した
Sphos:2-ジシクロヘキシルホスフィノ-2’,6’-ジメトキシビフェニル
TEA:トリエチルアミン
THF:テトラヒドロフラン
分析法A:カラム:Eclipse Plus C18 4.6×3.5μm;溶出剤A:H2O中の0.1%TFA;溶出剤B:CH3CN中の0.1%TFA;勾配:4分にわたって20-100%;流量:1.5ml/分;注入量1-5μL;温度:23℃;UV走査:220および250nm;シグナル設定-正のモードを走査。
調製法A:機器:Agilent Technologies 1200 Infinity Series Column:Gemini 5 μm NX-C18 110 A,250 x 21.2 mm;溶出剤A:H2O中の0.1%TFA;溶出剤B:CH3CN中の0.1%TFA;勾配:10-100%;流量:20mL/分;注入量0.5-2mL;温度:23℃;UV走査:254および220nm。
式(I-A)の構造を有する代表的な化合物は、スキームA1-A5において記載される一般的な合成手順を使用して合成可能である。
(1R,2S)-2-メチル-2-フェニルシクロプロパン-1-カルボン酸(Int-22)、
(1S,2R)-2-メチル-2-フェニルシクロプロパン-1-カルボン酸(Int-23)、
(1R,2R)-2-メチル-2-フェニルシクロプロパン-1-カルボン酸(Int-24)、
(1S,2S)-2-メチル-2-フェニルシクロプロパン-1-カルボン酸(Int-25)。
工程1:メチル(S)-2-((tert-ブトキシカルボニル)アミノ)-3-(3-フルオロ-4-(メチルカルバモイル)フェニル)プロパノエートの合成
インビトロ活性
MORアゴニストおよびアンタゴニストのアッセイ
μオピオイド受容体(MOR)アッセイを活性化する試験化合物の能力は、mOR受容体(CHO-K1 Multispan Inc.,Cat# C1350-1a)を発現する、安定してトランスフェクトされた細胞CHO細胞において評価され、その評価は、Multispan Inc.(26219 Eden Landing Road,Hayward,CA 94545)で、市販のキット(cAMP Hi-Range Kit; Cisbio,Cat# 62AM6PEC)を使用して、試験化合物で処置された細胞におけるcAMPレベルを測定することにより行われた。試験化合物の活性を、EC50(ベースラインとその最大応答の中間の応答を誘導する試験化合物の濃度)として、以下の表14に記録する。MOR活性に対して、「+++」は、100nM未満のEC50を表示し;「++」は、100nMから1,000nMまでのEC50を表示し;および、「+」は、1,000nMより大きいEC50を表示する。
μオピオイド受容体(MOR)アッセイに拮抗するか、またはそれを阻害する試験化合物の能力は、mOR受容体(CHO-K1 Multispan Inc.,Cat# C1350-1a)を発現する、安定してトランスフェクトされた細胞CHO細胞において評価され、その評価は、Multispan Inc.(26219 Eden Landing Road,Hayward,CA 94545)で、EC80のmORアゴニストDAMGOを用いて受容体を活性化した後に、市販のキット(cAMP Hi-Range Kit; Cisbio,Cat# 62AM6PEC)を使用して、試験化合物で処置された細胞におけるcAMPレベルを測定することにより行われた。試験化合物の活性を、IC50(ベースラインとその最大応答の中間の応答を誘導する試験化合物の濃度)として、以下の表14に記録する。MOR活性に対して、「+++」は、100nM未満のIC50を表示し;「++」は100nMから1,000nMまでのIC50を表示し;および、「+」は、1,000nMより大きいIC50を表示する。
μオピオイド受容体(MOR)アッセイを活性化する試験化合物の能力は、Multispan Inc.(26219 Eden Landing Road,Hayward,CA 94545)で、MOR受容体(CHO-K1 Multispan Inc.,Cat# C1350-1a)を発現する、安定してトランスフェクトされた細胞CHO細胞において評価された。MORを過剰発現する安定した細胞株から得られた細胞膜を、GTPγSアッセイを使用して、SPAビーズ(Perkin Elmer,Cat # RPNQ0001)にさらした。試験化合物の活性を、ベースラインとその最大応答の中間の応答を誘導する試験化合物の濃度である、EC50として、以下の表14に記録する。MOR活性に対して、「+++」は、100nM未満のEC50を表示し;「++」は、100nMから1,000nMまでのEC50を表示し;および、「+」は、1,000nMより大きいEC50を表示する。
κオピオイド受容体(KOR)を阻害する化合物の能力は、Multispan Inc.(26219 Eden Landing Road,Hayward,CA 94545)で、kOR受容体(CHO-K1 Multispan Inc.,Cat# C1352-1a)を発現する、安定してトランスフェクトされた細胞CHO細胞において評価され、その評価は、化合物で処置された細胞においてダイノルフィンBを用いてkOR受容体を活性化した後に、cAMPレベルを測定することにより行われた。cAMPレベルは、市販のキット(cAMP Hi-Range Kit; Cisbio,Cat# 62AM6PEC)を用いて測定された。試験化合物の活性を、IC50(試験化合物が、ダイノルフィンBによって誘導された活性化の50%を阻害する濃度)として、表14に記録する。KOR活性に対して、「+++:は、100nM未満のIC50を表示し;「++」は100nMから1,000nMまでのIC50を表示し;および、「+」は、1,000nMより大きいIC50を表示する。
インビボ活性
体重275-300グラムのオスのスプラーグドーリーラットを試験で使用した(1つの群当たりn=8-10)。動物に0.9%の生理食塩水を皮下注射する。注射の15、45、および80分後に、動物を摂氏52度に設定されたホットプレートに置き、ベースライン潜時(baseline latency)を記録する(ベースライン潜時=後足をなめる、後足が震える、後方に歩行する、ジャンプする、ことのいずれかからなる、第2の引っ込め反応(withdrawal response)までの平均時間)。1日後、ビヒクル溶液中の試験化合物、または溶液中の化合物の混合物を動物に皮下注射した。次に、試験潜時を記録した(試験潜時=記載された手順を使用して、15、45、80、120、180、および240分で測定された、ホットプレート上での引っ込め反応までの時間)。その後、時間を、%最大可能性効果(%MPE)=(test_latecy(試験潜時)-baseline_latency(ベースライン潜時))/(30秒-baseline_latency(ベースライン潜時))に変換した。ここで、30秒はカットオフ(cutoff)であり、損傷が起こると予想される時点であるため、この時点で反応が観察されない場合は、動物を取り除く。
体重275-300グラムのスプラーグドーリーラットをこの試験に使用した(1つの群当たりn=4-6)。動物を全身用の無制限のプレチスモグラフ(whole body unrestrained plethysmograph)に入れ、ベースライン呼吸を15分間記録した。次に、動物にフェンタニル(3mg/kg SC)を皮下注射し、呼吸を10~12分間モニタリングした。その後、動物に、試験化合物であるナロキソン(0.1mg/kg SC)あるいは化合物B-15(30mg/kg SC)のいずれかを注射し、呼吸を最大4時間記録した。事後に、処置条件を知らされていなかった実験者は、前述のようにトレースを分析し(Laferriere,A. ,et al.,Developmental Brain Research,2005,156(2):210-217)、各動物の毎分呼吸量(MV=一回呼吸量X1分当たりの呼吸数)を計算した。ベースライン期間(薬物後MV/平均ベースラインMV)の平均の%として、データを図2に示す。
Claims (19)
- 式(I)の構造を有する化合物、
ここで、
環Aは炭素環または複素環であり、
環Bは炭素環または複素環であり、
Lは環Cであり、
環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり、
R1とR2はそれぞれ、H、0-5のハロで置換された、(C1-C6)アルキルあるいはC3-C7シクロアルキルであり、
R3とR4はそれぞれ、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、炭素環、または炭素環アルキルであり、
R5 は、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり、
R 6 は、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり、
R7 は、-C(O)NR1R2、-NR1C(O)R2、-OC(O)R1、-C(O)OR1、-S(O)tNR1R2、-NR1S(O)tR2、-OH、-CN、ハロ、オキソ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり、
R8はHまたは(C1-C6)アルキルであり、
mは1-5であり、
nは0-5であり、および、
tは0-2である。 - 前記環Aはフェニル、ピリジニル、またはピラジニルであり、
前記環Cは、0-5のR7で置換された、C3-C7シクロアルキルまたは3-7員のヘテロシクロアルキルであり、
前記R1と前記R2はそれぞれ、H、0-3のハロで置換された、メチル、エチル、イソプロピル、またはシクロプロピルであり、
前記R3と前記R4はそれぞれ、H、(C1-C6)アルキル、(C1-C6)ハロアルキル、またはシクロプロピルメチルであり、
前記R5 は、-C(O)NR1R2、-OH、ハロ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり、
前記R6 は、ハロ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり、
前記R7 は、ハロ、(C1-C6)アルキル、(C1-C6)ハロアルキル、(C1-C6)アルコキシ、または炭素環であり、
前記R8はHであり、
前記mは1-3であり、および
前記nは0-3である、請求項1に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。 - 前記環Aはフェニルである、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記環Bはフェニル、インダゾリル、テトラヒドロイソキノリニル、2,3-ジヒドロインドリル、ベンゾキサゾロニル、またはピラゾロピリジニルである、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記環Bはフェニルである、請求項4に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記環Cはシクロプロピルまたはピロリジニルであり、シクロプロピルまたはピロリジニルは、0-5の前記R7で置換される、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 少なくとも1つの前記R7は、メチル、エチル、イソプロピル、またはシクロプロピルである、請求項6に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記環Cは、0-2の前記R7で置換されたシクロプロピルである、請求項7に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記環Cは、1個の前記R7で置換されたシクロプロピルであり、前記R7はメチルである、請求項8に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記環Cは、0個の前記R7で置換されたシクロプロピルである、請求項8に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記R3と前記R4はそれぞれ、H、メチル、エチル、またはシクロプロピルメチルである、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記R3と前記R4はそれぞれメチルである、請求項11に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記R5 は、-C(O)NR1R2、-OH、ハロ、または(C1-C6)アルキルである、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記R6 は、ハロ、メチル、メトキシ、またはシクロプロピルである、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記nは0である、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 前記R8はHである、請求項2に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 以下からなる群から選択された、請求項1に記載の化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩。
- 請求項1~17のいずれか1つの化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩、および薬学的に許容可能な担体、希釈剤、あるいは賦形剤を含む、医薬組成物。
- 疼痛を処置するための薬剤の製造における、請求項1~17のいずれか1つの化合物、または、その薬学的に許容可能な水和物、溶媒和物、同位体、あるいは塩の使用。
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WO2019195634A1 (en) | 2019-10-10 |
CA3096059A1 (en) | 2019-10-10 |
US11352316B2 (en) | 2022-06-07 |
CN112867705A (zh) | 2021-05-28 |
US20210163402A1 (en) | 2021-06-03 |
AU2019247842B2 (en) | 2023-08-31 |
US20210147343A1 (en) | 2021-05-20 |
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