KR20240115832A - 헌팅턴병을 치료하기 위한 htt 조절제 - Google Patents

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Publication number

KR20240115832A

KR20240115832A KR1020247019421A KR20247019421A KR20240115832A KR 20240115832 A KR20240115832 A KR 20240115832A KR 1020247019421 A KR1020247019421 A KR 1020247019421A KR 20247019421 A KR20247019421 A KR 20247019421A KR 20240115832 A KR20240115832 A KR 20240115832A

Authority

KR

South Korea

Prior art keywords

alkyl

mmol

methyl

heterocyclyl

optionally substituted

Prior art date

2021-11-17

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.)

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• 208000023105 Huntington disease Diseases 0.000 title claims abstract description 50
• 150000001875 compounds Chemical class 0.000 claims abstract description 234
• -1 cyano, hydroxy Chemical group 0.000 claims description 249
• 125000000217 alkyl group Chemical group 0.000 claims description 126
• 239000000203 mixture Substances 0.000 claims description 112
• 238000000034 method Methods 0.000 claims description 97
• 125000000623 heterocyclic group Chemical group 0.000 claims description 82
• 229910052739 hydrogen Inorganic materials 0.000 claims description 61
• 239000001257 hydrogen Substances 0.000 claims description 61
• 125000003118 aryl group Chemical group 0.000 claims description 57
• 125000001072 heteroaryl group Chemical group 0.000 claims description 53
• 150000003839 salts Chemical class 0.000 claims description 49
• 125000003545 alkoxy group Chemical group 0.000 claims description 41
• 229940002612 prodrug Drugs 0.000 claims description 41
• 239000000651 prodrug Substances 0.000 claims description 41
• 125000005843 halogen group Chemical group 0.000 claims description 37
• 125000004432 carbon atom Chemical group C* 0.000 claims description 36
• 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 32
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
• 239000008194 pharmaceutical composition Substances 0.000 claims description 30
• 125000005842 heteroatom Chemical group 0.000 claims description 28
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• 239000013543 active substance Substances 0.000 claims description 15
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 15
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 15
• 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 14
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 125000001424 substituent group Chemical group 0.000 claims description 11
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 11
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 9
• 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 8
• 125000002947 alkylene group Chemical group 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical group [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 10
• 238000011282 treatment Methods 0.000 abstract description 23
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 219
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• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 137
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 84
• 239000011541 reaction mixture Substances 0.000 description 72
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 71
• 238000006243 chemical reaction Methods 0.000 description 68
• 235000019439 ethyl acetate Nutrition 0.000 description 68
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 57
• 238000005481 NMR spectroscopy Methods 0.000 description 56
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 50
• 239000002904 solvent Substances 0.000 description 47
• 201000010099 disease Diseases 0.000 description 44
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 42
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• 108090000623 proteins and genes Proteins 0.000 description 38
• 238000002953 preparative HPLC Methods 0.000 description 37
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 37
• 239000000243 solution Substances 0.000 description 36
• 102000004169 proteins and genes Human genes 0.000 description 33
• 238000005160 1H NMR spectroscopy Methods 0.000 description 32
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• 230000002829 reductive effect Effects 0.000 description 32
• 230000004770 neurodegeneration Effects 0.000 description 30
• 239000000047 product Substances 0.000 description 30
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 27
• 125000003342 alkenyl group Chemical group 0.000 description 26
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
• 125000000304 alkynyl group Chemical group 0.000 description 23
• IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 23
• 239000002253 acid Substances 0.000 description 22
• 125000004404 heteroalkyl group Chemical group 0.000 description 22
• 125000001188 haloalkyl group Chemical group 0.000 description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
• 238000004587 chromatography analysis Methods 0.000 description 20
• 208000015122 neurodegenerative disease Diseases 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 238000000746 purification Methods 0.000 description 20
• 239000000377 silicon dioxide Substances 0.000 description 19
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 18
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 18
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
• 238000004808 supercritical fluid chromatography Methods 0.000 description 18
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 17
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
• 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 16
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
• 239000012074 organic phase Substances 0.000 description 15
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
• 150000001412 amines Chemical class 0.000 description 14
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
• 230000002209 hydrophobic effect Effects 0.000 description 14
• 210000002569 neuron Anatomy 0.000 description 14
• MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 13
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
• 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 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 11
• 229910000024 caesium carbonate Inorganic materials 0.000 description 11
• 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 11
• 208000024891 symptom Diseases 0.000 description 11
• 229910021529 ammonia Inorganic materials 0.000 description 10
• 150000001721 carbon Chemical group 0.000 description 10
• 125000004122 cyclic group Chemical group 0.000 description 10
• 238000001914 filtration Methods 0.000 description 10
• 229910000027 potassium carbonate Inorganic materials 0.000 description 10
• 239000000741 silica gel Substances 0.000 description 10
• 229910002027 silica gel Inorganic materials 0.000 description 10
• 239000007787 solid Substances 0.000 description 10
• 239000007858 starting material Substances 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
• 239000003153 chemical reaction reagent Substances 0.000 description 9
• 229910052805 deuterium Inorganic materials 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• 210000004227 basal ganglia Anatomy 0.000 description 8
• 125000003636 chemical group Chemical group 0.000 description 8
• 239000012043 crude product Substances 0.000 description 8
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• 238000001727 in vivo Methods 0.000 description 8
• 239000000463 material Substances 0.000 description 8
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• NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 8
• 238000006467 substitution reaction Methods 0.000 description 8
• 208000024827 Alzheimer disease Diseases 0.000 description 7
• 229920000858 Cyclodextrin Polymers 0.000 description 7
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
• 125000003710 aryl alkyl group Chemical group 0.000 description 7
• 210000004556 brain Anatomy 0.000 description 7
• 210000004027 cell Anatomy 0.000 description 7
• 239000003795 chemical substances by application 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
• 125000003107 substituted aryl group Chemical group 0.000 description 7
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• RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 6
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 6
• DLNWXJAMQKZKDZ-UHFFFAOYSA-N 5-chloro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)pyrazine-2-carboxamide Chemical compound CC1=CN(C=C(C=C2F)NC(C(C=N3)=NC=C3Cl)=O)C2=N1 DLNWXJAMQKZKDZ-UHFFFAOYSA-N 0.000 description 6
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
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• 238000003556 assay Methods 0.000 description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
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• 150000002367 halogens Chemical class 0.000 description 6
• LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 6
• 201000006417 multiple sclerosis Diseases 0.000 description 6
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
• 210000001577 neostriatum Anatomy 0.000 description 6
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• 229910000104 sodium hydride Inorganic materials 0.000 description 6
• 239000000126 substance Substances 0.000 description 6
• 125000000547 substituted alkyl group Chemical group 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
• 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 description 5
• 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 description 5
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• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
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• 125000005017 substituted alkenyl group Chemical group 0.000 description 5
• GZNAASVAJNXPPW-UHFFFAOYSA-M tin(4+) chloride dihydrate Chemical compound O.O.[Cl-].[Sn+4] GZNAASVAJNXPPW-UHFFFAOYSA-M 0.000 description 5
• FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 5
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• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
• OIJDAJASYWQSPS-UHFFFAOYSA-N 5-nitro-1H-indazol-6-ol Chemical compound Oc1cc2[nH]ncc2cc1[N+]([O-])=O OIJDAJASYWQSPS-UHFFFAOYSA-N 0.000 description 4
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• 125000006413 ring segment Chemical group 0.000 description 4
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