JP2018530571A - ヒストン脱アセチル化酵素6阻害剤としてのオキサジアゾールアミン誘導体化合物及びこれを含有する薬剤学的組成物 - Google Patents
ヒストン脱アセチル化酵素6阻害剤としてのオキサジアゾールアミン誘導体化合物及びこれを含有する薬剤学的組成物 Download PDFInfo
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- JP2018530571A JP2018530571A JP2018518487A JP2018518487A JP2018530571A JP 2018530571 A JP2018530571 A JP 2018530571A JP 2018518487 A JP2018518487 A JP 2018518487A JP 2018518487 A JP2018518487 A JP 2018518487A JP 2018530571 A JP2018530571 A JP 2018530571A
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- Prior art keywords
- amine
- oxadiazol
- pyrimidin
- cyclobutyl
- difluoromethyl
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- -1 Oxadiazoleamine derivative compound Chemical class 0.000 title claims description 41
- 229940122617 Histone deacetylase 6 inhibitor Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 407
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 108010023925 Histone Deacetylase 6 Proteins 0.000 claims abstract description 36
- 201000010099 disease Diseases 0.000 claims abstract description 35
- 230000003287 optical effect Effects 0.000 claims abstract description 27
- 230000000694 effects Effects 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 208000012902 Nervous system disease Diseases 0.000 claims abstract description 6
- 208000025966 Neurological disease Diseases 0.000 claims abstract description 6
- 208000035475 disorder Diseases 0.000 claims abstract description 6
- 230000002265 prevention Effects 0.000 claims abstract description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 4
- 206010008805 Chromosomal abnormalities Diseases 0.000 claims abstract description 4
- 208000031404 Chromosome Aberrations Diseases 0.000 claims abstract description 4
- 208000035473 Communicable disease Diseases 0.000 claims abstract description 4
- 206010010356 Congenital anomaly Diseases 0.000 claims abstract description 4
- 230000003542 behavioural effect Effects 0.000 claims abstract description 4
- 230000002124 endocrine Effects 0.000 claims abstract description 4
- 230000036244 malformation Effects 0.000 claims abstract description 4
- 230000003340 mental effect Effects 0.000 claims abstract description 4
- 208000030159 metabolic disease Diseases 0.000 claims abstract description 4
- 235000016709 nutrition Nutrition 0.000 claims abstract description 4
- 208000030212 nutrition disease Diseases 0.000 claims abstract description 4
- 208000029027 Musculoskeletal and connective tissue disease Diseases 0.000 claims abstract description 3
- 208000019498 Skin and subcutaneous tissue disease Diseases 0.000 claims abstract description 3
- 208000017520 skin disease Diseases 0.000 claims abstract description 3
- 102000011427 Histone Deacetylase 6 Human genes 0.000 claims abstract 8
- 239000000126 substance Substances 0.000 claims description 46
- 102000003964 Histone deacetylase Human genes 0.000 claims description 23
- 108090000353 Histone deacetylase Proteins 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 229930192474 thiophene Natural products 0.000 claims description 6
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- NZUUXQSBKZPFKK-UHFFFAOYSA-N 4-piperazin-1-ylmorpholine Chemical compound C1CNCCN1N1CCOCC1 NZUUXQSBKZPFKK-UHFFFAOYSA-N 0.000 claims description 4
- IWLBNXJONYNAEW-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-(1-phenylcyclobutyl)pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC=CC=C1)F IWLBNXJONYNAEW-UHFFFAOYSA-N 0.000 claims description 4
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- HNEATXXHHGDQQF-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(3-fluorophenyl)cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC(=CC=C1)F)F HNEATXXHHGDQQF-UHFFFAOYSA-N 0.000 claims description 4
- NYWYVJDCLKGRIO-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(3-methoxyphenyl)cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC(=CC=C1)OC)F NYWYVJDCLKGRIO-UHFFFAOYSA-N 0.000 claims description 4
- 108010033040 Histones Proteins 0.000 claims description 4
- KQAYHVMWQWFKFV-UHFFFAOYSA-N N-[1-(2-chlorophenyl)cyclobutyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC1=C(C=CC=C1)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F KQAYHVMWQWFKFV-UHFFFAOYSA-N 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
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- OHUXVGIHPZKNEF-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-(1-phenylcyclopentyl)pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCCC1)C1=CC=CC=C1)F OHUXVGIHPZKNEF-UHFFFAOYSA-N 0.000 claims description 3
- IRFXHUXQYBARTM-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-(1-phenylcyclopropyl)pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC=CC=C1)F IRFXHUXQYBARTM-UHFFFAOYSA-N 0.000 claims description 3
- URIYDONQDHNSLI-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(3,4-difluorophenyl)cyclopropyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC(=C(C=C1)F)F)F URIYDONQDHNSLI-UHFFFAOYSA-N 0.000 claims description 3
- XWIRZMLXWLSWLU-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(4-fluorophenyl)cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC=C(C=C1)F)F XWIRZMLXWLSWLU-UHFFFAOYSA-N 0.000 claims description 3
- IBSOZXONCGPOID-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(4-methoxyphenyl)cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC=C(C=C1)OC)F IBSOZXONCGPOID-UHFFFAOYSA-N 0.000 claims description 3
- OMTYOKNFBKZRCX-UHFFFAOYSA-N 3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]cyclobutyl]phenol Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C=1C=C(C=CC=1)O)F OMTYOKNFBKZRCX-UHFFFAOYSA-N 0.000 claims description 2
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- YPLIKXPJWPAMHH-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(2-fluorophenyl)cyclopropyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=C(C=CC=C1)F)F YPLIKXPJWPAMHH-UHFFFAOYSA-N 0.000 claims description 2
- ITTIVAGNYVVBML-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(2-methylphenyl)cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=C(C=CC=C1)C)F ITTIVAGNYVVBML-UHFFFAOYSA-N 0.000 claims description 2
- TWHOWWKLLANQQY-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(3,5-difluorophenyl)cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC(=CC(=C1)F)F)F TWHOWWKLLANQQY-UHFFFAOYSA-N 0.000 claims description 2
- HCTAUPUREYXKFK-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(3-fluorophenyl)cyclopropyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC(=CC=C1)F)F HCTAUPUREYXKFK-UHFFFAOYSA-N 0.000 claims description 2
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- RQQKXOMZYCDEAI-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-[3-(trifluoromethyl)phenyl]cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC(=CC=C1)C(F)(F)F)F RQQKXOMZYCDEAI-UHFFFAOYSA-N 0.000 claims description 2
- JUEKLLPPPOBEDZ-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC(=CC=C1)C(F)(F)F)F JUEKLLPPPOBEDZ-UHFFFAOYSA-N 0.000 claims description 2
- FASUTFGXOCYZBQ-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-[4-(trifluoromethyl)phenyl]cyclopropyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC=C(C=C1)C(F)(F)F)F FASUTFGXOCYZBQ-UHFFFAOYSA-N 0.000 claims description 2
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- UJBRSDCZMCQVNW-UHFFFAOYSA-N 5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-[4-(trifluoromethyl)phenyl]cyclopropyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC=C(C=C1)C(F)(F)F)(F)F UJBRSDCZMCQVNW-UHFFFAOYSA-N 0.000 claims description 2
- MFIHEGPDEQFOMI-UHFFFAOYSA-N N-(1-phenylcyclohexyl)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound C1(=CC=CC=C1)C1(CCCCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F MFIHEGPDEQFOMI-UHFFFAOYSA-N 0.000 claims description 2
- DLEMEQJHPARSIQ-UHFFFAOYSA-N N-(1-phenylcyclopentyl)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound C1(=CC=CC=C1)C1(CCCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F DLEMEQJHPARSIQ-UHFFFAOYSA-N 0.000 claims description 2
- WVPNPRFAWODGFM-UHFFFAOYSA-N N-(1-phenylcyclopropyl)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound C1(=CC=CC=C1)C1(CC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F WVPNPRFAWODGFM-UHFFFAOYSA-N 0.000 claims description 2
- RHMGLHIELWVWNJ-UHFFFAOYSA-N N-(1-pyridin-2-ylcyclobutyl)-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound N1=C(C=CC=C1)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F RHMGLHIELWVWNJ-UHFFFAOYSA-N 0.000 claims description 2
- DILYZXMTJRVDOS-UHFFFAOYSA-N N-[1-(2-chlorophenyl)cyclobutyl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC1=C(C=CC=C1)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F DILYZXMTJRVDOS-UHFFFAOYSA-N 0.000 claims description 2
- VEXKDMWBSMXQDS-UHFFFAOYSA-N N-[1-(2-fluorophenyl)cyclobutyl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound FC1=C(C=CC=C1)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F VEXKDMWBSMXQDS-UHFFFAOYSA-N 0.000 claims description 2
- DYDSYHHBSABPIC-UHFFFAOYSA-N N-[1-(2-methylphenyl)cyclobutyl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound C1(=C(C=CC=C1)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F)C DYDSYHHBSABPIC-UHFFFAOYSA-N 0.000 claims description 2
- NFYGXZGDNBEESM-UHFFFAOYSA-N N-[1-(3,4-difluorophenyl)cyclopropyl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound FC=1C=C(C=CC=1F)C1(CC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F NFYGXZGDNBEESM-UHFFFAOYSA-N 0.000 claims description 2
- NWZNBJWNRCSQBE-UHFFFAOYSA-N N-[1-(3-chloro-4-fluorophenyl)cyclobutyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC=1C=C(C=CC=1F)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F NWZNBJWNRCSQBE-UHFFFAOYSA-N 0.000 claims description 2
- DHBILDQTSYOIEV-UHFFFAOYSA-N N-[1-(3-chloro-4-fluorophenyl)cyclobutyl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC=1C=C(C=CC=1F)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F DHBILDQTSYOIEV-UHFFFAOYSA-N 0.000 claims description 2
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- MTYSEJFZQATPIA-UHFFFAOYSA-N N-[1-(3,4-dichlorophenyl)cyclobutyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC=1C=C(C=CC=1Cl)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F MTYSEJFZQATPIA-UHFFFAOYSA-N 0.000 claims 1
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- QEOWLDIVBPNHRL-UHFFFAOYSA-N N-[1-(3-chloro-2-fluorophenyl)cyclobutyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC=1C(=C(C=CC=1)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F)F QEOWLDIVBPNHRL-UHFFFAOYSA-N 0.000 claims 1
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- PHSJJZPJMHPELO-UHFFFAOYSA-N N-[1-(4-chloro-2-fluorophenyl)cyclopropyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC1=CC(=C(C=C1)C1(CC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F)F PHSJJZPJMHPELO-UHFFFAOYSA-N 0.000 claims 1
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- SJXWGDHDJLRCIY-UHFFFAOYSA-N N-[1-(5-chloro-2-fluorophenyl)cyclobutyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC=1C=CC(=C(C=1)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F)F SJXWGDHDJLRCIY-UHFFFAOYSA-N 0.000 claims 1
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- WHLAXDUXKMECTM-UHFFFAOYSA-N oxadiazol-4-amine Chemical class NC1=CON=N1 WHLAXDUXKMECTM-UHFFFAOYSA-N 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- GGZDLAOKPXEJCP-UHFFFAOYSA-N phenyl piperidine-1-carboxylate Chemical compound C1CCCCN1C(=O)OC1=CC=CC=C1 GGZDLAOKPXEJCP-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
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Abstract
【選択図】なし
Description
前記目的を解決するために、本発明では、下記化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩を提供する:
R1は、−CF2H又は−CF3であり;
L1又はL2は、それぞれ独立して、−(C1−C2アルキル)−又は何でもなく(null);
Z1〜Z4は、それぞれ独立して、N又はCRZであり(ここで、Z1〜Z4は、3つ以上が同時にNではない)、RZは、−H、−F、−Cl、−Br、−I、又は−O(C1−C4アルキル)であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、RCは、−H、−(C1−C6アルキル)、−(C1−C4アルキル)−OH、−(C1−C4アルキル)−O−(C1−C4アルキル)、−C(=O)−(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)−アリール、−(C1−C4アルキル)−C(=O)−O(C1−C4アルキル)、−(C1−C4アルキル)−NRARB、−S(=O)2−(C1−C4アルキル)、アリール、−(C1−C4アルキル)−アリール、−(C2−C4アルケニル)−アリール、ヘテロアリール、−(C1−C4アルキル)−ヘテロアリール、−C(=O)−(C3−C7シクロアルキル)、−(C2−C6ヘテロシクロアルキル)、又は−(C1−C4アルキル)−C(=O)−(C2−C6ヘテロシクロアルキル)であり、ここで、−(C1−C6アルキル)、−(C1−C4アルキル)−OH、−(C1−C4アルキル)−O−(C1−C4アルキル)、−C(=O)−(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)−アリール、−(C1−C4アルキル)−C(=O)−O(C1−C4アルキル)、−(C1−C4アルキル)−NRARB、−S(=O)2−(C1−C4アルキル)、アリール、−(C1−C4アルキル)−アリール、(C2−C4アルケニル)−アリール、ヘテロアリール、−(C1−C4アルキル)−ヘテロアリール、−C(=O)−(C3−C7シクロアルキル)、−C2−C6ヘテロシクロアルキル、又は−(C1−C4アルキル)−C(=O)−(C2−C6ヘテロシクロアルキル)の一つ以上のHは、−Xで置換されていてもよく;
a及びbは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−SO2−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ヘテロシクロアルキル、ここで、ヘテロシクロアルキルは、置換されないか、C1−C4アルキル又はヘテロシクロアルキルで置換されていてもよく、
Y2は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、
Y3〜Y5は、それぞれ独立して、−CH−又は−N−であり,
c〜fは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、c及びeが共に0ではなく、d及びfが共に0ではない)、
RA及びRBは、それぞれ独立して、−H又は−(C1−C4アルキル)であり、ここで、−(C1−C4アルキル)の一つ以上のHは、−X又は−OHで置換されていてもよい。
R1は、−CF2H又は−CF3であり;
L1及びL2は、何でもなく(null);
Z1及びZ3は、Nであり;
Z2及びZ4は、CRZであり、RZは、−H、−F、−Cl、−Br、−I、又は−O(C1−C4アルキル)であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり、ここで、−C(=O)−O(C1−C4アルキル)−アリールの一つ以上のHは、−Xで置換されていてもよく;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ピペリジン、モルホリノ、ピペラジン、又はピロリジン、ここで、ピペリジン、モルホリノ、ピペラジン、又はピロリジンは置換されないか、C1−C4アルキルで置換されていてもよいく、又は
Y2は、−O−であり、
Y3及びY5は、−CH−であり、
Y4は、−N−であり、
c及びeは、それぞれ独立して、0、1、又は2であり(但し、c及びeが共に0ではない)、
d及びfは、それぞれ独立して、0、1、2、又は3の整数である(但し、d及びfが共に0ではない)。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない;好ましくは、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、好ましくは、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、ピペリジン(ここで、ピペリジンは、置換されないか、C1−C4アルキルで置換されていてもよい)、又は
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−CH2−、−CH2−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、
R7は、−H又は−(C1−C4アルキル)である。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−、−NH−、又は
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);及び
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、ピペリジン、(ここで、ピペリジンは、置換されないか、C1−C4アルキルで置換されていてもよい)、又は
R7は、−H又は−(C1−C4アルキル)である。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、a及びbによって形成される環は、3〜7員の飽和シクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);及び
X1及びX2は、それぞれ独立して、N又はCであり、ここで、X1及びX2は、同時にNではない。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、a及びbによって形成される環は、3〜7員の飽和シクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);及び
X3及びX4は、それぞれ独立して、S又はCであり、ここで、X3及びX4は、同時にS又は同時にCではない。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、a及びbによって形成される環は、3〜7員の飽和シクロアルキルである);及び
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもない(null)。
本発明は、化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩の製造方法を提供する。
本発明は、下記化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩を有効成分として含有する薬剤学的組成物を提供する。
化学式Iの化合物の具体的な製造方法は、下記の通りである。
[ステップ1]エチル2−((1−フェニルシクロプロピル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]2−((1−フェニルシクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]エチル2−((1−フェニルシクロブチル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]1−フェニルシクロペンタン−1−カルボニトリルの合成
[ステップ1]2−((1−フェニルシクロペンチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−フェニルシクロヘキサン−1−カルボニトリルの合成
[ステップ1]2−((1−フェニルシクロヘキシル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−メトキシフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(4−メトキシフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−メトキシフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(3−メトキシフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−フルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(3−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2−フルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−フルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(4−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2−クロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(3−クロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(4−クロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2−クロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(4−クロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(ピリジン−2−イル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(ピリジン−2−イル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(3−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(o−トリル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(o−トリル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(m−トリル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(m−トリル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(p−トリル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(p−トリル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]ベンジルビス(2−クロロエチル)カルバメートの合成
[ステップ1]化合物1678の合成
[ステップ1]2−(メチルチオ)ピリミジン−5−カルボン酸の合成
[ステップ1]N’−(2,2−ジフルオロアセチル)−2−((1−(4−フルオロフェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(4−フルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]N’−(2,2−ジフルオロアセチル)−2−((1−(3−フルオロフェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(3−フルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]エチル4−((1−(3−クロロ−4−フルオロフェニル)シクロプロピル)アミノ)ベンゾエートの合成
[ステップ1]2−((1−(3−クロロ−4−フルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−(トリフルオロメチル)フェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]エチル2−((1−(3−(トリフルオロメチル)フェニル)シクロプロピル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(3−(トリフルオロメチル)フェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(4−(トリフルオロメチル)フェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,4−ジフルオロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(3,4−ジフルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−クロロ−4−フルオロフェニル)シクロブタン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(3−クロロ−4−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,5−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(ベンゾ[d][1,3]ジオキソール−5−イル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,5−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(4−(トリフルオロメトキシ)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,4,5−トリフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,3−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,6−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,3−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2,3−ジクロロフェニル)シクロブチル)アミノ)−N’−(2,2−ジフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,4−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(3,4−ジクロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2,4−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2,4−ジクロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2,6−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(ピリジン−3−イル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−(2−クロロ−4−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(2−クロロ−4−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−(2−クロロ−5−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(2−クロロ−5−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−(5−クロロ−2−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(5−クロロ−2−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−(3−クロロ−2−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(3−クロロ−2−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−ブロモフェニル)シクロブタン−1−カルボニトリル
[ステップ1]N−シクロブチリデン−2−メチルプロパン−2−スルフィンアミドの合成
[ステップ1]1−(2,4−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2−(トリフルオロメトキシ)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−ベンジルシクロブタン−1−アミンヒドロクロリドの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(2−(トリフルオロメトキシ)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(2,4−ジフルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(4−ブロモフェニル)シクロブチル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]エチル2−((1−(4−(1−エチルピペリジン−4−イル)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]エチル2−((1−(4−(1−イソプロピルピペリジン−4−イル)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]2−メチル−N−(1−(チオフェン−3−イル)シクロブチル)プロパン−2−スルフィンアミドの合成
[ステップ1]1−(チオフェン−2−イル)シクロプロパン−1−アミンの合成
[ステップ1]1−(4−(ピペリジン−1−イル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(4−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(4−(トリフルオロメチル)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,4−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−(3−ブロモ−4−フルオロフェニル)アセトニトリルの合成
[ステップ1]1−(2−メトキシフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(3−メトキシフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(4−メトキシフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(3−クロロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(3−クロロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−クロロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(4−クロロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−クロロ−3−フルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(o−トリル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(4−クロロ−2−フルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(3,5−ジフルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(3,4−ジフルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(3−ブロモフェニル)シクロブタン−1−カルボキサミドの合成
[ステップ1]1−(2,4−ジフルオロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]t−ブチル(1−(4−モルホリノフェニル)シクロブチル)カルバメートの合成
<実験例1>HDAC酵素活性の阻害の検索(in vitro)
HDAC1及びHDAC6酵素活性の阻害実験により、本発明の化学式Iで表される化合物のHDAC6の選択性を確認すべく、既存の開発物質を対照群とし、比較実験を行った。
Claims (12)
- 下記化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
R1は、−CF2H又は−CF3であり;
L1又はL2は、それぞれ独立して、−(C1−C2アルキル)−又は何でもなく(null);
Z1〜Z4は、それぞれ独立して、N又はCRZであり(ここで、Z1〜Z4は、3つ以上が同時にNではない)、RZは、−H、−F、−Cl、−Br、−I、又は−O(C1−C4アルキル)であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、RCは、−H、−(C1−C6アルキル)、−(C1−C4アルキル)−OH、−(C1−C4アルキル)−O−(C1−C4アルキル)、−C(=O)−(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)−アリール、−(C1−C4アルキル)−C(=O)−O(C1−C4アルキル)、−(C1−C4アルキル)−NRARB、−S(=O)2−(C1−C4アルキル)、アリール、−(C1−C4アルキル)−アリール、−(C2−C4アルケニル)−アリール、ヘテロアリール、−(C1−C4アルキル)−ヘテロアリール、−C(=O)−(C3−C7シクロアルキル)、−(C2−C6ヘテロシクロアルキル)、又は−(C1−C4アルキル)−C(=O)−(C2−C6ヘテロシクロアルキル)であり、ここで、−(C1−C6アルキル)、−(C1−C4アルキル)−OH、−(C1−C4アルキル)−O−(C1−C4アルキル)、−C(=O)−(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)−アリール、−(C1−C4アルキル)−C(=O)−O(C1−C4アルキル)、−(C1−C4アルキル)−NRARB、−S(=O)2−(C1−C4アルキル)、アリール、−(C1−C4アルキル)−アリール、(C2−C4アルケニル)−アリール、ヘテロアリール、−(C1−C4アルキル)−ヘテロアリール、−C(=O)−(C3−C7シクロアルキル)、−C2−C6ヘテロシクロアルキル、又は−(C1−C4アルキル)−C(=O)−(C2−C6ヘテロシクロアルキル)の一つ以上のHは、−Xで置換されていてもよく;
a及びbは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−SO2−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ヘテロシクロアルキル(ここで、ヘテロシクロアルキルは、置換されないか、C1−C4アルキル又はヘテロシクロアルキルで置換されていてもよい)、
Y2は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、
Y3〜Y5は、それぞれ独立して、−CH−又は−N−であり,
c〜fは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、c及びeが共に0ではなく、d及びfが共に0ではない)、
RA及びRBは、それぞれ独立して、−H又は−(C1−C4アルキル)である(ここで、−(C1−C4アルキル)の一つ以上のHは、−X又は−OHで置換されていてもよい)。 - 前記化学式Iで表される化合物は、
R1は、−CF2H又は−CF3であり;
L1及びL2は、何でもなく(null);
Z1及びZ3は、Nであり;
Z2及びZ4は、CRZであり、RZは、−H、−F、−Cl、−Br、−I、又は−O(C1−C4アルキル)であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり(ここで、−C(=O)−O(C1−C4アルキル)−アリールの一つ以上のHは、−Xで置換されていてもよい);
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ピペリジン、モルホリノ、ピペラジン、又はピロリジン(ここで、ピペリジン、モルホリノ、ピペラジン、又はピロリジンは置換されないか、C1−C4アルキルで置換されていてもよい)、又は
Y2は、−O−であり、
Y3及びY5は、−CH−であり、
Y4は、−N−であり、
c及びeは、それぞれ独立して、0、1、又は2であり(但し、c及びeが共に0ではない)、
d及びfは、それぞれ独立して、0、1、2、又は3の整数である(但し、d及びfが共に0ではない)、
請求項1に記載の化学式 I で表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩。 - 前記化学式Iで表される化合物は、下記化学式IIで表される化合物である、請求項1に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、ピペリジン(ここで、ピペリジンは、置換されないか、C1−C4アルキルで置換されていてもよい)、又は
- 前記化学式IIで表される化合物は、
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−CH2−、−CH2−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、
R7は、−H又は−(C1−C4アルキル)である、
請求項3に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩。 - 前記化学式Iで表される化合物は、下記に記載の化合物のうちから選択されるいずれか一つである、請求項1に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロプロピル)ピリミジン−2−アミン;
N−(1−フェニルシクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロペンチル)ピリミジン−2−アミン;
N−(1−フェニルシクロペンチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロヘキシル)ピリミジン−2−アミン;
N−(1−フェニルシクロヘキシル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(4−メトキシフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(3−メトキシフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(3−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(4−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−2−イル)シクロブチル)ピリミジン−2−アミン;
N−(1−(ピリジン−2−イル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(o−トリル)シクロブチル)ピリミジン−2−アミン;
N−(1−(o−トリル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(m−トリル)シクロブチル)ピリミジン−2−アミン;
N−(1−(m−トリル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(p−トリル)シクロブチル)ピリミジン−2−アミン;
N−(1−(p−トリル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
ベンジル4−((5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−イル)アミノ)−4−フェニルピペリジン−1−カルボキシレート;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(4−フェニルピペリジン−4−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(4−フルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(3−フルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
3−(1−((5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−イル)アミノ)シクロブチル)フェノール;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,4−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(3,4−ジフルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,5−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(ベンゾ[d][1,3]ジオキソール−5−イル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,5−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメトキシ)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,4,5−トリフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,3−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,6−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2,3−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,3−ジクロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3,4−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3,4−ジクロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,4−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,4−ジクロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,6−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−3−イル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロ−5−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロ−5−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(5−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(5−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−(オキセタン−3−イル)ピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(トシルメチル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,4−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−(トリフルオロメトキシ)フェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−ベンジルシクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−(トリフルオロメトキシ)フェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,4−ジフルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−メチルピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−エチルピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−イソプロピルピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(チオフェン−3−イル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(チオフェン−2−イル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(ピペリジン−1−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,4−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロ−3−モルホリノフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−メトキシフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−メトキシフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−メトキシフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロ−3−フルオロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(o−トリル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(4−クロロ−2−フルオロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,5−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,4−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(1−(オキセタン−3−イル)ピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,4−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;及び
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−モルホリノフェニル)シクロブチル)ピリミジン−2−アミン。 - 前記化学式Iで表される化合物は、下記に記載の化合物のうちから選択されるいずれか一つである、請求項5に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロペンチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;及び
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−2−イル)シクロブチル)ピリミジン−2−アミン。 - 前記化学式Iで表される化合物は、下記に記載の化合物のうちから選択されるいずれか一つである、請求項6に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;及び
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−2−イル)シクロブチル)ピリミジン−2−アミン。 - 請求項1乃至請求項7のいずれか1項に記載の化合物、その光学異性体、又はその薬剤学的に許容可能な塩を有効成分として含有する薬剤学的組成物。
- 請求項1乃至請求項7のいずれか1項に記載の化合物、その光学異性体、又はその薬剤学的に許容可能な塩を有効成分として含有するヒストン脱アセチル化酵素6(Histone deacetylase 6、HDAC6)の活性と関連する疾患の予防又は治療のための薬剤学的組成物。
- ヒストン脱アセチル化酵素6の活性と関連する疾患は、感染性疾患;新生物(neoplasm);内分泌;栄養及び代謝疾患;精神及び行動障害;神経疾患;眼及び付属器疾患;循環器疾患;呼吸器疾患;消化器疾患;皮膚及び皮下組織の疾患;筋骨格系及び結合組織の疾患;及び先天奇形、変形及び染色体異常より選択されるいずれか一つ以上である、請求項9に記載のヒストン脱アセチル化酵素6の活性と関連する疾患の予防又は治療のための薬剤学的組成物。
- 請求項1乃至請求項7のいずれか1項に記載の化学式Iで表される化合物、又はその光学異性体、又は薬剤学的に許容可能なその塩の治療学的に有効な量を投与するステップを含む、ヒストン脱アセチル化酵素媒介疾患の治療方法。
- ヒストン脱アセチル化酵素媒介疾患の予防又は治療のための薬剤の製造における、請求項1乃至請求項7のいずれか1項に記載の化学式Iで表される化合物、又はその光学異性体、又は薬剤学的に許容可能なその塩の用途。
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MY196174A (en) | 2023-03-20 |
JP6697074B2 (ja) | 2020-05-20 |
HRP20230201T1 (hr) | 2023-03-31 |
PT3362445T (pt) | 2023-03-20 |
KR101839137B1 (ko) | 2018-03-26 |
NZ740809A (en) | 2019-04-26 |
ES2940413T3 (es) | 2023-05-08 |
DK3362445T3 (da) | 2023-02-27 |
PH12018500773A1 (en) | 2018-10-29 |
EP3362445A4 (en) | 2019-05-22 |
US10494355B2 (en) | 2019-12-03 |
CA3001666C (en) | 2021-03-30 |
US20180273495A1 (en) | 2018-09-27 |
CA3001666A1 (en) | 2017-04-20 |
FI3362445T3 (fi) | 2023-03-21 |
TW201716397A (zh) | 2017-05-16 |
BR112018007289A2 (pt) | 2018-10-23 |
AU2016338118A1 (en) | 2018-04-12 |
PH12018500773B1 (en) | 2018-10-29 |
CN108699048B (zh) | 2021-12-28 |
HUE061967T2 (hu) | 2023-09-28 |
AU2016338118B2 (en) | 2019-03-14 |
TWI694073B (zh) | 2020-05-21 |
WO2017065473A1 (en) | 2017-04-20 |
MX2018004447A (es) | 2018-08-01 |
CN108699048A (zh) | 2018-10-23 |
KR20170043091A (ko) | 2017-04-20 |
EP3362445A1 (en) | 2018-08-22 |
PL3362445T3 (pl) | 2023-08-07 |
RU2695133C1 (ru) | 2019-07-22 |
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