JP2021515045A - インドリジン系化合物、その製造方法及び用途 - Google Patents
インドリジン系化合物、その製造方法及び用途 Download PDFInfo
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- JP2021515045A JP2021515045A JP2020568587A JP2020568587A JP2021515045A JP 2021515045 A JP2021515045 A JP 2021515045A JP 2020568587 A JP2020568587 A JP 2020568587A JP 2020568587 A JP2020568587 A JP 2020568587A JP 2021515045 A JP2021515045 A JP 2021515045A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 37
- 125000003406 indolizinyl group Chemical class C=1(C=CN2C=CC=CC12)* 0.000 title 1
- -1 indolizine compound Chemical class 0.000 claims abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 102100038970 Histone-lysine N-methyltransferase EZH2 Human genes 0.000 claims abstract description 30
- 101000882127 Homo sapiens Histone-lysine N-methyltransferase EZH2 Proteins 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 16
- 101001028782 Homo sapiens Histone-lysine N-methyltransferase EZH1 Proteins 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 60
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 56
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 52
- 229910052736 halogen Inorganic materials 0.000 claims description 46
- 150000002367 halogens Chemical class 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 38
- 125000001424 substituent group Chemical group 0.000 claims description 37
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000005842 heteroatom Chemical group 0.000 claims description 26
- 229920006395 saturated elastomer Polymers 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 229910052717 sulfur Inorganic materials 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- PCPQWYHRMVULIX-UHFFFAOYSA-P [1-[2,3-dihydroxy-4-[4-(oxoazaniumylmethylidene)pyridin-1-yl]butyl]pyridin-4-ylidene]methyl-oxoazanium;dinitrate Chemical compound [O-][N+]([O-])=O.[O-][N+]([O-])=O.C1=CC(=C[NH+]=O)C=CN1CC(O)C(O)CN1C=CC(=C[NH+]=O)C=C1 PCPQWYHRMVULIX-UHFFFAOYSA-P 0.000 claims description 14
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 14
- 229910052698 phosphorus Inorganic materials 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 10
- 230000014509 gene expression Effects 0.000 claims description 9
- RZRJACCZWZTYJY-UHFFFAOYSA-N tert-butylsulfanyl n,n-dimethylcarbamodithioate Chemical compound CN(C)C(=S)SSC(C)(C)C RZRJACCZWZTYJY-UHFFFAOYSA-N 0.000 claims description 9
- 239000013078 crystal Substances 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 230000035772 mutation Effects 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 6
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- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 230000004663 cell proliferation Effects 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 229910052805 deuterium Inorganic materials 0.000 claims description 5
- 238000000338 in vitro Methods 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 210000004881 tumor cell Anatomy 0.000 claims description 5
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 4
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical group CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000005620 boronic acid group Chemical group 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 4
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 4
- 239000000969 carrier Substances 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 238000006519 Mcmurry reaction Methods 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 claims description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
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- 238000005481 NMR spectroscopy Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
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- 238000002360 preparation method Methods 0.000 description 9
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- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000004429 atom Chemical group 0.000 description 8
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
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- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000002952 polymeric resin Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical class OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000004055 small Interfering RNA Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000005033 thiopyranyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
R1は、
R1は、
Rxは、H、ハロゲン、トリフルオロメチル基及びジフルオロメチル基からなる群より選ばれ;
R3は、
R55は、H、R551C1−C4アルキル基、R551C3−C8シクロアルキル基、ハロゲン、−CN、−NRcRd、(R551C1−C4アルキル基)O−、R551C1−C4アルキルスルホニル基、
R4又はR5は、それぞれ独立して、H、
R2は、メチル基であり;
R3は、
(1)水素化ナトリウム、カリウム tert−ブトキシド、水酸化ナトリウム、水酸化カリウム、炭酸カリウム、炭酸セシウム及び炭酸ナトリウムからなる群より選ばれる一つ又は複数の組合せである塩基の存在下で、化合物aと化合物bの縮合反応により、化合物cを生成する工程と;
(2)四塩化チタン、チタン酸テトラエチル、チタン酸テトライソプロピル、三フッ化ホウ素、塩化銅及び三塩化アルミニウムからなる群より選ばれる一つ又は複数の組合せであるルイス酸の存在下で、化合物cと第二級アミンの脱水反応によりエナミン化合物dを生成する工程と;
(3)化合物dの加水分解により、化合物eを生成する工程と;
(4)化合物eとアミンfの縮合反応により、化合物I−1を生成する工程と、
[その中、R1、R2、R4、R5、R6、R6’、R7、R8とR9の定義は、前記の通りであり、かつRkは、C1−C4直鎖状又は分岐鎖状のアルキル基であり;丸Xは、置換されてもよい4−7員の飽和又は不飽和の複素環基であり、前記複素環基は、少なくとも一つのN原子を含み、その任意の置換基の定義は、前記Xの置換基の通りである。]
を含む。
(5)テトラヒドロフラン、2−メチルテトラヒドロフラン、1,4−ジオキサン、ジクロロメタン、クロロホルム、四塩化炭素及び酢酸エチルからなる群より選ばれる一つ又は複数の組合せである不活性溶媒において、三塩化チタン又は四塩化チタンと、リチウム、ナトリウム、マグネシウム、亜鉛、水素化アルミニウムリチウム及び亜鉛銅偶からなる群より選ばれる一つ又は複数の組合せである還元性試薬との存在下で、化合物cと対応するケトンのマクマリー反応により、化合物gを生成する工程と;
(6)化合物gの加水分解反応により、化合物hを生成する工程と;
(7)化合物gとアミンfの縮合反応により、化合物I−2を生成する工程と;
[その中、R1、R2、R4、R5、R6、R6’、R7、R8とR9の定義は、前記の通りであり、かつRkは、C1−C4直鎖状又は分岐鎖状のアルキル基であり;丸Yは、置換されてもよい飽和又は不飽和の4−7員の環状炭化水素基又は置換されてもよい4−7員の飽和又は不飽和の複素環基であり;その中、前記複素環基は、O、N、S及びPからなる群より選ばれる1−2個のヘテロ原子を含み、その任意の置換基の定義は、前記Xの置換基の通りである。]
を含む。
(1)上記の式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグと、
(2)薬理学的許容される担体と、
を含む、医薬組成物を提供する。
(a)EZH1/2変異、活性又は発現量に関連する疾患を予防又は治療する医薬の製造;
(b)EZH1/2及びその変異体の活性の体外非治療的阻害;及び/又は
(c)腫瘍細胞の増殖の体外非治療的阻害、
からなる群より選ばれる使用を提供する。
特に定義しない限り、ここで用いる全ての技術用語及び科学用語は、本発明が属する分野の当業者によって一般的に理解されるものと同じ意味を有する。
ここで用いるように、具体的に挙げられた数値と共に使用される場合、「約」という用語は、当該値が挙げられた値から1%以下だけ変動できることを意味する。例えば、ここで用いるように、「約100」という表現は、99と101との間の全ての値(例えば、99.1、99.2、99.3、99.4等)を含む。
標準化学用語の定義は、参考文献(包括Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols.A(2000)and B(2001),Plenum Press,New York)に見つかることができる。特に説明しない限り、質量分析、NMR、IR及びUV/VIS分光法及び薬理学的方法のような本分野の技術範囲内の通常な方法を採用する。特に具体的に定義しない限り、本明細書には、分析化学、有機合成化学並びに医薬及び医薬化学に関連する記載で用いる用語は、本分野で既知のものである。化学合成、化学分析、医薬製造、製剤と送達、及び患者に対する治療には、標準的技術を使用することができる。例えば、キットに対するメーカーの説明書に準じてもよく、本分野で周知の方式又は本発明の説明に従って反応を実施し、精製を行ってもよい。一般的に、本明細書に引用及び記載されるいくつかの要約的及び具体的な文献における記載に従って、本分野で熟知の通常の方法により上記技術及び方法を実施することができる。本明細書には、当業者により基及びその置換基を選択して、安定な構造部分及び化合物を提供することができる。
本願では、用語「ハロゲン」とは、フッ素、塩素、臭素又はヨウ素を意味する。
「ヒドロキシ基」とは、−OH基を意味する。
「ヒドロキシアルキル基」とは、ヒドロキシ(−OH)で置換される以下で定義されるようなアルキル基を意味する。
「カルボニル」とは、−C(=O)−イル基を意味する。
「ニトロ基」とは、−NO2を意味する。
「シアノ」とは、−CNを意味する。
「アミノ」とは、−NH2を意味する。
「置換されるアミノ」とは、モノアルキルアミノ基、ジアルキルアミノ基、アルカノイルアミノ基、アラルキルアミノ基、ヘテロアラルキルアミノ基のような、以下で定義されるようなアルキル基、アルキルカルボニル基、アラルキル基、ヘテロアラルキル基の1つ又は2つで置換されるアミノ基を意味する。
「カルボキシル基」とは、−COOHを意味する。
本願では、基又はその他の基の一部として、用語「アルケニル基」とは、炭素原子と水素原子のみからなり、少なくとも1つの二重結合を含み、例えば2から14個(好ましくは2から10個、より好ましくは2から6個)の炭素原子を有し、かつ単結合で分子の残りの部分と連結する直鎖状又は分岐鎖状の鎖状炭化水素基を意味し、例えばエテニル基、プロペニル基、アリル基、ブタン−1−エニル基、ブタン−2−エニル基、ペンタン−1−エニル基、ペンタン−1,4−ジエニル基等があるが、これらに限定されない。
本願では、用語「ヘテロアリールアルキル基」とは、上記で定義されるヘテロアリール基で置換される上記で定義されるアルキル基を意味する。
ここで用いるの用語「治療」及びその他の類似の同義語は、以下の意味を含む。
(i)哺乳動物、特に当該疾患又は病症に罹りやすいが、当該疾患又は病症と診断されていない哺乳動物に、疾患又は病症が現れることを予防する;
(ii)疾患又は病症を阻害し、即ち、その発達を抑制する;
(iii)疾患又は病症を緩和し、即ち、当該疾患又は病症の状態を解消する;又は、
(iv)当該疾患又は病症により引き起こされる症状を軽減する。
1.式Iで示されるインドリジン系化合物又はその薬理学的許容される塩を提供する。
2.EZH1/2変異に関連する疾患を予防及び治療するための構造的に新規な医薬組成物を提供する。
1、PRC2複合体(EZH2Y641F)に対する化合物の活性の測定:
検出方法:均一時間分解蛍光法(Homogeneous Time−Resolved Fluorescence、HTRF)
検出方法:酵素結合免疫吸着測定(Enzyme−linked immunosorbent assay,ELISA)
その結果は、表1に示した。
Claims (11)
- 式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグであって、
その中、
R1は、
からなる群より選ばれ;
R10は、H、ハロゲン、−NH2、−NO2、置換されてもよいC1−C6アルキル基及び置換されてもよいC1−C4アルコキシ基からなる群より選ばれ;
R2は、H、ハロゲン、シアノ基及び置換されてもよいC1−C6アルキル基からなる群より選ばれ;
R3は、
であり;
R6とR6’は、それぞれ独立して、H、メチル基、エチル基、プロピル基及びシクロプロピル基からなる群より選ばれ、かつR6とR6’の少なくとも一つは、Hであり;
Xは、置換されてもよい飽和又は不飽和の4−7員の環状炭化水素基又は置換されてもよい4−7員の飽和又は不飽和の複素環基であり、前記複素環基は、O、N、S及びPからなる群より選ばれるヘテロ原子を1−2個含み;
R4とR5は、それぞれ独立して、H、ハロゲン、−COOH、−CN、置換されてもよいC1−C6アルキル基、置換されてもよい6−16員のアリール基、置換されてもよい5−16員のヘテロアリール基、置換されてもよい4−8員の飽和又は不飽和のシクロアルキル基、置換されてもよい4−8員の飽和又は不飽和の複素環基、置換されてもよいC1−C6アルキルカルボニル基、置換されてもよい−C(O)O−(C1−C6アルキル基)、−C(O)(NRaRb)、ボロン酸基、置換されてもよいC2−C8アルケニル基、置換されてもよいC2−C8アルキニル基、置換されてもよいC1−C6アルキルスルホニル基、置換されてもよいC1−C6アルキルスルフィニル基及び置換されてもよいC1−C6アルキルスルファニル基からなる群より選ばれ;その中、前記ヘテロアリール基又は複素環基は、N、O、S、Pからなる群より選ばれるヘテロ原子を1−3個含み;その中、Ra、Rbは、それぞれ独立して、H、置換されてもよいC1−C6アルキル基、置換されてもよい3−8員のシクロアルキル基及び置換されてもよい4−8員の複素環基からなる群より選ばれ、或いは、RaとRbとNは、連結して置換されてもよい4−8員の複素環を形成し;その中、前記複素環は、N、O、S及びPからなる群より選ばれるヘテロ原子を1−3個含み;
R7は、H及び置換されてもよいC1−C6アルキル基からなる群より選ばれ;
R8とR9は、それぞれ独立して、水素、重水素及び置換されてもよいC1−C6アルキル基からなる群より選ばれ;
R2、R7、R8、R9、R10、RaとRbでいう「置換されてもよい」の置換基とは、H、ハロゲン、C1−C4アルキル基、C1−C4ハロアルキル基、ニトロ基、−OH、アミノ基、メトキシ基及びジメチルアミノ基からなる群より選ばれ一つ又は複数の置換基を有することを意味する
式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグ。 - R1は、
であり;
R10は、H、ハロゲン、−NH2、−NO2、置換されてもよいC1−C6アルキル基及び置換されてもよいC1−C4アルコキシ基からなる群より選ばれ;
R2は、H、ハロゲン、シアノ基及び置換されてもよいC1−C6アルキル基からなる群より選ばれ;好ましくは、R2は、置換されてもよいC1−C4アルキル基であり;さらに好ましくは、メチル基であり;
R3は、
であり;
R6とR6’は、それぞれ独立して、H、メチル基、エチル基、プロピル基及びシクロプロピル基からなる群より選ばれ、かつR6とR6’の少なくとも一つは、Hであり;
Xは、置換されてもよい飽和又は不飽和の4−7員の環状炭化水素基、又は置換されてもよい4−7員の飽和又は不飽和の複素環基であり;その中、前記複素環基は、O、N、S、Pからなる群より選ばれるヘテロ原子を1−2個含み;Xでいう置換基は、−OH、ハロゲン、tert−ブチルオキシカルボニル基、−NRsRt、1−3つのRxで置換されるC1−C4アルキル基、1−3つのRxで置換されるC1−C4アルコキシ基、1−3つのRxで置換されるC1−C4アルキルカルボニル基、1−3つのRxで置換されるC1−C4アルコキシカルボニル基及び1−3つのRxで置換されるC1−C4アルキルスルホニル基からなる群より選ばれ;それぞれのRxは、独立して、H、ハロゲン、メチルアミノ基、ジメチルアミノ基、アミノ基、−OH、メトキシ基及びエトキシ基からなる群より選ばれ;
RsとRtは、それぞれ独立して、H、C1−C4アルキル基、C1−C4ハロアルキル基、
からなる群より選ばれ;
R4とR5は、それぞれ独立して、H、ハロゲン、−COOH、−CN、置換されてもよいC1−C6アルキル基、置換されてもよい6−16員のアリール基、置換されてもよい5−16員のヘテロアリール基、置換されてもよい4−8員の飽和又は不飽和のシクロアルキル基、置換されてもよい4−8員の飽和又は不飽和の複素環基、置換されてもよいC1−C6アルキルカルボニル基、置換されてもよい−C(O)O−(C1−C6アルキル基)、−C(O)(NRaRb)、ボロン酸基、置換されてもよいC2−C8アルケニル基、置換されてもよいC2−C8アルキニル基、置換されてもよいC1−C6アルキルスルホニル基、置換されてもよいC1−C6アルキルスルフィニル基及び置換されてもよいC1−C6アルキルスルファニル基からなる群より選ばれ;前記ヘテロアリール基又は複素環基は、N、O、S、Pからなる群より選ばれるヘテロ原子を1−3個含み;かつR4とR5でいう置換基は、ハロゲン、−CN、R45(C1−C4アルキル基)、R45(C1−C4アルコキシ基)、R45(C1−C4アルカノイル基)、R45(C1−C4アルキル基)スルホニル基、R45(C3−C8シクロアルキル基)、R45(4−8員の複素環基)及び−NRcRdからなる群より選ばれ;前記複素環基は、N及びOからなる群より選ばれるヘテロ原子を1−2個含む複素環基であり;
それぞれのR45は、独立して、H、−OH、ハロゲン、tert−ブチルオキシカルボニル基、ハロC1−C4アルキル基、C1−C4アルキル基、C1−C4アルコキシ基、C1−C4アシル基、ジメチルアミン基、メチルアミノ基、ジエチルアミン基、メチルエチルアミノ基、エチルアミン基、
からなる群より選ばれ;R451は、H、C1−C4アルキル基からなる群より選ばれ;その中、Ra、Rbは、それぞれ独立して、H、置換されてもよいC1−C6アルキル基、置換されてもよい3−8員のシクロアルキル基及び置換されてもよい4−8員の複素環基からなる群より選ばれ、或いはRaとRbとNは、連結して置換されてもよい4−8員の複素環を形成し;その中、前記複素環は、N、O、S及びPからなる群より選ばれるヘテロ原子を1−3個含み;
RcとRdは、それぞれ独立して、H、C1−C4アルキル基、C1−C4ハロアルキル基、
からなる群より選ばれ;
R7は、H及び置換されてもよいC1−C6アルキル基からなる群より選ばれ;
R8とR9は、それぞれ独立して、水素、重水素及び置換されてもよいC1−C6アルキル基からなる群より選ばれ;
R2、R7、R8、R9、R10、RaとRbでいう「置換される」の置換基とは、H、ハロゲン、C1−C4アルキル基、C1−C4ハロアルキル基、ニトロ基、−OH、アミノ基、メトキシ基及びジメチルアミノ基からなる群より選ばれ一つ又は複数の置換基を有することを意味する、
ことを特徴とする、請求項1に記載の式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグ。 - R3は、
からなる群より選ばれ;
その中、Rhは、H、1−3つのRxで置換されるC1−C4アルキル基、1−3つのRxで置換されるC1−C4アルキルカルボニル基、1−3つのRxで置換されるC1−C4アルコキシカルボニル基、1−3つのRxで置換されるC1−C4アルキルスルホニル基及びtert−ブチルオキシカルボニル基からなる群より選ばれ;
Rjは、−OH、ハロゲン、1−3つのRxで置換されるC1−C4アルキル基、 1−3つのRxで置換されるC1−C4アルコキシ基及び−NRsRtからなる群より選ばれ;
Rxは、H、ハロゲン及び−OHからなる群より選ばれ;
RsとRtは、それぞれ独立して、H、C1−C4アルキル基、C1−C4ハロアルキル基、
からなる群より選ばれ;
R6とR6’は、それぞれ独立して、H、メチル基及びエチル基からなる群より選ばれ、かつR6とR6’の少なくとも一つは、Hであり;
より好ましくは、R3は、
からなる群より選ばれ;
その中、Rhは、H及びRx(C1−C3アルキル基)からなる群より選ばれ;
Rjは、−OH、ハロゲン、Rx(C1−C3アルキル基)、Rx(C1−C3アルコキシ基)及び−N(C1−C3アルキル基)2からなる群より選ばれ;
Rxは、H、ハロゲン、トリフルオロメチル基及びジフルオロメチル基からなる群より選ばれ;
R6とR6’は、それぞれ独立して、H、メチル基及びエチル基からなる群より選ばれ、かつR6とR6’の少なくとも一つは、Hであり;
最も好ましくは、
R3は、
からなる群より選ばれ;
Rhは、フッ素で置換されるC1−C3アルキル基からなる群より選ばれ;
R6とR6’は、それぞれ独立して、H及びメチル基からなる群より選ばれ、かつR6とR6’の少なくとも一つは、Hである、
ことを特徴とする、請求項1に記載の式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグ。 - R4又はR5は、それぞれ独立して、H、R55C1−C4アルキル基、−CN、ハロゲン、R55C1−C4アルキルカルボニル基、R55(C1−C4アルコキシ基)カルボニル基、−COOH、−C(O)(NRaRb)、
及びR55C1−C3アルキニル基からなる群より選ばれ;
nは、R55置換基の数であり、1、2及び3からなる群より選ばれ;
R55は、H、R551C1−C4アルキル基、R551C3−C8シクロアルキル基、ハロゲン、−CN、−NRcRd、(R551C1−C4アルキル基)O−、R551C1−C4アルキルスルホニル基、
R551(C1−C6)アルキル基OC(O)−、−COOH及び−C(O)(NRaRb)からなる群より選ばれ;その中、R551は、H、−OH、ハロゲン、ハロC1−C4アルキル基、C1−C4アルキル基、C1−C4アルコキシ基、アミノ基、ジメチルアミン基、メチルアミノ基、ジエチルアミン基、メチルエチルアミノ基、エチルアミン基、
であり;
Ra、Rbは、それぞれ独立して、H、C1−C4アルキル基、Rb’’(C1−C4)アルキル基、フェニル基、ハロフェニル基、及びRb’で置換される複素環基からなる群より選ばれ;或いはRaとRbと連結するNは、一緒にしてRb’で置換される4−8員の複素環基を形成し、前記複素環基は、N及びOからなる群より選ばれるヘテロ原子を1−2個含み;
Rb’’は、H、−OH、C1−C3アルコキシ基、ジメチルアミン基、
からなる群より選ばれ;
Rb’は、H、C1−C4アルキル基、tert−ブチルオキシカルボニル基及びC1−C4アルカノイル基からなる群より選ばれ;
より好ましくは、
R4又はR5は、それぞれ独立して、H、
からなる群より選ばれ;
nは、R55置換基の数であり、1及び2からなる群より選ばれ;
R55は、H、C1−C4アルキル基、ハロゲン、−NH2、(C1−C2アルキル基)NH−及びジメチルアミン基からなる群より選ばれる、
ことを特徴とする、請求項1に記載の式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグ。 - R3は、
であり;
R6とR6’は、それぞれ独立して、H、メチル基、エチル基及びプロピル基からなる群より選ばれ、かつR6とR6’の少なくとも一つは、Hであり;
Xは、置換されてもよいピラニル基、置換されてもよいピペリジニル基、置換されてもよいピペラジニル基及び置換されてもよいモルホリニル基からなる群より選ばれ、かつXでいう置換基は、C1−C4アルキル基及びハロC1−C4アルキル基からなる群より選ばれ;より好ましくは、Xでいう置換基は、トリフルオロエチルであり;
R2は、メチル基であり;
R10は、未置換又はハロゲン置換のC1−C4アルキル基及び未置換又はハロゲン置換のC1−C4アルコキシ基からなる群より選ばれ;
R4、R5は、それぞれ独立して、H、置換されてもよいピリジル基、置換されてもよいピリミジニル基、置換されてもよいピリダジニル基、置換されてもよいピラジル基、置換されてもよいトリアゾリル基及び置換されてもよいピロロピリジル基からなる群より選ばれ;
R4とR5でいう置換基は、H、C1−C4アルキル基、ハロゲン及び−NRcRdからなる群より選ばれ;
RcとRdは、それぞれ独立して、H、C1−C4アルキル基及びハロC1−C4アルキル基からなる群より選ばれる、
ことを特徴とする、請求項1に記載の式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグ。 - R2は、メチル基であり;
R3は、
であり;R6とR6’は、それぞれ独立して、H又はメチル基からなる群より選ばれ、かつR6とR6’の少なくとも一つは、Hであり;
Xは、モルホリニル基、トリフルオロエチルピペラジニル基及びトリフルオロエチルピペリジニル基からなる群より選ばれ;さらに好ましくは、モルホリニル基、2,2,2−トリフルオロエチルピペラジニル基又は2,2,2−トリフルオロエチルピペリジニル基であり;
R4とR5は、独立して、H、ジメチルアミノピリジン及びメチルアミノピリジンからなる群より選ばれ;さらに好ましくは、H、2−ジメチルアミノピリジン又は2−メチルアミノピリジンであり;
R7、R8とR9は、水素であり;
R10は、メトキシ基である、
ことを特徴とする、請求項1に記載の式Iで示されるインドリジン系化合物、その薬理学的許容される塩、エナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグ。 - 上記の式Iで示されるインドリジン系化合物又はその薬理学的許容される塩の製造方法であって、以下の方法のいずれかを含み、即ち、
方法一:
(1)塩基の存在下で、化合物aと化合物bの縮合反応により、化合物cを生成する工程と;
(2)ルイス酸の存在下で、化合物cと第二級アミンの脱水反応によりエナミン化合物dを生成する工程と;
(3)化合物dの加水分解により、化合物eを生成する工程と;
(4)化合物eとアミンfの縮合反応により、化合物I−1を生成する工程と、
[その中、R1、R2、R4、R5、R6、R6’、R7、R8とR9の定義は、請求項1に記載の通りであり、かつRkは、C1−C4直鎖状又は分岐鎖状のアルキル基であり;丸Xは、置換されてもよい4−7員の飽和又は不飽和の複素環基であり、前記複素環基は、少なくとも一つのN原子を含み、その任意の置換基の定義は、請求項1記載のXの置換基の通りである]
を含む方法一と、
方法二:
(5)不活性溶媒において、三塩化チタン又は四塩化チタンと、還元性試薬との存在下で、化合物cと対応するケトンのマクマリー反応により、化合物gを生成する工程と;
(6)化合物gの加水分解反応により、化合物hを生成する工程と;
(7)化合物gとアミンfの縮合反応により、化合物I−2を生成する工程と;
[その中、R1、R2、R4、R5、R6、R6’、R7、R8とR9の定義は、請求項1に記載の通りであり、かつRkは、C1−C4直鎖状又は分岐鎖状のアルキル基であり;丸Yは、であり置換されてもよい飽和又は不飽和の4−7員の環状炭化水素基又は置換されてもよい4−7員の飽和又は不飽和の複素環基であり;その中、前記複素環基は、O、N、S及びPからなる群より選ばれる1−2個のヘテロ原子を含み、その任意の置換基の定義は、請求項1記載のXの置換基の通りである]
を含む方法二と、
を含む上記の式Iで示されるインドリジン系化合物又はその薬理学的許容される塩の製造方法。 - (1)活性成分として、治療有効量の請求項1〜7のいずれか一項に記載のインドリジン系化合物、その薬理学的許容される塩、そのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグと、
(2)薬理学的許容される担体と、
を含む、ことを特徴とする医薬組成物。 - 請求項1〜7のいずれか一項に記載のインドリジン系化合物、その薬理学的許容される塩、そのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、結晶多型又はプロドラッグ、又は請求項9に記載の医薬組成物の使用であって、
(a)EZH1/2変異、活性又は発現量に関連する疾患を予防又は治療する医薬の製造;
(b)EZH2及びその変異体の活性の体外非治療的阻害;及び/又は
(c)腫瘍細胞の増殖の体外非治療的阻害、
からなる群より選ばれる使用。 - 前記EZH1/2変異、活性又は発現量に関連する疾患は、腫瘍、及び自己免疫性疾患からなる群より選ばれる、
ことを特徴とする請求項11に記載の用途。
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