JP2020534317A - チエノジアゼピン誘導体とその応用 - Google Patents
チエノジアゼピン誘導体とその応用 Download PDFInfo
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- JP2020534317A JP2020534317A JP2020516591A JP2020516591A JP2020534317A JP 2020534317 A JP2020534317 A JP 2020534317A JP 2020516591 A JP2020516591 A JP 2020516591A JP 2020516591 A JP2020516591 A JP 2020516591A JP 2020534317 A JP2020534317 A JP 2020534317A
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- CCDMBTCSHSROMD-UHFFFAOYSA-N 7h-thieno[3,2-c]diazepine Chemical class C1=CN=NC2=CCSC2=C1 CCDMBTCSHSROMD-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 283
- 150000003839 salts Chemical class 0.000 claims abstract description 47
- 239000003814 drug Substances 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims description 181
- -1 2-oxaspiro [3.4] octyl Chemical group 0.000 claims description 80
- 229910052794 bromium Inorganic materials 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 229910052740 iodine Inorganic materials 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 6
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 5
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940125763 bromodomain inhibitor Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- YPWFNLSXQIGJCK-UHFFFAOYSA-N 7-oxabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1O2 YPWFNLSXQIGJCK-UHFFFAOYSA-N 0.000 claims description 2
- 230000003213 activating effect Effects 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical group O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical group O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 claims description 2
- 238000010276 construction Methods 0.000 claims 4
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims 1
- JDDQECMBPWVIRU-UHFFFAOYSA-N 4-azaspiro[2.4]heptane Chemical compound C1CC11NCCC1 JDDQECMBPWVIRU-UHFFFAOYSA-N 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940127557 pharmaceutical product Drugs 0.000 claims 1
- 102000001805 Bromodomains Human genes 0.000 abstract description 10
- 108050009021 Bromodomains Proteins 0.000 abstract description 10
- 239000000126 substance Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 245
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- 206010028980 Neoplasm Diseases 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 238000000746 purification Methods 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- YQYBUJYBXOVWQW-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3,4-dihydro-1H-isoquinolin-2-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1CC2=CC=CC=C2CC1 YQYBUJYBXOVWQW-UHFFFAOYSA-N 0.000 description 27
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- 239000008346 aqueous phase Substances 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 23
- 239000007821 HATU Substances 0.000 description 22
- 238000004809 thin layer chromatography Methods 0.000 description 22
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- 238000012360 testing method Methods 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 239000000460 chlorine Substances 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 239000005909 Kieselgur Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 12
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 229910052717 sulfur Inorganic materials 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 11
- 125000004429 atom Chemical group 0.000 description 11
- 239000001257 hydrogen Substances 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 0 CC(C)(C)OC(NC(C=CN12)=CC1=NC=C(*)C2=O)=O Chemical compound CC(C)(C)OC(NC(C=CN12)=CC1=NC=C(*)C2=O)=O 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 10
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 10
- 230000004614 tumor growth Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
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- 125000000623 heterocyclic group Chemical group 0.000 description 9
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- 239000002904 solvent Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 150000002430 hydrocarbons Chemical group 0.000 description 8
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- 238000005259 measurement Methods 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 125000004434 sulfur atom Chemical group 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
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- 125000003342 alkenyl group Chemical group 0.000 description 3
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- 238000010171 animal model Methods 0.000 description 3
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 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 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 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
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 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
- 229910052722 tritium Inorganic materials 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
- 230000001875 tumorinhibitory effect Effects 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本発明は、チエノジアゼピン誘導体、及びBET Bromodomain抑制剤に関連の疾患を治療するための医薬品の製造への応用に関する。特に、本発明は、式(I)、式(II)で表される化合物及びその薬学的に許容可能な塩に関する。
ヒストンリジンのアセチル化の識別は、ヒストンのアセチル化が関与したエピジェネティクスの調節においえ、重要なステップである。アセチル化したヒストンリジンがブロモドメイン(bromodomains, BRD)ドメインによって特異的に識別されることによって、クロマチン調節因子を特定の領域に動員し、遺伝子発現調節を調整することができる。そのうち、ブロモドメイン−アンド−エクストラターミナル(bromodomain and extra−terminal(BET))タンパク質ファミリーに作用するBRDドメインは、主要な癌の遺伝子c−MYCおよび抗アポトーシスタンパク質の発現を調節することができる。BETタンパク質を標的とする特異的な抑制剤は、エピジェネティクスの制御メカニズムを標的とする抗癌剤と抗炎症剤の研究において、注目されている。BETメインファミリーには、BRD2、BRD3、BRD4およびBRDTからなるブロモドメイン(bromodomain)を持つ4つのタンパク質を含んでいる。
本発明は、式(I)と式(II)で表される化合物、その異性体又はその薬学的に許容可能な塩を提供する。
Tは、CH又はNから選択され、
R1は、1、2又は3個のR基で置換されてもよいC1−3アルキル基、C1−3アルコキシルから選択され、
R2、R3、R4は、それぞれ独立して、H、F、Cl、Br、I、OH、NH2、CNから選択され、又はそれぞれ独立して、1、2又は3個のR基で置換されてもよいC1−6アルキル基、C1−6ヘテロアルキル基から選択され、
R5は、Hから選択され、又は、1、2又は3個のR基で置換されてもよいC1−3アルキル基から選択され、
R6は、それぞれ独立して、H、F、Cl、Br、I、OH、NH2、CNから選択され、又は、それぞれ独立して、1、2又は3個のR基で置換されてもよいC1−6アルキル基、C1−6ヘテロアルキル基から選択され、或いは、同じ炭素原子に結合する2つのR6基は、結合した炭素原子と共に−C(=O)に形成し、
環Aは、C3−7シクロアルキル基、5〜12員のヘテロシクロアルキル基、5〜6員のヘテロアリール基から選択され、
環Bは、4〜7員のヘテロシクロアルキル基から選択され、
且つ構造
nは、0、1、2、3、4、5又は6から選択され、
Rは、それぞれ独立して、F、Cl、Br、I、OH、NH2、CNから選択され、又は、1、2又は3個のR’基で置換されてもよいC1−6アルキル基、C1−6ヘテロアルキル基から選択され、
R’は、それぞれ独立して、F、Cl、Br、I、OH、NH2、CN、Meから選択され、
「*」で付けた炭素原子は不斉炭素原子であり、(R)又は(S)の単一のエナンチオマー又は一つのエナンチオマーに富む形式であり、
上記C1−6ヘテロアルキル基、5〜12員のヘテロシクロアルキル基、5−6員のヘテロアリール基、4〜7員のヘテロシクロアルキル基における“ヘテロ”は、N、−O−、−S−、−NH−、−C(=O)NH−、−C(=O)−、−C(=O)O−、−S(=O)2−、−S(=O)−、−C(=O)S−から選択され、
上記ヘテロ原子又はヘテロ原子団の数は、それぞれ独立して、1、2、3又は4から選択される。
T1は、−S(=O)−、−S(=O)2−、−N(R6)−、−O−、−C(R6)(R6)−、
T2は、それぞれ独立して、−NH−、−O−、−S−から選択され、
R1〜R6は、前記と同じ意味であり、
「*」で付けた炭素原子は不斉炭素原子であり、(R)又は(S)の単一のエナンチオマー又は一つのエナンチオマーに富む形式である。
(定義と説明)
本発明において、特に明記しない限り、明細書で記載している用語や語句は、以下の意味を有する。特定の用語や語句は、特別な定義がなければ、不明確又は不明瞭と見なされるべきではなくて、通常の意味として理解すべきである。商品名が記載されている場合、対応する市販品又はその有効成分を指すものとして理解する。本明細書で使用される「薬学的に許容可能」という用語や語句は、健全な医学的判断の範囲内で、過度の毒性や刺激性がなくて、且つアレルギー反応及びその他の問題や合併症を起こさなくて、ヒト及び動物の組織と接触して使用するのに適した化合物、材料、組成物、及び/又は投薬形態の意味を指して、妥当な利点・欠点の比率の意味にも繋がる。
本発明の化合物は、顕著なBET Bromodomain抑制活性を有し、顕著な腫瘍抑制効果を有し、且つ動物に対して良好な耐性(tolerance)を示す。一方、本発明の化合物は、生体内で薬物動態クリアランスが低く、吸収が良好である。
以下は、実施例に基づいて本発明を詳細に説明するが、本発明に対して何らかの不利な制限を意図することがない。本文は本発明を詳しく説明して、その具体的な実施形態も公開しているが、当業者にとって、本発明の趣旨及び範囲を逸脱しない限り、本発明の具体的な実施形態に対して各種の変更及び改良を行うことは、自明である。
1H NMR (400 MHz, CDCl3) δppm 8.98 (br s, 1H), 7.46 (d, 8.4Hz, 2H), 7.35 (d, 8.4Hz, 2H), 4.80 (d, J=8.8Hz, 1H), 3.93 (d, J=8.6Hz, 1H), 2.28 (s, 3H), 1.59 (s, 3H).
実験準備:
1)BPS社のBRD4−BD1およびBRD4−BD2タンパク質、ANASPEC社のポリペプチド、PerkinElmer社のテスト試薬を用意した。
2)TR−FRET実験原理に従って、試験化合物をスクリーニングした。
3)関連の対照化合物
1)化合物プレートの準備:
Echoにて化合物プレートを準備:
Echoにて化合物を希釈し、3倍連続希釈で10個の濃度(20000、6666.67、2222.22、740.74、246.91、82.305、27.435、9.145、3.048、と1.016nM)を準備した。
関連する反応試薬は、実験当日に準備した。
a)1X assay bufferを用意し、
b)実験用の3X溶液を用意し、
1. 試薬を取り出して氷上に放置し、自然に融解した後、用意し、
2. 1X assay bufferで、実験用の「溶液 A」(タンパク質溶液)、「溶液B」(ポリペプチド溶液)、および「溶液 C」(テスト試薬溶液)を調製し、実験反応システムで各成分の3X溶液を調合した。溶液A、溶液B、溶液Cの量は、実験で必要な量に対して十分でなければならない。
実験プレートは、化合物を勾配濃度で、DMSO溶液を含み、実験前にECHOにて用意したプレートある。
a)実験プレートを取り出し、「溶液A」(タンパク質溶液)を5μL/ウェルで実験プレートの列2〜23に添加し、次に1X assay bufferを5μL/ウェルで実験プレートの列1、24に添加した。列1と24は、実験システムの最小コントロールとして使用された。
b)1000rpmでの遠心分離を30秒間行った。
c)プレートを23℃で20分間インキュベートした。
d)20分間のインキュベーション後、「溶液B」(ポリペプチド溶液)を5μL/ウェルで実験プレートの列1〜24に添加した。
e)1000rpmでの遠心分離を30秒間行った。
f)プレートを23℃で20分間インキュベートした。
g)20分間のインキュベーション後、「溶液C」(テスト試薬溶液)を5μL/ウェルで実験プレートの列1〜24に添加した。
h)1000rpmでの遠心分離を30秒間行った。
i)プレートを23℃で40分間インキュベートした。
j)実験プレートをEnVisionに配置し、プレートを読み取った。
a)各実験プレートの最大コントロール(Max control)と最小コントロール(Min control)を使用して、各プレートのZ’値が> 0.5になるように、実験プレートのZ’値を計算した。
b)XLFIT5によって対照化合物のシグナルからIC50値を計算し、履歴データの平均値の3倍以内に維持された。結果を表1に示した。
1. 実験設計
2.1実験動物
種類:マウス
種族:BALB/cヌードマウス
週齢と体重:6〜8週齢、18〜22グラムの体重
ジェンダー:雌
サプライヤー:Shanghai Sippr−BK実験動物株式会社
3.1細胞培養
ヒト乳癌細胞株MDA−MB−231_luc細胞をin vitroで、単層培養し、培養条件は、10%ウシ胎児血清、100 U/mlペニシリン、100μg/ mlストレプトマイシンを含むRPMI−1640培地(販売者:Gibco、製品番号:22400−089、製造バッチ番号:4868546)であった。培養は37℃、5%CO2で行った。週に二回、パンクレアチン−EDTAを利用して常用の消化処理継代を行った。細胞が指数増殖期にあるとき、細胞を採取し、カウントし、接種した。
0.2ml 10×106個の MDA−MB−231_luc細胞を各ヌードマウスの右後背(PBS:Matrigel=1:1)にそれぞれ皮下接種した。腫瘍平均体積が100−150mm3になるとグループ分けて投与を始めた。
実験指標とは、腫瘍成長の抑制、遅延又は治癒ができるかどうかことを指す。週に二回ノギスで腫瘍直径を測定した。腫瘍体積の算出式がV=0.5a× b2であり、aとbがそれぞれ腫瘍の長径と短径を示した。
各グループの各時点での腫瘍体積の平均値および標準誤差(SEM)を統計分析した。試験終了時である投与後21日目に治療群(薬物投与グループ)が最良の治療効果を示したことから、このデータに基づいて統計解析を行い、群間の相違を評価した。2つ群の間に比較するためにT検定を用いた。3つ以上の群間の比較ではone−way ANOVAを用いた。F値に有意差がある場合、Games−Howell法を使い検定を行った。F値に有意差がない場合、Dunnet (2−sided)法を使い検定した。SPSS17.0ですべてのデータ解析を行った。p<0.05である場合、有意差があると考慮された。
21日投与した後、化合物32の腫瘍抑制率TGI=54.85%,T/C=52.99%,p=0.200;動物の体重に有意な変化はなく、良好な耐性(tolerance)を示した。
1. 実験設計
表2と同じように試験化合物を用意し、動物グループ分けと投与計画は表3と同じようであった。
2. 実験材料
2.1実験動物
種類:マウス
種族:BALB/cヌードマウス
週齢と体重:6〜8週齢、18〜22グラムの体重
ジェンダー:雄
サプライヤー:Shanghai Sippr−BK実験動物株式会社
3.1細胞培養
ヒト前立腺癌PC−3細胞をin vitroで、単層培養し、培養条件は、10%ウシ胎児血清、100 U/mlペニシリン、100μg/ mlストレプトマイシンを含むF−12K培地(販売者:Gibco、製品番号:21127−022、製造バッチ番号:1868870)であった。培養は37℃、5%CO2で行った。週に二回、パンクレアチン−EDTAを利用して常用の消化処理継代を行った。細胞が指数増殖期にあるとき、細胞を採取し、カウントし、接種した。
0.1mL 10*106個のPC−3細胞を各ヌードマウスの右後背にそれぞれ皮下接種した。腫瘍平均体積が100−150mm3になるとグループ分けて投与を始めた。
21日投与した後、溶媒対照グループと比べて、化合物32を投与した場合、顕著な腫瘍抑制 (T/C=44.63%,TGI=58.4%,p=0.033)を示し、また、動物は良好な耐性(tolerance)を示した。
Balb/cマウス(雌)を試験動物として使用した。化合物32を静脈内投与および胃内投与にてマウスに投与し、その後、異なる時点での血漿中の薬物濃度をLC/MS/MS法により測定した。マウスにおける化合物32のin vivo薬物動態学的挙動が研究され、薬物動態学的特性が評価された。
1.1 試験薬物:化合物32
適切な量のサンプルを採取し、DMSOの最終容量で5%を追加し、次に20%HP−β−CDの最終容量で95%を追加した。混合物を超音波で攪拌して、0.5 mg/mLの透明な溶液を得た。ろ過後、静脈内投与で使用した。
適量のサンプルを採取し、0.5%カルボキシメチルセルロースナトリウム溶液に溶解した。混合物を超音波で攪拌して0.5 mg/mLの均一な懸濁液を得た。これを胃内投与で使用した。
8匹のBalb/cマウス(雌)を2つのグループに分けた。一晩絶食後、第1のグループに対して、2.5mL/kgと1 mg/kgの投与量で静脈内投与した。第2のグループは、5mL/kgと2 mg/kgの投与量で胃内投与した。
Balb/cマウス(雌)に対して静脈内投与した後、0.0833、0.25、0.5、1、2、4、8、24時間の各時点で異なるマウスから30μLの血液を採取し、2μLのEDTA−K2を含む試験チューブに入れた。そして、Balb/cマウス(雌)に対して胃内投与した後、0.25、0.5、1、2、4、8、24時間の各時点で異なるマウスから30μLの血液が採取され、2μLのEDTA−K2を含む試験チューブに入れた。チューブを3000gで15分間遠心分離して血漿を分離し、分離した血漿を−60℃で保存した。投与の2時間後に動物は食物を摂取することができた。
2.1実験動物
種類:マウス
種族:C57BL6マウス
週齢と体重:6〜7週齢、16−20グラムの体重
ジェンダー:雌
サプライヤー:上海SLAC実験動物株式会社
3.1細胞培養
マウス大腸癌細胞MC38細胞(OBiO Technology (Shanghai) Corp., Ltd.)をin vitroで、単層培養し、培養条件は、10%ウシ胎児血清を含むDMEM培地(販売者:Gibco、製品番号:12100)であった。培養は37℃、5%CO2にてインキュベータで行った。0.25%のパンクレアチン−EDTAを利用して常用の消化処理継代を行った。指数増殖期に細胞飽和度が80%〜90%になったとき、細胞を採取し、カウントし、接種した。
0.1mL 2×105個のMC38細胞を各ヌードマウスの右後背にそれぞれ皮下接種した。腫瘍平均体積が約70mm3になると腫瘍体積に従って、ランダムにグループ分けて投与を始めた。
週に二回ノギスで腫瘍直径を測定した。腫瘍体積の算出式がV=0.5a× b2であり、aとbがそれぞれ腫瘍の長径と短径を示した。
化合物の腫瘍抑制治療効果は、TGI(%)又は相対腫瘍増殖率T/C(%)で評価された。相対腫瘍増殖率T/C(%)は、算出式がT/C%=TRTV/CRTV× 100%(TRTV:薬物投与グループRTV、CRTV:陰性対照グループRTV)。腫瘍測定結果に基づいて、相対腫瘍体積(relative tumor volume、RTV)を算出し、算出式がRTV=Vt/V0であり、ここで、V0がグループ分け投与時(即ちD0)に測定された平均腫瘍体積であり、Vtがある一回測定時の平均腫瘍体積であり、TRTVとCRTVが同じ日付のデータから採取された。
TGI(%)は、腫瘍成長抑制率を反映する。TGI(%)の算出は、TGI(%)=[(1−(ある薬物投与グループの投与完了時の平均腫瘍体積−該薬物投与グループの投与開始時の平均腫瘍体積))/(溶媒対照グループ治療完了時の平均腫瘍体積−溶媒対照グループの治療開始時の平均腫瘍体積)]×100%になる。
実験完了の場合、腫瘍重量を量り、Tweight/Cweightを計算し、Tweight:薬物投与グループの腫瘍重量であり、Cweight:溶媒対照グループの腫瘍重量であった。
実験終了時の腫瘍体積と腫瘍重量に基づいて、SPSSソフトウェアを使用して統計分析を行った。2つ群の間に比較するためにT検定を用いた。3つ以上の群間の比較ではone−way ANOVAを用いた。分散が均一である場合(F値に有意差がない場合)、LSD法を使い検定した。分散が均一でない場合(F値に有意差がある場合)、Games−Howell法を使い検定した。p<0.05である場合、有意差があると考慮された。
投与20日後の試験化合物32では、15mg/kg投与群の場合:相対腫瘍増殖率T/C = 33.68%、腫瘍増殖抑制率TGI = 68.81%、p <0.0001であった。また、25mg/kg投与群の場合:相対腫瘍増殖率T/C = 27.59%、TGI = 75.21%、p <0.0001であった。50mg/kg投与群の場合:T/C = 10.04%、TGI = 93.46%、p <0.0001であった。各投与グループには有意な腫瘍抑制効果を示し、良好な耐性(tolerance)を示した。
Claims (23)
- 式(I)と式(II)で表される化合物、その異性体又はその薬学的に許容可能な塩、
Tは、CH又はNから選択され、
R1は、1、2又は3個のR基で置換されてもよいC1−3アルキル基又はC1−3アルコキシルから選択され、
R2、R3、R4は、それぞれ独立して、H、F、Cl、Br、I、OH、NH2、CNから選択され、又は、それぞれ独立して、1、2又は3個のR基で置換されてもよいC1−6アルキル基又はC1−6ヘテロアルキル基から選択され、
R5は、Hから選択され、又は、1、2又は3個のR基で置換されてもよいC1−3アルキル基から選択され、
R6は、それぞれ独立して、H、F、Cl、Br、I、OH、NH2、CNから選択され、又は、それぞれ独立して、1、2又は3個のR基で置換されてもよいC1−6アルキル基又はC1−6ヘテロアルキル基から選択され、
或いは、同じ炭素原子に結合する2つのR6基は、結合した炭素原子と共に−C(=O)に形成し、
環Aは、C3−7シクロアルキル基、5〜12員のヘテロシクロアルキル基又は5〜6員のヘテロアリール基から選択され、
環Bは、4〜7員のヘテロシクロアルキル基から選択され、
且つ構造
nは、0、1、2、3、4、5又は6から選択され、
Rは、それぞれ独立して、F、Cl、Br、I、OH、NH2、CNから選択され、又は、1、2又は3個のR’基で置換されてもよいC1−6アルキル基又はC1−6ヘテロアルキル基から選択され、
R’は、それぞれ独立して、F、Cl、Br、I、OH、NH2、CN又はMeから選択され、
「*」で付けた炭素原子は不斉炭素原子であり、(R)又は(S)の単一のエナンチオマー又は一つのエナンチオマーに富む形式であり;
上記C1−6ヘテロアルキル基、5〜12員のヘテロシクロアルキル基、5−6員のヘテロアリール基、4〜7員のヘテロシクロアルキル基の“ヘテロ”は、N、−O−、−S−、−NH−、−C(=O)NH−、−C(=O)−、−C(=O)O−、−S(=O)2−、−S(=O)−、−C(=O)S−から選択され、
上記ヘテロ原子又はヘテロ原子団の数は、それぞれ独立して、1、2、3又は4から選択される。 - Rは、F、Cl、Br、I、OH、NH2、CNから選択され、又は、1、2又は3個のR’基で置換されてもよいC1−3アルキル基又はC1−3アルコキシルから選択される請求項1に記載の化合物、その異性体又はその薬学的に許容可能な塩。
- R2、R3、R4は、それぞれ独立して、H、F、Cl、Br、I、OH、NH2、CNから選択され、又は、それぞれ独立して、1、2又は3個のR基で置換されてもよいC1−3アルキル基又はC1−3アルコキシルから選択される請求項1〜4の何れか1項に記載の化合物、その異性体又はその薬学的に許容可能な塩。
- R5は、H又はMeから選択される請求項1〜4の何れか1項に記載の化合物、その異性体又はその薬学的に許容可能な塩。
- R6は、それぞれ独立して、H、F、Cl、Br、I、OH、NH2、CNから選択され、又は、それぞれ独立して、1、2又は3個のR基で置換されてもよいC1−3アルキル基又はC1−3ヘテロアルキル基から選択される請求項1〜4の何れか1項に記載の化合物、その異性体又はその薬学的に許容可能な塩。
- 環Aは、C4−6シクロアルキル基、ピロリジン−2−オニル、ピリミジン−4(3H)−オニル、5−アザスピロ[2.4]ヘプタン−4−オニル、4−アザスピロ[2.4]ヘプタン−5−オニル、テトラヒドロチオフェン−1,1−ジオキシド基、テトラヒドロチオフェン−1−オキシド基、テトラヒドロフラニル、ピロリジニル、ジヒドロチオフェン−2(3H)−オニル、2−オキサスピロ[3.4]オクチル、ジヒドロフラン−2(3H)−オニル、1,4,7,10−テトラオキサシクロドデシル、1,2,5−オキサジアゾリル、7−オキサビシクロ−[2.2.1]ヘプタン、ピロリジン−2,5−ジオン、5,5−ジメチル−ジヒドロフラン−2(3H)−オニルから選択される請求項1〜4の何れか1項に記載の化合物、その異性体又はその薬学的に許容可能な塩。
- 治療有効量の活性化成分としての請求項1〜20の何れか1項に記載の化合物、その異性体又はその薬学的に許容可能な塩と、薬学的に許容可能な担体を含む医薬組成物。
- 請求項1〜20の何れか1項に記載の化合物、その異性体又はその薬学的に許容可能な塩、又は請求項21に記載の組成物のBET Bromodomain抑制剤に関連の医薬品の製造への応用。
- 上記BET Bromodomain抑制剤に関連の医薬品は抗癌剤であることを特徴とする請求項22に記載の応用。
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CN111372937A (zh) | 2020-07-03 |
CA3076759A1 (en) | 2019-03-28 |
US20210017190A1 (en) | 2021-01-21 |
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