JP6871864B2 - イソオキサゾリル置換ベンズイミダゾール類 - Google Patents
イソオキサゾリル置換ベンズイミダゾール類 Download PDFInfo
- Publication number
- JP6871864B2 JP6871864B2 JP2017554817A JP2017554817A JP6871864B2 JP 6871864 B2 JP6871864 B2 JP 6871864B2 JP 2017554817 A JP2017554817 A JP 2017554817A JP 2017554817 A JP2017554817 A JP 2017554817A JP 6871864 B2 JP6871864 B2 JP 6871864B2
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- Prior art keywords
- dimethylisoxazole
- benzo
- propan
- mmol
- tetrahydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Isooxazolyl-substituted benzimidazoles Chemical class 0.000 title claims description 297
- 238000000034 method Methods 0.000 claims description 90
- 150000001875 compounds Chemical class 0.000 claims description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 25
- BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 6
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 6
- BHPOPMOJRYUDRJ-HNNXBMFYSA-N 4-[2-[(2S)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiane 1,1-dioxide Chemical compound ClC1=C(C=C(C=C1)C[C@H](C)C1=NC2=C(N1C1CCS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C)F BHPOPMOJRYUDRJ-HNNXBMFYSA-N 0.000 claims description 5
- WBZVRBGKEKLFLH-UHFFFAOYSA-N 4-[2-[1-(3-fluoro-4-methoxyphenyl)propan-2-yl]-1-(1-methylpiperidin-4-yl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound FC=1C=C(C=CC=1OC)CC(C)C1=NC2=C(N1C1CCN(CC1)C)C=CC(=C2)C=1C(=NOC=1C)C WBZVRBGKEKLFLH-UHFFFAOYSA-N 0.000 claims description 5
- OTBQXPWXXLCVLF-UHFFFAOYSA-N 4-[2-[1-(4-chlorophenyl)propan-2-yl]-1-[2-(oxan-4-yl)ethyl]benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound ClC1=CC=C(C=C1)CC(C)C1=NC2=C(N1CCC1CCOCC1)C=CC(=C2)C=1C(=NOC=1C)C OTBQXPWXXLCVLF-UHFFFAOYSA-N 0.000 claims description 5
- RPKFLAADTHHFKD-UHFFFAOYSA-N 4-[2-[2-(4-ethylphenyl)ethyl]-1-(3-methylsulfonylpropyl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound C(C)C1=CC=C(C=C1)CCC1=NC2=C(N1CCCS(=O)(=O)C)C=CC(=C2)C=1C(=NOC=1C)C RPKFLAADTHHFKD-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- XSTMVQCDNYDUTB-QVKFZJNVSA-N (3R)-3-[2-[(2R)-1-(4-chlorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiolane 1,1-dioxide Chemical compound ClC1=CC=C(C=C1)C[C@@H](C)C1=NC2=C(N1[C@H]1CS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C XSTMVQCDNYDUTB-QVKFZJNVSA-N 0.000 claims description 4
- QWBZQXJWPWFMJY-KUHUBIRLSA-N (3S)-3-[2-[(2R)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiolane 1,1-dioxide Chemical compound ClC1=C(C=C(C=C1)C[C@@H](C)C1=NC2=C(N1[C@@H]1CS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C)F QWBZQXJWPWFMJY-KUHUBIRLSA-N 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- KZKRRZFCAYOXQE-UHFFFAOYSA-N 1$l^{2}-azinane Chemical group C1CC[N]CC1 KZKRRZFCAYOXQE-UHFFFAOYSA-N 0.000 claims description 4
- KNVIVWSPIBYDFF-UHFFFAOYSA-N 3,5-dimethyl-4-[1-[2-(oxan-4-yl)ethyl]-2-(2-quinoxalin-2-ylethyl)benzimidazol-5-yl]-1,2-oxazole Chemical compound CC1=NOC(=C1C1=CC2=C(N(C(=N2)CCC2=NC3=CC=CC=C3N=C2)CCC2CCOCC2)C=C1)C KNVIVWSPIBYDFF-UHFFFAOYSA-N 0.000 claims description 4
- FABLOVUTFJUNGU-OAHLLOKOSA-N 4-[2-[(2R)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-1-(oxan-4-yl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound ClC1=C(C=C(C=C1)C[C@@H](C)C1=NC2=C(N1C1CCOCC1)C=CC(=C2)C=1C(=NOC=1C)C)F FABLOVUTFJUNGU-OAHLLOKOSA-N 0.000 claims description 4
- BPDXPVYBBSRIIL-QRWLVFNGSA-N 4-[2-[(2R)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-1-[(3S)-1-methylsulfonylpyrrolidin-3-yl]benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound ClC1=C(C=C(C=C1)C[C@@H](C)C1=NC2=C(N1[C@@H]1CN(CC1)S(=O)(=O)C)C=CC(=C2)C=1C(=NOC=1C)C)F BPDXPVYBBSRIIL-QRWLVFNGSA-N 0.000 claims description 4
- BHPOPMOJRYUDRJ-OAHLLOKOSA-N 4-[2-[(2R)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiane 1,1-dioxide Chemical compound ClC1=C(C=C(C=C1)C[C@@H](C)C1=NC2=C(N1C1CCS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C)F BHPOPMOJRYUDRJ-OAHLLOKOSA-N 0.000 claims description 4
- FABLOVUTFJUNGU-HNNXBMFYSA-N 4-[2-[(2S)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-1-(oxan-4-yl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound ClC1=C(C=C(C=C1)C[C@H](C)C1=NC2=C(N1C1CCOCC1)C=CC(=C2)C=1C(=NOC=1C)C)F FABLOVUTFJUNGU-HNNXBMFYSA-N 0.000 claims description 4
- RRZLWLFTAMKGLZ-UHFFFAOYSA-N 4-[2-[1-(4-fluorophenyl)propan-2-yl]-1-(oxan-4-yl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound FC1=CC=C(C=C1)CC(C)C1=NC2=C(N1C1CCOCC1)C=CC(=C2)C=1C(=NOC=1C)C RRZLWLFTAMKGLZ-UHFFFAOYSA-N 0.000 claims description 4
- DWJBRGAMYXHJNF-UHFFFAOYSA-N 4-[2-[1-[3-chloro-4-(difluoromethoxy)phenyl]propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiane 1,1-dioxide Chemical compound ClC=1C=C(C=CC=1OC(F)F)CC(C)C1=NC2=C(N1C1CCS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C DWJBRGAMYXHJNF-UHFFFAOYSA-N 0.000 claims description 4
- JQJDYGGJAAINAI-UHFFFAOYSA-N 4-[2-[1-[3-chloro-4-(trifluoromethoxy)phenyl]propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiane 1,1-dioxide Chemical compound ClC=1C=C(C=CC=1OC(F)(F)F)CC(C)C1=NC2=C(N1C1CCS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C JQJDYGGJAAINAI-UHFFFAOYSA-N 0.000 claims description 4
- XRWQARNNJAOEHK-UHFFFAOYSA-N 4-[2-[1-[3-fluoro-4-(trifluoromethoxy)phenyl]propan-2-yl]-1-[2-(oxan-4-yl)ethyl]benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound FC=1C=C(C=CC=1OC(F)(F)F)CC(C)C1=NC2=C(N1CCC1CCOCC1)C=CC(=C2)C=1C(=NOC=1C)C XRWQARNNJAOEHK-UHFFFAOYSA-N 0.000 claims description 4
- DITAJUILNIQJOY-UHFFFAOYSA-N 4-[2-[2-(3,4-dichlorophenyl)ethyl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiane 1,1-dioxide Chemical compound ClC=1C=C(CCC2=NC3=C(N2C2CCS(CC2)(=O)=O)C=CC(=C3)C=2C(=NOC=2C)C)C=CC=1Cl DITAJUILNIQJOY-UHFFFAOYSA-N 0.000 claims description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- QWBZQXJWPWFMJY-AUUYWEPGSA-N (3R)-3-[2-[(2R)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiolane 1,1-dioxide Chemical compound ClC1=C(C=C(C=C1)C[C@@H](C)C1=NC2=C(N1[C@H]1CS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C)F QWBZQXJWPWFMJY-AUUYWEPGSA-N 0.000 claims description 3
- QWBZQXJWPWFMJY-IFXJQAMLSA-N (3R)-3-[2-[(2S)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiolane 1,1-dioxide Chemical compound ClC1=C(C=C(C=C1)C[C@H](C)C1=NC2=C(N1[C@H]1CS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C)F QWBZQXJWPWFMJY-IFXJQAMLSA-N 0.000 claims description 3
- XSTMVQCDNYDUTB-VFNWGFHPSA-N (3S)-3-[2-[(2R)-1-(4-chlorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiolane 1,1-dioxide Chemical compound ClC1=CC=C(C=C1)C[C@@H](C)C1=NC2=C(N1[C@@H]1CS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C XSTMVQCDNYDUTB-VFNWGFHPSA-N 0.000 claims description 3
- YVPRMLGNBIORND-UHFFFAOYSA-N 3,5-dimethyl-4-[1-(oxan-4-yl)-2-[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzimidazol-5-yl]-1,2-oxazole Chemical compound N1C=C(C=2C1=NC=CC=2)CCC1=NC2=C(N1C1CCOCC1)C=CC(=C2)C=1C(=NOC=1C)C YVPRMLGNBIORND-UHFFFAOYSA-N 0.000 claims description 3
- FNVVWEQRAYYHDI-KTQQKIMGSA-N 3-[2-[(2S)-1-[3-chloro-4-(difluoromethoxy)phenyl]propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiolane 1,1-dioxide Chemical compound ClC=1C=C(C=CC=1OC(F)F)C[C@H](C)C1=NC2=C(N1C1CS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C FNVVWEQRAYYHDI-KTQQKIMGSA-N 0.000 claims description 3
- BPDXPVYBBSRIIL-MGPUTAFESA-N 4-[2-[(2S)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-1-[(3R)-1-methylsulfonylpyrrolidin-3-yl]benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound ClC1=C(C=C(C=C1)C[C@H](C)C1=NC2=C(N1[C@H]1CN(CC1)S(=O)(=O)C)C=CC(=C2)C=1C(=NOC=1C)C)F BPDXPVYBBSRIIL-MGPUTAFESA-N 0.000 claims description 3
- BPDXPVYBBSRIIL-YWZLYKJASA-N 4-[2-[(2S)-1-(4-chloro-3-fluorophenyl)propan-2-yl]-1-[(3S)-1-methylsulfonylpyrrolidin-3-yl]benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound ClC1=C(C=C(C=C1)C[C@H](C)C1=NC2=C(N1[C@@H]1CN(CC1)S(=O)(=O)C)C=CC(=C2)C=1C(=NOC=1C)C)F BPDXPVYBBSRIIL-YWZLYKJASA-N 0.000 claims description 3
- JFYFGMZXYKPHGE-UHFFFAOYSA-N 4-[2-[1-(3-fluoro-4-methoxyphenyl)propan-2-yl]-1-(1-methylpyrrolidin-3-yl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound FC=1C=C(C=CC=1OC)CC(C)C1=NC2=C(N1C1CN(CC1)C)C=CC(=C2)C=1C(=NOC=1C)C JFYFGMZXYKPHGE-UHFFFAOYSA-N 0.000 claims description 3
- AURGEOWPYKNQGY-UHFFFAOYSA-N 4-[2-[1-(3-fluoro-4-methoxyphenyl)propan-2-yl]-1-(oxan-4-ylmethyl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound FC=1C=C(C=CC=1OC)CC(C)C1=NC2=C(N1CC1CCOCC1)C=CC(=C2)C=1C(=NOC=1C)C AURGEOWPYKNQGY-UHFFFAOYSA-N 0.000 claims description 3
- RWAOOAQJCDUFFD-UHFFFAOYSA-N 4-[2-[1-(4-chloro-3-fluorophenyl)propan-2-yl]-1-(3-methylsulfonylpropyl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound ClC1=C(C=C(C=C1)CC(C)C1=NC2=C(N1CCCS(=O)(=O)C)C=CC(=C2)C=1C(=NOC=1C)C)F RWAOOAQJCDUFFD-UHFFFAOYSA-N 0.000 claims description 3
- BXALTSVBGWREIK-OAHLLOKOSA-N 4-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(2R)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]propan-2-yl]benzimidazol-1-yl]thiane 1,1-dioxide Chemical compound CC1=NOC(=C1C1=CC2=C(N(C(=N2)[C@@H](CC2=CC(=C(C=C2)OC(F)(F)F)F)C)C2CCS(CC2)(=O)=O)C=C1)C BXALTSVBGWREIK-OAHLLOKOSA-N 0.000 claims description 3
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000003003 spiro group Chemical group 0.000 claims description 3
- XZONENCODLMUJT-UHFFFAOYSA-N 4-[2-[1-(4-chlorophenyl)propan-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)benzimidazol-1-yl]thiane 1,1-dioxide Chemical compound ClC1=CC=C(C=C1)CC(C)C1=NC2=C(N1C1CCS(CC1)(=O)=O)C=CC(=C2)C=1C(=NOC=1C)C XZONENCODLMUJT-UHFFFAOYSA-N 0.000 claims description 2
- FBLUWXMUNIEXMT-UHFFFAOYSA-N 4-[2-[1-[3-fluoro-4-(trifluoromethoxy)phenyl]propan-2-yl]-1-(1-methylpyrrolidin-3-yl)benzimidazol-5-yl]-3,5-dimethyl-1,2-oxazole Chemical compound FC=1C=C(C=CC=1OC(F)(F)F)CC(C)C1=NC2=C(N1C1CN(CC1)C)C=CC(=C2)C=1C(=NOC=1C)C FBLUWXMUNIEXMT-UHFFFAOYSA-N 0.000 claims description 2
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- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- 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
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、一連の新規ベンズイミダゾリルイソオキサゾール類並びにそれらのp300及び/又はCBP活性のモジュレーターとしての使用に関する。
遺伝子修飾及びエピジェネティック修飾は、癌疾患の進行の全てのステージにとって重大な意味を持ち、エピジェネティックなサイレンシングは、癌の全ての特徴に関与する遺伝子らの誤制御において重要であることが示されてきた(Jones, P.A. and Baylin, S.B. (2007)“The epigenomics of cancer”, Cell, Vol. 128, pp. 683-692)。根底にある制御を媒介するエピジェネティック修飾としては、DNAメチル化及び翻訳後ヒストン修飾が挙げられる。後者としては、メチル化、アセチル化、及びユビキチン化が挙げられる。DNA脱メチル化剤及びヒストンデアセチラーゼ阻害剤は、抗腫瘍活性を示して、数多くの剤が、血液学的悪性疾患の治療における使用のために認可されてきた。ヒストン及び非ヒストンタンパク質をアセチル化するヒストンアセチルトランスフェラーゼ(HAT)を含む、ヒストン修飾を媒介する酵素は、小分子化合物薬物治療の第二世代の標的の波の代表的なものである。
R0及びRは、同一であるか又は異なり、それぞれH又はC1-6アルキルであり;
R9、R9’及びR9’’は、同一であるか又は異なり、それぞれH又はFであり;
Xは、-(alk)n-、-alk-C(=O)-NR-、-alk-NR-C(=O)-又は-alk-C(=O)-であり;
R1は、-S(=O)2R'、非置換又は置換の4〜6員のC-結合型複素環基及び下記式:
R2及びR2'は、同一であるか又は異なり、それぞれH又はC1-6アルキルであるか;あるいはR2とR2'とが、それらが結合しているC原子と一緒になって、C3-6シクロアルキル基を形成し;
R3及びR3'は、同一であるか又は異なり、それぞれH、C1-6アルキル、OH又はFであり;
R4は、非置換であるか又は置換されている、フェニル又は5〜12員のN含有ヘテロアリール基であり;
alkは、C1-6アルキレンであり;
R'は、C1-6アルキルであり;かつ
nは、0又は1である)
のベンズイミダゾリルイソオキサゾールである化合物、又はその医薬上許容される塩を提供する。
R9、R9'及びR9''は、式(I)について上記したとおりであり;
X'は、C1-3アルキレン又は-(CH2)-C(=O)-NH-であり;
R2'は、H、Me又はEtであり;
R5はHであり、かつR6は-S(=O)2Meであるか、又はR5及びR6は、それらが結合している炭素原子と一緒になって、ピロリジニル、チオピラニル、ピラニル及びピペリジニルから選択される非置換又は置換の複素環基を形成し;
Wは、C又はNであり;かつ
R7及びR8は、それらが結合しているC又はN原子と一緒になって、フェニル、ピリジニル、ピリミジニル、キノリニル、イソキノリニル、ピロロピリジニル及びキノキサリニルから選択される、非置換又は置換の基を形成する)を有する。
(a) 上記のとおりの本発明の化合物;及び
(b) 化学療法剤
を含む製品を提供する。化学療法剤は、例えば、アンドロゲン受容体遮断薬又はCYP17A1阻害剤であってもよい。より具体的には、それは、エンザルタミド又はアビラテロンであってもよい。
全ての出発物質及び溶剤は、商業的供給源から入手したか、又は文献引用に従って調製した。他に記載されていない限り、全ての反応は撹拌した。有機溶液は、ルーチン的に無水硫酸マグネシウム上で乾燥させた。水素付加は、記載された条件下で、Thales H-cubeフロー反応器上で実行した。
逆相高速液体クロマトグラフィー:
分析用HPLCをWaters Xselect CSH C18, 2.5μm, 4.6×30 mmカラム、 0.1% 含水ギ酸中のMeCN中0.1%のギ酸の勾配で溶出;Waters Xbridge BEH C18, 2.5μm, 4.6×30 mmカラム、10 mM 炭酸水素アンモニウム水溶液中のMeCNの勾配で溶出、を使用して実行した。溶出されたピークのUVスペクトルは、Agilent 1100システム上のダイオードアレイ又は可変波長検出器のいずれかを使用して測定した。
1H NMRスペクトルは、Bruker Avance III 分光計上で、400 MHzで、残留の重水素化されていない溶剤をリファレンスとして使用して、取得した。
(R)-3-(3-(4-クロロフェニル)プロパノイル)-4-イソプロピルオキサゾリジン-2-オン
THF(100 mL)中の(S)-4-イソプロピルオキサゾリジン-2-オン(3.24 g, 25.1 mmol)の溶液を-78℃まで冷却した。N-ブチルリチウム(10.23 mL, 25.6 mmol)を滴下によって添加した。添加が完了したら、THF(8 mL)中の粗3-(4-クロロフェニル)プロパノイルクロリド(5.5 g, 27.1 mmol)を滴下によって添加した。CO2/アセトンバスを所定の位置に置き、反応混合物を18時間にわたって、室温まで温まらせておいた。飽和塩化アンモニウム(30 mL)を反応混合物に添加した。10分間撹拌した後、溶剤を真空中で除去し、残渣をDCM(300 mL)と水(100 mL)との間で分配させた。有機層を回収し、ブライン(2×100 mL)で洗浄し、次に、相分離カートリッジを通過させた。溶剤を真空中で除去し、粗生成物をクロマトグラフィー(120 gシリカ, イソヘキサン中0〜100 %のEtOAc, グラジエント溶離)によって精製し、(S)-3-(3-(4-クロロフェニル)プロパノイル)-4-イソプロピルオキサゾリジン-2-オン(6.42 g, 21.71 mmol, 87.0 %の収率)を、白色の結晶性固体として得た;Rt 2.54分(方法1), m/z 296 / 298 (M+H)+ (ES+)。
THF(100 mL, 35.4 mmol)中の(R)-4-イソプロピルオキサゾリジン-2-オン(4.57 g, 35.4 mmol)の溶液を-78℃まで冷却した。n-ブチルリチウム(15.57 mL, 38.9 mmol)を滴下によって添加した。添加が完了したら、THF(8 mL)中の粗3-(4-クロロ-3-フルオロフェニル)プロパノイルクロリド(7.82 g, 35.4 mmol)を滴下によって添加した。CO2/アセトンバスを所定の位置に置き、反応混合物を18時間にわたって、室温まで温まらせておいた。飽和塩化アンモニウム(30 mL)を反応混合物に添加した。10分間撹拌した後、溶剤を真空中で除去し、残渣をDCM(300 mL)と水(100 mL)との間で分配させた。有機層を回収し、ブライン(2×100 mL)で洗浄し、次に相分離カートリッジを通過させた。溶剤を真空中で除去し、粗生成物をクロマトグラフィー(120 gシリカ, イソヘキサン中0〜100 %のEtOAc, グラジエント溶離)によって精製し、(R)-3-(3-(4-クロロ-3-フルオロフェニル)プロパノイル)-4-イソプロピルオキサゾリジン-2-オン(7.52 g, 23.48 mmol, 66.4 %の収率)を、薄黄色の固体として得た; Rt 2.55分(方法1), m/z 313 / 315 (M+H)+ (ES+)。
THF(100 mL, 35.4 mmol)中の(S)-4-イソプロピルオキサゾリジン-2-オン(4.57 g, 35.4 mmol)の溶液を-78℃まで冷却した。n-ブチルリチウム(15.57 mL, 38.9 mmol)を滴下によって添加した。添加が完了したら、THF(8 mL)中の粗3-(4-クロロ-3-フルオロフェニル)プロパノイルクロリド(7.82 g, 35.4 mmol)を滴下によって添加した。CO2/アセトンバスを所定の位置に置き、反応混合物を18時間にわたって、室温まで温まらせておいた。飽和塩化アンモニウム(30 mL)を反応混合物に添加した。10分間撹拌した後、溶剤を真空中で除去し、残渣をDCM(300 mL)と水(100 mL)との間で分配させた。有機層を回収し、ブライン(2×100 mL)で洗浄し、次に相分離カートリッジを通過させた。溶剤を真空中で除去し、粗生成物をクロマトグラフィー(120 gシリカ, イソヘキサン中0〜100 %のEtOAc, グラジエント溶離)によって精製し、(S)-3-(3-(4-クロロ-3-フルオロフェニル)プロパノイル)-4-イソプロピルオキサゾリジン-2-オン(6.16 g, 16.88 mmol, 47.7 %の収率)を白色固体として得た;Rt 2.55分(方法1), m/z 313 / 315 (M+H)+ (ES+)。
THF(100 mL)中の(R)-4-イソプロピルオキサゾリジン-2-オン(2.60 g, 20.14 mmol)の溶液を-78℃まで冷却した。N-ブチルリチウム(8.22 mL, 20.54 mmol)を滴下によって添加した。添加が完了したら、THF(10 mL)中の粗3-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパノイルクロリド(5.45 g, 20.14 mmol)を滴下によって添加した。CO2/アセトンバスを所定の位置に置き、反応混合物を18時間にわたって、室温まで温まらせておいた。飽和塩化アンモニウム(30 mL)を反応混合物に添加した。10分間撹拌した後、溶剤を真空中で除去し、残渣をEtOAc(300 mL)と水(100 mL)との間で分配させた。有機層を回収し、ブライン(2×100 mL)で洗浄し、次に48時間静置させておいた。有機溶液を乾燥させ(MgSO4)、次に相分離カートリッジを通過させた。溶剤を真空中で除去し、粗生成物をクロマトグラフィー(120 gシリカ, イソヘキサン中0〜100%のEtOAc, グラジエント溶離)によって精製し、(R)-3-(3-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパノイル)-4-イソプロピルオキサゾリジン-2-オン(5.94 g, 14.71 mmol, 73.1 %の収率)を白色の結晶性固体として得た。Rt 2.68分(方法1), m/z 質量イオンなし (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.35 (m, 2H), 7.21 (ddd, J = 8.5, 2.1, 1.1 Hz, 1H), 4.42 - 4.20 (m, 3H), 3.27 (ddd, J = 17.3, 8.3, 6.8 Hz, 1H), 3.09 (dt, J = 17.3, 7.3 Hz, 1H), 2.92 (td, J = 7.3, 2.7 Hz, 2H), 2.13 (hd, J = 7.0, 3.8 Hz, 1H), 0.84 (d, J = 7.1 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H)。
N-(4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロフェニル)-1-メチルピロリジン-3-アミン
4-(3,5-ジメチルイソオキサゾール-4-イル)-N1-(3-(メチルスルホニル)プロピル)ベンゼン-1,2-ジアミン
4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール
4-((4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロフェニル)アミノ)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
N-(4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロフェニル)テトラヒドロ-2H-ピラン-4-アミン
3,5-ジメチル-4-(2-(1-(ピリジン-2-イル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)イソオキサゾール
tert-ブチル-4-(((4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロフェニル)アミノ)メチル)ピペリジン-1-カルボキシラート
4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロ-N-((テトラヒドロ-2H-ピラン-4-イル)メチル)アニリン
4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロ-N-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)アニリン
4-(2-(1-(3-クロロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
4-(2-(1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
4-(2-(3,4-ジクロロフェネチル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
4-(2-(4-エチルフェネチル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール
4-(2-(2-(1H-ピロロ[2,3-b]ピリジン-3-イル)エチル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール
3,5-ジメチル-4-(2-(2-(キノキサリン-2-イル)エチル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)イソオキサゾール
tert-ブチル 2-((4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロフェニル)アミノ)アセタート
2-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(3-フルオロ-4-メトキシフェネチル)-1H-ベンゾ[d]イミダゾール-1-イル)-N-(テトラヒドロフラン-3-イル)アセトアミド
Tert-ブチル 2-((4-ブロモ-2-ニトロフェニル)アミノ)アセタート
メチル 3-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)-2-メチルプロパノアート
4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
3-(2-((R)-1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド及び3-(2-((S)-1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド
(R)-3-(4-クロロ-3-フルオロフェニル)-N-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(((R)-1-(メチルスルホニル)ピロリジン-3-イル)アミノ)フェニル)-2-メチルプロパンアミド
4-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((R)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール
4-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((R)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール
(R)-4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
(S)-4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
Tert-ブチル (S)-3-((4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロフェニル)アミノ)ピロリジン-1-カルボキシラート
Tert-ブチル (S)-3-((2-((S)-3-(4-クロロ-3-フルオロフェニル)-2-メチルプロパンアミド)-4-(3,5-ジメチルイソオキサゾール-4-イル)フェニル)アミノ)ピロリジン-1-カルボキシラート
(R)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
(S)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
(R)-3-((4-(3,5-ジメチルイソオキサゾール-4-イル)-2-ニトロフェニル)アミノ)テトラヒドロチオフェン 1,1-ジオキシド
((R)-3-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド
(R)-3-(2-((R)-1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド
(R)-N-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-((1,1-ジオキシドテトラヒドロ-2H-チオピラン-4-イル)アミノ)フェニル)-3-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)-2-メチルプロパンアミド
(S)-4-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド
(S)-4-(2-(メチルチオ)エチル)-2-フェニル-4,5-ジヒドロオキサゾール
(S)-3-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド
(R)-3-(4-クロロ-3-フルオロフェニル)-N-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-((テトラヒドロ-2H-ピラン-4-イル)アミノ)フェニル)-2-メチルプロパンアミド
(S)-3-(4-クロロ-3-フルオロフェニル)-N-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-((テトラヒドロ-2H-ピラン-4-イル)アミノ)フェニル)-2-メチルプロパンアミド
EP300及びBRD4 BD1への結合の表面プラズモン共鳴(BIAcore)解析
EP300及びBRD4への化合物の結合のBIAcoreデータを、T200 BIAcore装置を4℃で使用して取得した。His-tagged EP300ブロモドメイン(1046-1163)及びBRD4ブロモドメイン1(49-170)タンパク質を、キャプチャー法及びアミンカップリング法の組み合わせを介してNTAチップ上に捕捉した。NTA基を最初に30mM塩化ニッケルでキレート化し、次に0.2 M N-エチル-N'-(ジエチルアミノプロピル)-カルボジイミド(EDC)及び0.05μM N-ヒドロキシコハク酸イミド(NHS)で活性化した。
PBS 0.05% Tween-20中9.6Mに希釈されたブロモドメインタンパク質を10l/分で注入し、共有結合させた。エタノールアミン注入は、表面上の未反応部分をキャップして、カップリングしていないタンパク質を除去するために実施した。典型的な固定化は、表面上に〜2〜4kRUの固定化タンパク質をもたらした。
試験化合物を、ランニングバッファー(0.005% Tween-20を含むPBS, 0.1% DMSO)中1、10、100、1000及び10000 nMの溶液を得るために、段階希釈した。試験は、終始90μL/分の流量を使用して、ランニングバッファーの5回繰り返しの注射からなるバッファーでの空試験を点在させた、化合物の濃度を上昇させながらの注射から構成された。
1:1 相互作用モデルを使用してBIAevaluation(GE Healthcare)でセンサーグラムを解析してka及びkd値を得、結合の速度論を説明した。KD値は、kd及びkaの商から導き出した。全ての化合物を、EP300及びBRD4ブロモドメイン表面に対して2回試験し、速度論及び親和性パラメーターの幾何平均を得た。試験した全ての化合物が、0.5〜10,000 nMの範囲内のKD値を示した。
22Rv1細胞株はATCC(UK)から取得し、供給者の推奨法に従って培養した。代表的な化合物の細胞増殖阻害活性を、CellTiter-Glo(登録商標) Luminescent Cell Viability Assayキット(Promega, USA)を使用して決定した。
22Rv1細胞を、10% ウシ胎児血清、2mM グルタミン、1mM ピルビン酸ナトリウム及び100ユニットのペニシリン-100μg のストレプトマイシンを含有するRPMI 1640培地中で維持した。細胞を、37℃で、95% O2及び5% CO2の加湿雰囲気下でインキュベートした。2000個の細胞を、Poly-D-リジン(PDL)コーティングした96ウェルの黒色の透明底プレート(VWR, UK)の各ウェル当たり、50μLの増殖培地中に播種した。48時間後、培地を除去し、希釈した試験化合物を含有する増殖培地で置換した。化合物の希釈は、DMSO貯蔵液を10mMの最高濃度から半分ログ(half log)間隔で、合計7回希釈分を段階希釈することによって行った。各希釈時点の1μlのアリコートを、99μlの増殖培地に添加して、50μLを細胞を含む各ウェルに添加し、最高濃度の時点(1% DMSO)で、100μMの化合物を供給した。1% DMSO処理細胞が、ハイコントロールの役割を果たした。
細胞をさらに72時間、37℃でインキュベートし、細胞生存率をCellTiter-Glo(登録商標) Luminescent Cell Viability Assayを、製造者の指示に従って使用して決定した。簡単には、増殖培地の容積と等量のCellTiter-Glo(登録商標)試薬を、各ウェルに添加した。プレートをおよそ2分間振とうさせ、室温(22oC)で10分間インキュベートした。発光シグナルをEnvisionプレートリーダーを、1秒/ウェルのインテグレーションタイムで使用して測定した。
全データを、6つのハイコントロールの平均値に対して適合させた。最大半抑制濃度(IC50)を、Dotmaticsソフトウェア(UK)を使用して、データを4パラメーターのロジスティック曲線にフィットさせて算出した。試験した全ての化合物が、100nM〜100μM、典型的には100nM〜30μM、の範囲内、のIC50値を示した。
細胞ベースのアッセイは、系の複雑性が原因で、いくらかの変動性を示す可能性があり、アッセイの条件を変動させるために、これらのアッセイの結果も変動し得ることが理解される。いくらかのレベルの細胞増殖阻害は、化合物が特定の細胞におけるいくらかの阻害活性を有することを意味している一方で、試験した最も高い濃度未満での阻害の欠如は必ずしも化合物が細胞に対して阻害活性を有していないことを示すものではない。
それぞれ0.15 gの重さで、25 mgの本発明の化合物を含有する錠剤は、以下の通りに製造される:
10,000個の錠剤の組成
本発明の化合物(250 g)
乳糖(800 g)
トウモロコシデンプン(415g)
タルク粉末(30 g)
ステアリン酸マグネシウム(5 g)
本発明の化合物、乳糖及びトウモロコシデンプンの半分を混合する。混合物を次に、0.5 mmの網目サイズの篩を押し通す。トウモロコシデンプン(10 g)を温かい水(90 ml)に懸濁する。得られたペーストを使用して、粉末を顆粒化する。顆粒を乾燥させ、1.4 mmの網目サイズの篩上で、小さな断片へと粉砕する。残りの分量のデンプン、タルク及びマグネシウムを添加し、注意深く混合し、錠剤へと加工する。
本発明の化合物 200 mg
塩化水素水溶液0.1M又は
水酸化ナトリウム水溶液0.1M適量 pH4.0〜7.0に調製
滅菌水適量 10 mLに調製
本発明の化合物を水の大半(35°-40℃)中に溶解し、pHを必要に応じて塩化水素又は水酸化ナトリウムで4.0〜7.0の間に調整する。次にバッチの容積を水で整え、滅菌ミクロポアフィルターを通して、滅菌した10 mLの琥珀色のガラスバイアル(タイプ1)中に濾過し、滅菌した栓及びオーバーシールで密封する。
本発明の化合物 200 mg
ベンジルアルコール 0.10 g
グリコフロール75 1.45 g
注射剤に適量の水 3.00 mLに調製
本発明の化合物を、グリコフロール中に溶解する。次にベンジルアルコールを添加して溶解させ、水を3 mlになるまで添加する。次に混合物を滅菌ミクロポアフィルターを通して濾過し、滅菌した3 mlのガラスバイアル(タイプ1)中に密封する。
本発明の化合物 250 mg
ソルビトール溶液 1.50 g
グリセロール 2.00 g
安息香酸ナトリウム 0.005 g
香料 0.0125 mL
純水適量 5.00 mLに調製
本発明の化合物をグリセロールと純水の大半との混合物中に溶解する。次に、その溶液に、安息香酸ナトリウムの水溶液を添加し、次いで、ソルビトール溶液を添加し、最後に香料を添加する。容積を純水で調整し、よく混合する。
本発明は、以下の態様を提供する。
[1] 下記式(I)
(式中:
R 0 及びRは、同一であるか又は異なり、それぞれH又はC 1-6 アルキルであり;
R 9 、R 9’ 及びR 9’’ は、同一であるか又は異なり、それぞれH又はFであり;
Xは、-(alk) n -、-alk-C(=O)-NR-、-alk-NR-C(=O)-又は-alk-C(=O)-であり;
R 1 は、-S(=O) 2 R'、非置換又は置換の4〜6員のC-結合型複素環基及び下記式:
のN-結合型スピロ基から選択され;
R 2 及びR 2' は、同一であるか又は異なり、それぞれH又はC 1-6 アルキルであるか;あるいはR 2 とR 2' とが、それらが結合しているC原子と一緒になって、C 3-6 シクロアルキル基を形成し;
R 3 及びR 3' は、同一であるか又は異なり、それぞれH、C 1-6 アルキル、OH又はFであり;
R 4 は、非置換であるか又は置換されている、フェニル又は5〜12員のN含有ヘテロアリール基であり;
alkは、C 1-6 アルキレンであり;
R'は、C 1-6 アルキルであり;かつ
nは、0又は1である)
のベンズイミダゾリルイソオキサゾールである化合物、又はその医薬上許容される塩。
[2] 前記ベンズイミダゾリルイソオキサゾールが、下記式(Ia):
(式中、R 9 、R 9’ 、R 9’’ 、X、R 1 、R 2 、R 2’ 、R 3 、R 3’ 及びR 4 のそれぞれが、[1]中で、式(I)について記載したとおりである)を有する、[1]に記載の化合物。
[3] 前記ベンズイミダゾリルイソオキサゾールが、下記式(Ib):
(式中:
R 9 、R 9' 及びR 9'' は、式(I)について上記したとおりであり;
X'は、C 1-3 アルキレン又は-(CH 2 )-C(=O)-NH-であり;
R 2' は、H、Me又はEtであり;
R 5 は、Hであり、R 6 は、-S(=O) 2 Meであるか、又はR 5 及びR 6 は、それらが結合している炭素原子と一緒になって、ピロリジニル、チオピラニル、ピラニル及びピペリジニルから選択される非置換又は置換の複素環基を形成し;
Wは、C又はNであり;かつ
R 7 及びR 8 はそれらが結合しているC又はN原子と一緒になって、フェニル、ピリジニル、ピリミジニル、キノリニル、イソキノリニル、ピロロピリジニル及びキノキサリニルから選択される、非置換又は置換の基を形成する)を有する、[1]に記載の化合物。
[4] R 2 (式(I)及び式(Ia)の場合)がHであり、R 2’ がC 1-6 アルキルであり、C-R 2’ 結合が、
化合物がRエナンチオマーである、前記[1]〜[3]のいずれか一項に記載の化合物。
[5] 4-(2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1-(1-メチルピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(1-メチルピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
4-(2-(1-(4-フルオロフェニル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
3,5-ジメチル-4-(2-(1-(ピリジン-2-イル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)イソオキサゾール;
4-(2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
1-(4-((2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)メチル)ピペリジン-1-イル)エタン-1-オン;
4-(2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1-((テトラヒドロ-2H-ピラン-4-イル)メチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(3-クロロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
4-(2-(1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
4-(2-(3,4-ジクロロフェネチル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
4-(2-(4-エチルフェネチル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(2-(1H-ピロロ[2,3-b]ピリジン-3-イル)エチル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
3,5-ジメチル-4-(2-(2-(キノキサリン-2-イル)エチル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)イソオキサゾール;
2-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(3-フルオロ-4-メトキシフェネチル)-1H-ベンゾ[d]イミダゾール-1-イル)-N-(テトラヒドロフラン-3-イル)アセトアミド;
2-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(3-フルオロ-4-メトキシフェネチル)-1H-ベンゾ[d]イミダゾール-1-イル)-N-(テトラヒドロフラン-3-イル)アセトアミド;
2-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)-N-(テトラヒドロフラン-3-イル)アセトアミド;
4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(R)-4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(S)-4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
3-(2-((R)-1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド;
3-(2-((S)-1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド;
4-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((R)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((R)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(R)-4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(S)-4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
4-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((S)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((S)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(R)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(S)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
((R)-3-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
((R)-3-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
(R)-3-(2-((R)-1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
(R)-4-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(S)-4-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(S)-3-(2-((R)-1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド;
(S)-3-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド;
(S)-3-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド;
(R)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(S)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
及びその医薬上許容される塩から選択される[1]に記載の化合物。
[6] 式(II):
(式中、R 1 、R 2 、R 2’ 、R 3 、R 3’ 、R 4 、R 9 、R 9’ 及びR 9’’ のそれぞれは、式(I)について上記したとおりである)の化合物を、式(III):
(式中、R 0 及びRのそれぞれは、式(I)について上記したとおりである)のボロン酸で水性エタノール中、Pd(PPh 3 ) 4 及びNa 2 CO 3 の存在下で処理することを含む、[1]に記載の化合物を製造する方法。
[7] 得られた式(I)のベンズイミダゾリルイソオキサゾールをその医薬上許容される塩へと変換させることをさらに含む、[6]に記載の方法。
[8] 医薬上許容される担体又は希釈剤と、有効成分として[1]〜[5]のいずれか1項に記載の化合物とを含む、医薬組成物。
[9] 療法による人体又は動物体の治療のための、[1]〜[5]のいずれか1項に記載の化合物の使用。
[10] p300及び/又はCBP活性のモジュレーターとしての、[1]〜[5]のいずれか1項に記載の化合物の使用。
[11] 癌の治療における、[1]〜[5]のいずれか1項に記載の化合物の使用。
[12] 前記癌が、ARを発現する癌である、[11]に記載の化合物の使用。
[13] p300及び/又はCBP活性のモジュレーターとして使用するための医薬の製造における、[1]〜[5]のいずれか1項に記載の化合物の使用。
[14] [1]〜[5]のいずれか1項に記載の化合物を、癌の治療を必要とする患者に投与することを含む、癌の治療方法。
[15] 前記化合物が、放射線療法と同時に又は連続して投与される;あるいは別の1つの化学療法剤又は複数の化学療法剤と同時に、連続して、又は組み合わせ製剤として投与される、[14]に記載の方法。
[16] 癌の予防的又は治療処置において、別々に、同時に又は連続して投与するための、
(a) [1]〜[5]のいずれか1項に記載の化合物;及び
(b) 化学療法剤
を含む製品。
Claims (7)
- 下記式(I)
(式中:
R0及びRは、同一であるか又は異なり、それぞれH又はC1-6アルキルであり;
R9、R9’及びR9’’は、同一であるか又は異なり、それぞれH又はFであり;
Xは、-(alk)n-、-alk-C(=O)-NR-、-alk-NR-C(=O)-又は-alk-C(=O)-であり;
R1は、-S(=O)2R'、非置換又は置換の4〜6員のC-結合型複素環基及び下記式:
のN-結合型スピロ基から選択され;
R2及びR2'は、同一であるか又は異なり、それぞれH又はC1-6アルキルであるか;あるいはR2とR2'とが、それらが結合しているC原子と一緒になって、C3-6シクロアルキル基を形成し;
R3及びR3'は、同一であるか又は異なり、それぞれH、C1-6アルキル、OH又はFであり;
R4は、非置換であるか又は置換されている、フェニル又は5〜12員のN含有ヘテロアリール基であり;
alkは、C1-6アルキレンであり;
R'は、C1-6アルキルであり;かつ
nは、0又は1である)
のベンズイミダゾリルイソオキサゾールである化合物、又はその医薬上許容される塩。 - 前記ベンズイミダゾリルイソオキサゾールが、下記式(Ib):
(式中:
R9、R9'及びR9''は、式(I)について上記したとおりであり;
X'は、C1-3アルキレン又は-(CH2)-C(=O)-NH-であり;
R2'は、H、Me又はEtであり;
R5及びR6は、それらが結合している炭素原子と一緒になって、ピロリジニル、チオピラニル、ピラニル及びピペリジニルから選択される非置換又は置換の複素環基を形成し;
Wは、C又はNであり;かつ
R7及びR8はそれらが結合しているC又はN原子と一緒になって、フェニル、ピリジニル、ピリミジニル、キノリニル、イソキノリニル、ピロロピリジニル及びキノキサリニルから選択される、非置換又は置換の基を形成する)を有する、請求項1に記載の化合物。 - 4-(2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1-(1-メチルピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(1-メチルピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン1,1-ジオキシド;
4-(2-(1-(4-フルオロフェニル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
3,5-ジメチル-4-(2-(1-(ピリジン-2-イル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)イソオキサゾール;
4-(2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1-(1-メチルピペリジン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
1-(4-((2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)メチル)ピペリジン-1-イル)エタン-1-オン;
4-(2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1-((テトラヒドロ-2H-ピラン-4-イル)メチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(3-クロロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
4-(2-(1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
4-(2-(3,4-ジクロロフェネチル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン1,1-ジオキシド;
4-(2-(4-エチルフェネチル)-1-(3-(メチルスルホニル)プロピル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(2-(1H-ピロロ[2,3-b]ピリジン-3-イル)エチル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
3,5-ジメチル-4-(2-(2-(キノキサリン-2-イル)エチル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)イソオキサゾール;
2-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(3-フルオロ-4-メトキシフェネチル)-1H-ベンゾ[d]イミダゾール-1-イル)-N-(テトラヒドロフラン-3-イル)アセトアミド;
2-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(3-フルオロ-4-メトキシフェネチル)-1H-ベンゾ[d]イミダゾール-1-イル)-N-(テトラヒドロフラン-3-イル)アセトアミド;
2-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-メトキシフェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)-N-(テトラヒドロフラン-3-イル)アセトアミド;
4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン1,1-ジオキシド;
(R)-4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(S)-4-(2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1-(2-(テトラヒドロ-2H-ピラン-4-イル)エチル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
3-(2-((R)-1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
3-(2-((S)-1-(3-クロロ-4-(ジフルオロメトキシ)フェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
4-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((R)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((R)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(R)-4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン1,1-ジオキシド;
(S)-4-(2-(1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン1,1-ジオキシド;
4-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((S)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
4-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-((S)-1-(メチルスルホニル)ピロリジン-3-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(R)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(S)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
((R)-3-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
((R)-3-(2-((S)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
(R)-3-(2-((R)-1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
(R)-4-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(S)-4-(5-(3,5-ジメチルイソオキサゾール-4-イル)-2-(1-(3-フルオロ-4-(トリフルオロメトキシ)フェニル)プロパン-2-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロ-2H-チオピラン 1,1-ジオキシド;
(S)-3-(2-((R)-1-(4-クロロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン 1,1-ジオキシド;
(S)-3-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
(S)-3-(2-((R)-1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-5-(3,5-ジメチルイソオキサゾール-4-イル)-1H-ベンゾ[d]イミダゾール-1-イル)テトラヒドロチオフェン1,1-ジオキシド;
(R)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
(S)-4-(2-(1-(4-クロロ-3-フルオロフェニル)プロパン-2-イル)-1-(テトラヒドロ-2H-ピラン-4-イル)-1H-ベンゾ[d]イミダゾール-5-イル)-3,5-ジメチルイソオキサゾール;
及びその医薬上許容される塩から選択される請求項1に記載の化合物。 - 得られた式(I)のベンズイミダゾリルイソオキサゾールをその医薬上許容される塩へと変換させることをさらに含む、請求項6に記載の方法。
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2016
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- 2016-04-20 CN CN201680035337.3A patent/CN107750249A/zh active Pending
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- 2016-04-20 HU HUE16718863A patent/HUE056334T2/hu unknown
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- 2016-04-20 JP JP2017554817A patent/JP6871864B2/ja active Active
- 2016-04-20 ES ES16718863T patent/ES2888473T3/es active Active
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Also Published As
Publication number | Publication date |
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CN107750249A (zh) | 2018-03-02 |
US20180127402A1 (en) | 2018-05-10 |
HUE056334T2 (hu) | 2022-02-28 |
GB201506658D0 (en) | 2015-06-03 |
DK3286183T3 (da) | 2021-09-20 |
ES2888473T3 (es) | 2022-01-04 |
EP3286183B1 (en) | 2021-08-25 |
WO2016170324A1 (en) | 2016-10-27 |
US10118920B2 (en) | 2018-11-06 |
JP2018519249A (ja) | 2018-07-19 |
EP3286183A1 (en) | 2018-02-28 |
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