JP6258918B2 - ヒストンデアセチラーゼ（ｈｄａｃｓ）阻害剤 - Google Patents
ヒストンデアセチラーゼ（ｈｄａｃｓ）阻害剤 Download PDFInfo
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- JP6258918B2 JP6258918B2 JP2015505789A JP2015505789A JP6258918B2 JP 6258918 B2 JP6258918 B2 JP 6258918B2 JP 2015505789 A JP2015505789 A JP 2015505789A JP 2015505789 A JP2015505789 A JP 2015505789A JP 6258918 B2 JP6258918 B2 JP 6258918B2
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- Prior art keywords
- oxo
- dihydro
- hydroxyacrylamide
- ethyl
- hydroxyamino
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- 102000003964 Histone deacetylase Human genes 0.000 title claims description 16
- 108090000353 Histone deacetylase Proteins 0.000 title claims description 16
- 239000003112 inhibitor Substances 0.000 title description 2
- -1 N-hydroxyaminocarbonyl Chemical group 0.000 claims description 121
- 150000001875 compounds Chemical class 0.000 claims description 100
- 229910052739 hydrogen Inorganic materials 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 34
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 201000011510 cancer Diseases 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 239000003981 vehicle Substances 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- VAAWIYIVFTYJRI-VQHVLOKHSA-N (e)-n-hydroxy-3-[4-oxo-3-(2-phenylethyl)quinazolin-7-yl]prop-2-enamide Chemical compound C=1C(/C=C/C(=O)NO)=CC=C(C2=O)C=1N=CN2CCC1=CC=CC=C1 VAAWIYIVFTYJRI-VQHVLOKHSA-N 0.000 claims description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 8
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- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- NAMOJMZBPJZNOD-CMDGGOBGSA-N (e)-3-[2-ethyl-7-fluoro-4-oxo-3-(2-phenylethyl)quinazolin-6-yl]-n-hydroxyprop-2-enamide Chemical compound CCC1=NC2=CC(F)=C(\C=C\C(=O)NO)C=C2C(=O)N1CCC1=CC=CC=C1 NAMOJMZBPJZNOD-CMDGGOBGSA-N 0.000 claims description 6
- 231100000135 cytotoxicity Toxicity 0.000 claims description 6
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- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- DROCPQHWNIUOQA-CSKARUKUSA-N (e)-3-(3-benzyl-2-methyl-4-oxoquinazolin-7-yl)-n-hydroxyprop-2-enamide Chemical compound CC1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1CC1=CC=CC=C1 DROCPQHWNIUOQA-CSKARUKUSA-N 0.000 claims description 5
- KOGSPXQDGNAZKQ-YRNVUSSQSA-N (e)-3-[2-cyclopropyl-4-oxo-3-(2-phenylethyl)quinazolin-7-yl]-n-hydroxyprop-2-enamide Chemical compound C=1C(/C=C/C(=O)NO)=CC=C(C(N2CCC=3C=CC=CC=3)=O)C=1N=C2C1CC1 KOGSPXQDGNAZKQ-YRNVUSSQSA-N 0.000 claims description 5
- OSGSDDYIACXJCX-ACCUITESSA-N (e)-3-[2-ethyl-4-oxo-3-(3-phenylpropyl)quinazolin-7-yl]-n-hydroxyprop-2-enamide Chemical compound CCC1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1CCCC1=CC=CC=C1 OSGSDDYIACXJCX-ACCUITESSA-N 0.000 claims description 5
- MDTWRJDWPUJHKT-CSKARUKUSA-N (e)-n-hydroxy-3-(2-methyl-4-oxo-3-phenylquinazolin-7-yl)prop-2-enamide Chemical compound CC1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1C1=CC=CC=C1 MDTWRJDWPUJHKT-CSKARUKUSA-N 0.000 claims description 5
- STSNTVHQAOSMDW-ZHACJKMWSA-N (e)-n-hydroxy-3-(2-methyl-4-oxo-3-phenylquinazolin-8-yl)prop-2-enamide Chemical compound CC1=NC2=C(\C=C\C(=O)NO)C=CC=C2C(=O)N1C1=CC=CC=C1 STSNTVHQAOSMDW-ZHACJKMWSA-N 0.000 claims description 5
- NVEBAMFLYZFKKW-CSKARUKUSA-N (e)-n-hydroxy-3-[2-methyl-4-oxo-3-(2-phenylethyl)quinazolin-7-yl]prop-2-enamide Chemical compound CC1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1CCC1=CC=CC=C1 NVEBAMFLYZFKKW-CSKARUKUSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
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- HKISHKJJYBCZQL-UXBLZVDNSA-N (e)-3-[2-ethyl-3-[2-(4-fluorophenyl)ethyl]-4-oxoquinazolin-7-yl]-n-hydroxyprop-2-enamide Chemical compound CCC1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1CCC1=CC=C(F)C=C1 HKISHKJJYBCZQL-UXBLZVDNSA-N 0.000 claims description 4
- DWWXXRKGLLUOGK-YRNVUSSQSA-N (e)-3-[2-ethyl-3-[2-(4-methoxyphenyl)ethyl]-4-oxoquinazolin-7-yl]-n-hydroxyprop-2-enamide Chemical compound CCC1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1CCC1=CC=C(OC)C=C1 DWWXXRKGLLUOGK-YRNVUSSQSA-N 0.000 claims description 4
- AULBTEVAVDTQLP-PKNBQFBNSA-N (e)-3-[2-ethyl-4-oxo-3-(2-phenylethyl)quinazolin-7-yl]-n-hydroxyprop-2-enamide Chemical compound CCC1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1CCC1=CC=CC=C1 AULBTEVAVDTQLP-PKNBQFBNSA-N 0.000 claims description 4
- RGKDACUEVSPDNA-CMDGGOBGSA-N (e)-3-[2-ethyl-6-fluoro-4-oxo-3-(2-phenylethyl)quinazolin-7-yl]-n-hydroxyprop-2-enamide Chemical compound CCC1=NC2=CC(\C=C\C(=O)NO)=C(F)C=C2C(=O)N1CCC1=CC=CC=C1 RGKDACUEVSPDNA-CMDGGOBGSA-N 0.000 claims description 4
- DRLAOVNZDDOIAG-CMDGGOBGSA-N (e)-3-[7-chloro-2-ethyl-4-oxo-3-(2-phenylethyl)quinazolin-6-yl]-n-hydroxyprop-2-enamide Chemical compound CCC1=NC2=CC(Cl)=C(\C=C\C(=O)NO)C=C2C(=O)N1CCC1=CC=CC=C1 DRLAOVNZDDOIAG-CMDGGOBGSA-N 0.000 claims description 4
- KUKBDBQCXIHWRC-ZHACJKMWSA-N (e)-n-hydroxy-3-(2-methyl-4-oxo-3-phenylquinazolin-5-yl)prop-2-enamide Chemical compound CC1=NC2=CC=CC(\C=C\C(=O)NO)=C2C(=O)N1C1=CC=CC=C1 KUKBDBQCXIHWRC-ZHACJKMWSA-N 0.000 claims description 4
- SDVRJMHVMXPKQZ-PKNBQFBNSA-N (e)-n-hydroxy-3-[4-oxo-3-(2-phenylethyl)-2-propan-2-ylquinazolin-7-yl]prop-2-enamide Chemical compound CC(C)C1=NC2=CC(\C=C\C(=O)NO)=CC=C2C(=O)N1CCC1=CC=CC=C1 SDVRJMHVMXPKQZ-PKNBQFBNSA-N 0.000 claims description 4
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- VLBQAJZSHGGUBQ-UHFFFAOYSA-N 4-[[2-ethyl-4-oxo-3-(2-phenylethyl)quinazolin-6-yl]methyl]-n-hydroxybenzamide Chemical compound C1=C2C(=O)N(CCC=3C=CC=CC=3)C(CC)=NC2=CC=C1CC1=CC=C(C(=O)NO)C=C1 VLBQAJZSHGGUBQ-UHFFFAOYSA-N 0.000 claims description 4
- LQAXATZNWUNYBS-UHFFFAOYSA-N 4-[[2-ethyl-4-oxo-3-(2-phenylethyl)quinazolin-7-yl]methyl]-n-hydroxybenzamide Chemical compound C=1C=C2C(=O)N(CCC=3C=CC=CC=3)C(CC)=NC2=CC=1CC1=CC=C(C(=O)NO)C=C1 LQAXATZNWUNYBS-UHFFFAOYSA-N 0.000 claims description 4
- HPCPCLJRBNRLLW-UHFFFAOYSA-N 4-[[2-ethyl-4-oxo-3-(2-phenylethyl)quinazolin-8-yl]methyl]-n-hydroxybenzamide Chemical compound C1=CC=C2C(=O)N(CCC=3C=CC=CC=3)C(CC)=NC2=C1CC1=CC=C(C(=O)NO)C=C1 HPCPCLJRBNRLLW-UHFFFAOYSA-N 0.000 claims description 4
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- 230000003831 deregulation Effects 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- JNOVVOHLHNGPOH-CSKARUKUSA-N (e)-n-hydroxy-3-(2-methyl-4-oxo-3-phenylquinazolin-6-yl)prop-2-enamide Chemical compound CC1=NC2=CC=C(\C=C\C(=O)NO)C=C2C(=O)N1C1=CC=CC=C1 JNOVVOHLHNGPOH-CSKARUKUSA-N 0.000 claims description 3
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- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
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- WBEKWMCWJUVKEG-UHFFFAOYSA-N 2-[7-chloro-2-ethyl-4-oxo-3-(2-phenylethyl)quinazolin-6-yl]-N-hydroxyprop-2-enamide Chemical compound ClC1=C(C=C2C(N(C(=NC2=C1)CC)CCC1=CC=CC=C1)=O)C(C(=O)NO)=C WBEKWMCWJUVKEG-UHFFFAOYSA-N 0.000 claims 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
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Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
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Landscapes
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| EP2200439B1 (en) | 2007-10-01 | 2017-03-22 | Lixte Biotechnology, Inc. | Hdac inhibitors |
| ES2736200T3 (es) | 2009-07-22 | 2019-12-26 | Univ Illinois | Inhibidores de HDAC y métodos terapéuticos que utilizan los mismos |
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| JP2015512939A (ja) | 2015-04-30 |
| TWI481597B (zh) | 2015-04-21 |
| CN104364237B (zh) | 2016-08-24 |
| EP2836484A4 (en) | 2015-09-02 |
| AU2013246278B2 (en) | 2016-11-03 |
| US9155739B2 (en) | 2015-10-13 |
| TW201345898A (zh) | 2013-11-16 |
| KR101781922B1 (ko) | 2017-09-26 |
| EP2836484B1 (en) | 2017-06-14 |
| EP2836484A1 (en) | 2015-02-18 |
| US9387209B2 (en) | 2016-07-12 |
| CN104364237A (zh) | 2015-02-18 |
| US20150196563A1 (en) | 2015-07-16 |
| US20130267542A1 (en) | 2013-10-10 |
| BR112014025122B1 (pt) | 2022-08-16 |
| ES2630062T3 (es) | 2017-08-17 |
| IL235053A (en) | 2017-09-28 |
| BR112014025122A2 (pt) | 2021-07-06 |
| RU2629947C2 (ru) | 2017-09-05 |
| RU2014144142A (ru) | 2016-06-10 |
| WO2013154870A1 (en) | 2013-10-17 |
| KR20150000901A (ko) | 2015-01-05 |
| AU2013246278A1 (en) | 2014-11-13 |
| IN2014MN02104A (forum.php) | 2015-09-04 |
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