RU2629947C2 - Ингибиторы деацетилаз гистонов (hdacs) - Google Patents
Ингибиторы деацетилаз гистонов (hdacs) Download PDFInfo
- Publication number
- RU2629947C2 RU2629947C2 RU2014144142A RU2014144142A RU2629947C2 RU 2629947 C2 RU2629947 C2 RU 2629947C2 RU 2014144142 A RU2014144142 A RU 2014144142A RU 2014144142 A RU2014144142 A RU 2014144142A RU 2629947 C2 RU2629947 C2 RU 2629947C2
- Authority
- RU
- Russia
- Prior art keywords
- oxo
- hydroxyamino
- hydroxyaminocarbonyl
- dihydro
- ethyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims abstract 5
- 102000006947 Histones Human genes 0.000 title 1
- 108010033040 Histones Proteins 0.000 title 1
- -1 N-hydroxyaminocarbonylphenyl Chemical group 0.000 claims abstract description 122
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 73
- 239000001257 hydrogen Substances 0.000 claims abstract description 45
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 31
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 31
- 125000003118 aryl group Chemical group 0.000 claims abstract description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 22
- 230000000694 effects Effects 0.000 claims abstract description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 17
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical group 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 230000001771 impaired effect Effects 0.000 claims abstract description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 206010029098 Neoplasm skin Diseases 0.000 claims abstract description 5
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
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- 206010073071 hepatocellular carcinoma Diseases 0.000 claims abstract description 4
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims abstract description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims abstract description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims abstract description 3
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims abstract description 3
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims abstract description 3
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- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims abstract description 3
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- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims abstract description 3
- 206010023774 Large cell lung cancer Diseases 0.000 claims abstract description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims abstract description 3
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- 206010041067 Small cell lung cancer Diseases 0.000 claims abstract description 3
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- 206010017758 gastric cancer Diseases 0.000 claims abstract description 3
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 3
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 8
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- 150000002431 hydrogen Chemical class 0.000 claims description 15
- 239000003937 drug carrier Substances 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 239000000460 chlorine Substances 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 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
- 239000003276 histone deacetylase inhibitor Substances 0.000 claims description 8
- 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 7
- 229940121372 histone deacetylase inhibitor Drugs 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
- 208000024827 Alzheimer disease Diseases 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-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
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 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 4
- 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 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
- 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 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
- 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 4
- 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 4
- 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 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
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-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
- VERZRJYONMSRFY-UHFFFAOYSA-N 4-[2-ethyl-4-oxo-3-(2-phenylethyl)quinazolin-8-yl]-n-hydroxybenzamide Chemical compound CCC1=NC2=C(C=3C=CC(=CC=3)C(=O)NO)C=CC=C2C(=O)N1CCC1=CC=CC=C1 VERZRJYONMSRFY-UHFFFAOYSA-N 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
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 4
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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 3
- 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
- PYZKRYQFSYSEQK-VQHVLOKHSA-N (e)-n-hydroxy-3-[3-[2-(1h-indol-3-yl)ethyl]-2-methyl-4-oxoquinazolin-7-yl]prop-2-enamide Chemical compound C1=CC=C2C(CCN3C(=O)C4=CC=C(\C=C\C(=O)NO)C=C4N=C3C)=CNC2=C1 PYZKRYQFSYSEQK-VQHVLOKHSA-N 0.000 claims description 3
- 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 3
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| CN108349985A (zh) | 2015-09-14 | 2018-07-31 | 无限药品股份有限公司 | 异喹啉酮的固体形式、其制备方法、包含其的组合物及其使用方法 |
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| CN111517977B (zh) * | 2020-05-28 | 2023-05-23 | 爱斯特（成都）生物制药股份有限公司 | 一种合成2,4-二氟-3-三甲基乙酰胺基苯甲酸的方法 |
| JP2023530788A (ja) * | 2020-06-08 | 2023-07-19 | アンジー ファーマシューティカル カンパニー リミテッド | 選択的ｈｄａｃ６阻害剤として有用なキナゾリン誘導体 |
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| WO2025085669A1 (en) * | 2023-10-18 | 2025-04-24 | Gilva Therapeutics Co., Ltd. | Quinazolinone derivatives for hdac inhibition |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL6716429A (enExample) * | 1966-12-02 | 1968-06-04 | ||
| DE1620284A1 (de) * | 1965-05-12 | 1970-03-12 | Sumitomo Chemical Co | Verfahren zur Herstellung von Chinazolinonderivaten |
| SU419034A3 (ru) * | 1969-08-02 | 1974-03-05 | Сигехо Инаба, Мичихиро Ямамото, Кикуо Исизуми, Казуо Мори | СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ ХИНАЗОЛИНА1Изобретение относитс к способу получени новых производных хиназолина, которые обладают улучшенными лекарственными свойствами и могут найти нрименение в фармацевтической промышленности.Предлагаетс основанный на известной реакции алкилировани хиназолннов способ получени производных хиназолина общей формулы ICnH,n--R.Примером галоида в формуле I могут служить атомы хлора, брома, фтора и йода; Ci—С4-алкилов — метил, этил, н-пропил, изо- пропил, н-бутил, изобутил и т/?ет-бутил; 5 Ci—С4-алкоксильных групп — метокси-, эток- СИ-, н-пропокси-, изопронокси-, н-бутокси-, изо- бутокси- и грег-бутоксигруппы; Сз—Се-цикло- алкилов — циклопропил, циклобутил, цикло- пентил, циклогексил, метилциклопропил, ди- 10 метилциклопронил и т. п. группы. Когда СпН2п группа — алкилен с 1—3 атомами углерода, она может быть представлена такими группами, как метиленова , этиленова , 1-метилэти- ленова , 2-метилэтиленова и триметиленова .где D — группаСпособ получени соединений формулы 1 заключаетс в том, что 1-незамеш,енное производное хиназолина общей формулы П15Нг; , :- ;-О "^ О ."^ -'.RI, R2 и Rs каждый — водород, галоид, нит- рогруппа, Ci—С4-алкил, Ci—Сгалкоксил, С\—С4-алкилтиогруП'Па, Ci—С^алкилсульфо- группа, Ci—С4-алкилсульфинильна группа, грифторметил;R4 — Сз—Сб-циклоалг-'ил;W — кислород или сера;п — О или целое число от 1 до 3.2025где RI, Ra, D и W имеют вышеуказанные зна- 30 чени . |
| US4054658A (en) * | 1974-02-06 | 1977-10-18 | William H. Rorer, Inc. | Therapeutic compositions containing methaqualone |
| US4276295A (en) * | 1978-12-19 | 1981-06-30 | Masayuki Ishikawa | 3-Aromatic moiety substituted-4(3H)-quinazolinones, process for production thereof, and use thereof |
| US20060052345A1 (en) * | 2002-11-04 | 2006-03-09 | Nps Pharmaceuticals, Inc. | Quinazolinone compounds as calcilytics |
| US20070032502A1 (en) * | 2005-07-15 | 2007-02-08 | Schering Corporation | Quinazoline derivatives useful in cancer treatment |
| US20090082365A1 (en) * | 2005-12-08 | 2009-03-26 | Novartis Ag | Trisubstituted Quinazolinone Derivatives as Vanilloid Antagonists |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3488890B2 (ja) * | 1993-11-09 | 2004-01-19 | アグロカネショウ株式会社 | ３−ｎ−置換キナゾリノン誘導体、その製造法および該化合物を含有する除草剤 |
| EP1524262A1 (en) * | 2000-03-24 | 2005-04-20 | Methylgene, Inc. | Inhibitors of histone deacetylase |
| ATE489360T1 (de) * | 2000-03-24 | 2010-12-15 | Methylgene Inc | Inhibitoren der histon-deacetylase |
| ITMI20041869A1 (it) | 2004-10-01 | 2005-01-01 | Dac Srl | Nuovi inibitori delle istone deacetilasi |
| CN101287706A (zh) | 2005-09-21 | 2008-10-15 | 尼科梅德有限责任公司 | 作为组蛋白脱乙酰基酶抑制剂的磺酰基吡咯盐酸盐 |
| GB0619753D0 (en) | 2006-10-06 | 2006-11-15 | Chroma Therapeutics Ltd | Enzyme inhibitors |
| GB0624187D0 (en) | 2006-12-04 | 2007-01-10 | Jackson William P | HDAC inhibitors |
| WO2008087514A2 (en) | 2007-01-17 | 2008-07-24 | Orchid Research Laboratories Limited | Hdac inhibitors |
| US20100261710A1 (en) | 2007-08-21 | 2010-10-14 | Arqule, Inc. | HDAC Inhibitors |
| AU2008307541B2 (en) | 2007-10-01 | 2015-02-12 | Lixte Biotechnology, Inc. | HDAC inhibitors |
| WO2011011186A2 (en) | 2009-07-22 | 2011-01-27 | The Board Of Trustees Of The University Of Illinois | Hdac inhibitors and therapeutic methods using the same |
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Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1620284A1 (de) * | 1965-05-12 | 1970-03-12 | Sumitomo Chemical Co | Verfahren zur Herstellung von Chinazolinonderivaten |
| NL6716429A (enExample) * | 1966-12-02 | 1968-06-04 | ||
| SU419034A3 (ru) * | 1969-08-02 | 1974-03-05 | Сигехо Инаба, Мичихиро Ямамото, Кикуо Исизуми, Казуо Мори | СПОСОБ ПОЛУЧЕНИЯ ПРОИЗВОДНЫХ ХИНАЗОЛИНА1Изобретение относитс к способу получени новых производных хиназолина, которые обладают улучшенными лекарственными свойствами и могут найти нрименение в фармацевтической промышленности.Предлагаетс основанный на известной реакции алкилировани хиназолннов способ получени производных хиназолина общей формулы ICnH,n--R.Примером галоида в формуле I могут служить атомы хлора, брома, фтора и йода; Ci—С4-алкилов — метил, этил, н-пропил, изо- пропил, н-бутил, изобутил и т/?ет-бутил; 5 Ci—С4-алкоксильных групп — метокси-, эток- СИ-, н-пропокси-, изопронокси-, н-бутокси-, изо- бутокси- и грег-бутоксигруппы; Сз—Се-цикло- алкилов — циклопропил, циклобутил, цикло- пентил, циклогексил, метилциклопропил, ди- 10 метилциклопронил и т. п. группы. Когда СпН2п группа — алкилен с 1—3 атомами углерода, она может быть представлена такими группами, как метиленова , этиленова , 1-метилэти- ленова , 2-метилэтиленова и триметиленова .где D — группаСпособ получени соединений формулы 1 заключаетс в том, что 1-незамеш,енное производное хиназолина общей формулы П15Нг; , :- ;-О "^ О ."^ -'.RI, R2 и Rs каждый — водород, галоид, нит- рогруппа, Ci—С4-алкил, Ci—Сгалкоксил, С\—С4-алкилтиогруП'Па, Ci—С^алкилсульфо- группа, Ci—С4-алкилсульфинильна группа, грифторметил;R4 — Сз—Сб-циклоалг-'ил;W — кислород или сера;п — О или целое число от 1 до 3.2025где RI, Ra, D и W имеют вышеуказанные зна- 30 чени . |
| US4054658A (en) * | 1974-02-06 | 1977-10-18 | William H. Rorer, Inc. | Therapeutic compositions containing methaqualone |
| US4276295A (en) * | 1978-12-19 | 1981-06-30 | Masayuki Ishikawa | 3-Aromatic moiety substituted-4(3H)-quinazolinones, process for production thereof, and use thereof |
| US20060052345A1 (en) * | 2002-11-04 | 2006-03-09 | Nps Pharmaceuticals, Inc. | Quinazolinone compounds as calcilytics |
| US20070032502A1 (en) * | 2005-07-15 | 2007-02-08 | Schering Corporation | Quinazoline derivatives useful in cancer treatment |
| US20090082365A1 (en) * | 2005-12-08 | 2009-03-26 | Novartis Ag | Trisubstituted Quinazolinone Derivatives as Vanilloid Antagonists |
| RU2008127257A (ru) * | 2005-12-08 | 2010-01-20 | Новартис АГ (CH) | Тризамещенные производные хиназолинона в качестве ваниллоидных антагонистов |
Non-Patent Citations (2)
| Title |
|---|
| US 2009082365 A1, 26.03.2009 * |
| и * |
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| US20150196563A1 (en) | 2015-07-16 |
| EP2836484B1 (en) | 2017-06-14 |
| BR112014025122A2 (pt) | 2021-07-06 |
| TWI481597B (zh) | 2015-04-21 |
| US20130267542A1 (en) | 2013-10-10 |
| US9387209B2 (en) | 2016-07-12 |
| RU2014144142A (ru) | 2016-06-10 |
| CN104364237B (zh) | 2016-08-24 |
| ES2630062T3 (es) | 2017-08-17 |
| EP2836484A4 (en) | 2015-09-02 |
| IN2014MN02104A (enExample) | 2015-09-04 |
| US9155739B2 (en) | 2015-10-13 |
| BR112014025122B1 (pt) | 2022-08-16 |
| KR20150000901A (ko) | 2015-01-05 |
| CN104364237A (zh) | 2015-02-18 |
| JP2015512939A (ja) | 2015-04-30 |
| JP6258918B2 (ja) | 2018-01-10 |
| IL235053A (en) | 2017-09-28 |
| KR101781922B1 (ko) | 2017-09-26 |
| AU2013246278B2 (en) | 2016-11-03 |
| TW201345898A (zh) | 2013-11-16 |
| EP2836484A1 (en) | 2015-02-18 |
| WO2013154870A1 (en) | 2013-10-17 |
| AU2013246278A1 (en) | 2014-11-13 |
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