JP4953456B2 - 選択的アンドロゲン受容体モジュレーター(sarm)として有用な新規なベンゾイミダゾール誘導体 - Google Patents
選択的アンドロゲン受容体モジュレーター(sarm)として有用な新規なベンゾイミダゾール誘導体 Download PDFInfo
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- JP4953456B2 JP4953456B2 JP2007534694A JP2007534694A JP4953456B2 JP 4953456 B2 JP4953456 B2 JP 4953456B2 JP 2007534694 A JP2007534694 A JP 2007534694A JP 2007534694 A JP2007534694 A JP 2007534694A JP 4953456 B2 JP4953456 B2 JP 4953456B2
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- alkyl
- dichloro
- ethyl
- trifluoro
- mmol
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- 239000000849 selective androgen receptor modulator Substances 0.000 title description 4
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 title description 3
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 302
- 150000001875 compounds Chemical class 0.000 claims description 280
- -1 5,6-dichloro-1H-benzimidazol-2-yl Chemical group 0.000 claims description 137
- 229910052736 halogen Inorganic materials 0.000 claims description 110
- 150000002367 halogens Chemical class 0.000 claims description 110
- 239000001257 hydrogen Substances 0.000 claims description 105
- 229910052739 hydrogen Inorganic materials 0.000 claims description 105
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 51
- 150000002431 hydrogen Chemical class 0.000 claims description 47
- 125000001424 substituent group Chemical group 0.000 claims description 45
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- GJNGKNSKNKYXFT-UHFFFAOYSA-N 1-(5,6-dichloro-1h-benzimidazol-2-yl)-2,2,2-trifluoroethanol Chemical compound ClC1=C(Cl)C=C2NC(C(O)C(F)(F)F)=NC2=C1 GJNGKNSKNKYXFT-UHFFFAOYSA-N 0.000 claims description 3
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 481
- 235000019439 ethyl acetate Nutrition 0.000 description 215
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 188
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 141
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- 239000000203 mixture Substances 0.000 description 134
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- 238000006243 chemical reaction Methods 0.000 description 82
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- 239000000243 solution Substances 0.000 description 74
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 58
- 238000004440 column chromatography Methods 0.000 description 57
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- 125000001072 heteroaryl group Chemical group 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 39
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- 238000000034 method Methods 0.000 description 38
- KOCYANYHJKEPAO-UHFFFAOYSA-N 1,4-dichloro-2-(2,2,2-trifluoroethyl)benzimidazole Chemical compound C1=CC=C2N(Cl)C(CC(F)(F)F)=NC2=C1Cl KOCYANYHJKEPAO-UHFFFAOYSA-N 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
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- WTPSGAGGBLVYRS-UHFFFAOYSA-N 5,6-dichloro-2-(2,2,2-trifluoroethyl)-1h-benzimidazole Chemical compound ClC1=C(Cl)C=C2NC(CC(F)(F)F)=NC2=C1 WTPSGAGGBLVYRS-UHFFFAOYSA-N 0.000 description 28
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- 125000003118 aryl group Chemical group 0.000 description 25
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 23
- 238000005259 measurement Methods 0.000 description 23
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- 238000003756 stirring Methods 0.000 description 20
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 20
- 239000000284 extract Substances 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
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- 239000002253 acid Substances 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
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- 125000003282 alkyl amino group Chemical group 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 125000005842 heteroatom Chemical group 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
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- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 14
- 125000000753 cycloalkyl group Chemical group 0.000 description 13
- 239000012299 nitrogen atmosphere Substances 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
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- 229910052717 sulfur Inorganic materials 0.000 description 11
- 102000001307 androgen receptors Human genes 0.000 description 10
- 108010080146 androgen receptors Proteins 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- 239000002775 capsule Substances 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- BVKGUTLIPHZYCX-UHFFFAOYSA-N 3,3,3-trifluoro-2-hydroxypropanoic acid Chemical compound OC(=O)C(O)C(F)(F)F BVKGUTLIPHZYCX-UHFFFAOYSA-N 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
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Landscapes
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| US60/614,751 | 2004-09-30 | ||
| PCT/US2005/034462 WO2006039243A1 (en) | 2004-09-30 | 2005-09-26 | Novel benzimidazole derivatives useful as selective androgen receptor modulators (sarms) |
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| JP2008514707A JP2008514707A (ja) | 2008-05-08 |
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| JP2007534694A Expired - Fee Related JP4953456B2 (ja) | 2004-09-30 | 2005-09-26 | 選択的アンドロゲン受容体モジュレーター(sarm)として有用な新規なベンゾイミダゾール誘導体 |
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| US8152837B2 (en) | 2004-10-20 | 2012-04-10 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods for posterior dynamic stabilization of the spine |
| US8945183B2 (en) | 2004-10-20 | 2015-02-03 | Vertiflex, Inc. | Interspinous process spacer instrument system with deployment indicator |
| US8128662B2 (en) | 2004-10-20 | 2012-03-06 | Vertiflex, Inc. | Minimally invasive tooling for delivery of interspinous spacer |
| WO2009009049A2 (en) | 2004-10-20 | 2009-01-15 | Vertiflex, Inc. | Interspinous spacer |
| US9023084B2 (en) | 2004-10-20 | 2015-05-05 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods for stabilizing the motion or adjusting the position of the spine |
| US8123782B2 (en) | 2004-10-20 | 2012-02-28 | Vertiflex, Inc. | Interspinous spacer |
| US8012207B2 (en) | 2004-10-20 | 2011-09-06 | Vertiflex, Inc. | Systems and methods for posterior dynamic stabilization of the spine |
| US9119680B2 (en) | 2004-10-20 | 2015-09-01 | Vertiflex, Inc. | Interspinous spacer |
| US7763074B2 (en) | 2004-10-20 | 2010-07-27 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods for posterior dynamic stabilization of the spine |
| US8409282B2 (en) | 2004-10-20 | 2013-04-02 | Vertiflex, Inc. | Systems and methods for posterior dynamic stabilization of the spine |
| US8425559B2 (en) | 2004-10-20 | 2013-04-23 | Vertiflex, Inc. | Systems and methods for posterior dynamic stabilization of the spine |
| US8167944B2 (en) | 2004-10-20 | 2012-05-01 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods for posterior dynamic stabilization of the spine |
| US8277488B2 (en) | 2004-10-20 | 2012-10-02 | Vertiflex, Inc. | Interspinous spacer |
| US8613747B2 (en) | 2004-10-20 | 2013-12-24 | Vertiflex, Inc. | Spacer insertion instrument |
| US8317864B2 (en) | 2004-10-20 | 2012-11-27 | The Board Of Trustees Of The Leland Stanford Junior University | Systems and methods for posterior dynamic stabilization of the spine |
| US9161783B2 (en) | 2004-10-20 | 2015-10-20 | Vertiflex, Inc. | Interspinous spacer |
| BRPI0517925A (pt) * | 2004-11-02 | 2008-10-21 | Pfizer | derivados de sulfonil benzimidazol |
| WO2009086010A2 (en) | 2004-12-06 | 2009-07-09 | Vertiflex, Inc. | Spacer insertion instrument |
| EA015542B1 (ru) | 2006-01-24 | 2011-08-30 | Янссен Фармацевтика Н.В. | Новые 2-замещённые бензимидазолы в качестве селективных модуляторов рецептора андрогена (sarms) |
| US8845726B2 (en) | 2006-10-18 | 2014-09-30 | Vertiflex, Inc. | Dilator |
| AU2008241447B2 (en) | 2007-04-16 | 2014-03-27 | Vertiflex, Inc. | Interspinous spacer |
| JP5400032B2 (ja) * | 2007-04-20 | 2014-01-29 | ザ リサーチ ファウンデーション オブ ザ ステイト ユニヴァーシティ オブ ニューヨーク | ベンズイミダゾール及びその医薬組成物 |
| AU2009206098B2 (en) | 2008-01-15 | 2014-10-30 | Vertiflex, Inc. | Interspinous spacer |
| MX2010009162A (es) | 2008-02-22 | 2010-12-21 | Radius Health Inc | Moduladores selectivos del receptor de androgeno. |
| US8268872B2 (en) | 2008-02-22 | 2012-09-18 | Radius Health, Inc. | Selective androgen receptor modulators |
| WO2009123164A1 (ja) * | 2008-04-02 | 2009-10-08 | 塩野義製薬株式会社 | 血管内皮リパーゼ阻害活性を有するヘテロ環誘導体 |
| EP2512357B1 (en) | 2009-12-15 | 2016-07-13 | Vertiflex, Inc. | Spinal spacer for cervical and other vertebra, and associated systems |
| EP2531029B1 (en) | 2010-02-04 | 2016-10-19 | Radius Health, Inc. | Selective androgen receptor modulators |
| WO2011143469A1 (en) | 2010-05-12 | 2011-11-17 | Radius Health,Inc | Therapeutic regimens |
| US8642632B2 (en) | 2010-07-02 | 2014-02-04 | Radius Health, Inc. | Selective androgen receptor modulators |
| BR112013007685B1 (pt) | 2010-09-28 | 2021-11-09 | Radius Pharmaceuticals, Inc | Compostos moduladores de receptor andrógeno seletivos, composição farmacêutica compreendendo os referidos compostos, método de identificação de um composto capaz de modular um receptor andrógeno, usos de um composto ou da composição e processo para a preparação de um composto |
| WO2013116823A1 (en) * | 2012-02-02 | 2013-08-08 | The Research Foundation Of State University Of New York | Benzimidazoles and uses thereof |
| US9675303B2 (en) | 2013-03-15 | 2017-06-13 | Vertiflex, Inc. | Visualization systems, instruments and methods of using the same in spinal decompression procedures |
| US10287617B2 (en) | 2014-03-11 | 2019-05-14 | Colorado State University Research Foundation | Methods for in vitro—in vivo efficacy determination |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE947610C (de) | 1955-04-30 | 1956-08-23 | Basf Ag | Verfahren zur Herstellung von Benzimidazoinen |
| US3325271A (en) * | 1963-07-17 | 1967-06-13 | United States Borax Chem | Herbicidal composition and method employing substituted benzimidazoles |
| US3897432A (en) * | 1971-04-21 | 1975-07-29 | Merck & Co Inc | Substituted benzimidazole derivatives |
| SE357932B (enExample) * | 1972-01-27 | 1973-07-16 | Malaga Ab | |
| US3987182A (en) * | 1974-06-17 | 1976-10-19 | Schering Corporation | Novel benzimidazoles useful as anti-androgens |
| NZ221729A (en) * | 1986-09-15 | 1989-07-27 | Janssen Pharmaceutica Nv | Imidazolyl methyl-substituted benzimidazole derivatives and pharmaceutical compositions |
| JPH05163246A (ja) * | 1991-12-17 | 1993-06-29 | Nippon Oil & Fats Co Ltd | ペルフルオロ−オキサ−アルキル基含有ベンズイミダゾール誘導体及びその製造方法 |
| GB9310069D0 (en) * | 1993-05-17 | 1993-06-30 | Zeneca Ltd | Heterocyclic compounds |
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- 2005-09-26 EP EP05800116.5A patent/EP1805147B1/en not_active Not-in-force
- 2005-09-26 CN CN2005800407430A patent/CN101065363B/zh not_active Expired - Fee Related
- 2005-09-26 CA CA002582356A patent/CA2582356A1/en not_active Abandoned
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| AR050966A1 (es) | 2006-12-06 |
| AU2005292345B9 (en) | 2011-12-15 |
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| US8586616B2 (en) | 2013-11-19 |
| EP1805147A1 (en) | 2007-07-11 |
| US7566733B2 (en) | 2009-07-28 |
| AU2005292345A1 (en) | 2006-04-13 |
| WO2006039243A1 (en) | 2006-04-13 |
| US20110086883A1 (en) | 2011-04-14 |
| MY147985A (en) | 2013-02-28 |
| US20060116412A1 (en) | 2006-06-01 |
| JP2008514707A (ja) | 2008-05-08 |
| CA2582356A1 (en) | 2006-04-13 |
| EP1805147B1 (en) | 2014-08-13 |
| AU2005292345B2 (en) | 2011-12-01 |
| TW200621725A (en) | 2006-07-01 |
| US20090258909A1 (en) | 2009-10-15 |
| CN101065363A (zh) | 2007-10-31 |
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