JP6317807B2 - Ep4媒介性の疾病及び病態の治療に使用するためのep4受容体選択性アゴニストとしてのラクタム化合物 - Google Patents
Ep4媒介性の疾病及び病態の治療に使用するためのep4受容体選択性アゴニストとしてのラクタム化合物 Download PDFInfo
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- JP6317807B2 JP6317807B2 JP2016502973A JP2016502973A JP6317807B2 JP 6317807 B2 JP6317807 B2 JP 6317807B2 JP 2016502973 A JP2016502973 A JP 2016502973A JP 2016502973 A JP2016502973 A JP 2016502973A JP 6317807 B2 JP6317807 B2 JP 6317807B2
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- Prior art keywords
- hydroxy
- methyl
- oxopyrrolidin
- thiophene
- methylnon
- Prior art date
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 15
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- 101150109738 Ptger4 gene Proteins 0.000 title description 2
- 230000001404 mediated effect Effects 0.000 title description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 336
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 277
- 150000001875 compounds Chemical class 0.000 claims description 229
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 138
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 134
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 claims description 130
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 101
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 97
- 125000000217 alkyl group Chemical group 0.000 claims description 59
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- AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 claims description 6
- AEDIXYWIVPYNBI-UHFFFAOYSA-N heptanamide Chemical compound CCCCCCC(N)=O AEDIXYWIVPYNBI-UHFFFAOYSA-N 0.000 claims description 6
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- LSHMGTXEUMQTLQ-DMBFJYOSSA-N 7-[(2r)-2-[(e,3r)-3-hydroxy-3-(1-pent-2-ynylcyclobutyl)prop-1-enyl]-5-oxopyrrolidin-1-yl]heptanoic acid Chemical compound CCC#CCC1([C@H](O)\C=C\[C@@H]2N(C(=O)CC2)CCCCCCC(O)=O)CCC1 LSHMGTXEUMQTLQ-DMBFJYOSSA-N 0.000 claims description 3
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- 125000003118 aryl group Chemical group 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
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- 238000000926 separation method Methods 0.000 description 27
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- 239000007787 solid Substances 0.000 description 25
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- 239000012071 phase Substances 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 150000001299 aldehydes Chemical class 0.000 description 22
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- RWFPXJAUVOBOLJ-UHFFFAOYSA-N acetic acid;ethyl acetate;heptane Chemical compound CC(O)=O.CCOC(C)=O.CCCCCCC RWFPXJAUVOBOLJ-UHFFFAOYSA-N 0.000 description 17
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
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- HKTGGDULWDLYKQ-UHFFFAOYSA-N methyl 4-(2-oxoethyl)benzoate Chemical compound COC(=O)C1=CC=C(CC=O)C=C1 HKTGGDULWDLYKQ-UHFFFAOYSA-N 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
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- RAZRDLCYULHOOA-CYBMUJFWSA-N methyl 2-[4-[[(2r)-2-(hydroxymethyl)-5-oxopyrrolidin-1-yl]methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1CN1C(=O)CC[C@@H]1CO RAZRDLCYULHOOA-CYBMUJFWSA-N 0.000 description 5
- PEWBMZHUUHFHBI-CYBMUJFWSA-N methyl 2-[4-[[(2r)-2-formyl-5-oxopyrrolidin-1-yl]methyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1CN1C(=O)CC[C@@H]1C=O PEWBMZHUUHFHBI-CYBMUJFWSA-N 0.000 description 5
- HCYTZTWQJDECJT-MXQLGCADSA-N methyl 5-[(z)-3-[(2r)-2-(hydroxymethyl)-5-oxopyrrolidin-1-yl]prop-1-enyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1\C=C/CN1C(=O)CC[C@@H]1CO HCYTZTWQJDECJT-MXQLGCADSA-N 0.000 description 5
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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| PCT/US2014/029057 WO2014144584A2 (en) | 2013-03-15 | 2014-03-14 | Lactam compounds as ep4 receptor-selective agonists for use in the treatment of ep4-mediated diseases and conditions |
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| CA2879506C (en) | 2012-07-19 | 2020-10-27 | Cayman Chemical Company, Inc. | Difluorolactam compositions for ep4-mediated osteo related diseases and conditions |
| AU2014290512A1 (en) | 2013-07-19 | 2015-11-12 | Cayman Chemical Company, Inc. | Methods, systems, and compositions for promoting bone growth |
| CN107365329B (zh) * | 2016-05-12 | 2019-02-01 | 华东师范大学 | 一种3-甲基-2-氧代-5-庚炔基磷酸二甲酯的制备方法 |
| ES2929799T3 (es) | 2017-12-25 | 2022-12-01 | Asahi Kasei Pharma Corp | Compuestos que contienen resto de 2-oxo-1,3,4-tiadiazinan-3-ilo con actividad agonista del receptor EP4 |
| SG11202110742TA (en) | 2019-04-02 | 2021-10-28 | Aligos Therapeutics Inc | Compounds targeting prmt5 |
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| US3975399A (en) | 1974-08-06 | 1976-08-17 | E. I. Du Pont De Nemours And Company | 1,5-Disubstituted-2-pyrrolidinones, -3-pyrrolin-2-ones, and -4-pyrrolin-2-ones |
| DE2517771A1 (de) | 1975-04-18 | 1976-10-28 | Schering Ag | Neue prostaglandin-acetylen-analoga und verfahren zu ihrer herstellung |
| DE2528664A1 (de) | 1975-06-27 | 1977-01-13 | Hoechst Ag | Pyrrolidone und verfahren zu ihrer herstellung |
| CA1085859A (en) | 1975-06-27 | 1980-09-16 | Wilhelm Bartmann | Pyrrolidones and process for their manufacture |
| DE2619638A1 (de) | 1976-05-04 | 1977-11-17 | Hoechst Ag | Pyrrolidone und verfahren zu ihrer herstellung |
| US4268522A (en) | 1976-06-14 | 1981-05-19 | Pfizer Inc. | 13,14-Dihydro-15-alkenyl- and 13,14-dihydro-15-alkynyl prostaglandins and analogs thereof |
| US4320136A (en) | 1980-08-11 | 1982-03-16 | E. I. Du Pont De Nemours And Company | 8-Aza-16,16-difluoroprostanoids |
| US6043275A (en) | 1998-04-16 | 2000-03-28 | Ono Pharmaceutical Co., Ltd. | 3,7-dithiaprostanoic acid derivative |
| US6894175B1 (en) | 1999-08-04 | 2005-05-17 | The Procter & Gamble Company | 2-Decarboxy-2-phosphinico prostaglandin derivatives and methods for their preparation and use |
| TWI247606B (en) | 1999-11-24 | 2006-01-21 | Ono Pharmaceutical Co | Treating agent for osteopenic diseases |
| WO2001046140A1 (en) | 1999-12-22 | 2001-06-28 | Pfizer Products Inc. | Ep4 receptor selective agonists in the treatment of osteoporosis |
| US20010056060A1 (en) | 2000-02-07 | 2001-12-27 | Cameron Kimberly O. | Treatment of osteoporsis with EP2/EP4 receptor selective agonists |
| WO2002024647A1 (en) | 2000-09-21 | 2002-03-28 | Ono Pharmaceutical Co., Ltd. | Ep4 receptor agonists containing 8-azaprostaglandin derivatives as the active ingredient |
| SI1339678T1 (sl) * | 2000-11-27 | 2007-12-31 | Pfizer Prod Inc | Selektivni agonisti EP4 receptorja pri zdravljenju osteoporoze |
| AU2002328338C1 (en) | 2001-07-16 | 2009-01-08 | Ono Pharmaceutical Co., Ltd | 2 pyrrolidone derivatives as prostanoid agonists |
| AU2002328855B2 (en) | 2001-07-16 | 2005-11-24 | F. Hoffmann-La Roche Ag | Prostaglandin Analogues As EP4 Receptor Agonists |
| KR100826866B1 (ko) | 2001-07-23 | 2008-05-06 | 오노 야꾸힝 고교 가부시키가이샤 | Ep4 아고니스트를 유효 성분으로 하는 골량 저하질환의 치료제 |
| US7410991B2 (en) | 2001-10-23 | 2008-08-12 | Laboratoires Serono S.A. | Pyrazolidinone compounds as ligands of the prostaglandin EP2 and/or EP4 receptors |
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| CA2466751A1 (en) | 2001-12-03 | 2003-06-12 | Merck And Co., Inc. | Ep4 receptor agonist, compositions and methods thereof |
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| EP1490055A1 (en) | 2002-03-18 | 2004-12-29 | Pfizer Products Inc. | Use of selective ep4 receptor agonists for the treatment of liver failure, loss of patency of the ductus arteriosus, glaucoma or ocular hypertension |
| ATE336247T1 (de) | 2002-03-18 | 2006-09-15 | Pfizer Prod Inc | Verwendung von selektiven ep4 rezeptor agonisten zur behandlung von krankheiten |
| US6573294B1 (en) | 2002-05-14 | 2003-06-03 | Allergan, Inc. | 8-azaprostaglandin analogs as agents for lowering intraocular pressure |
| WO2003103604A2 (en) * | 2002-06-01 | 2003-12-18 | Applied Research Systems Ars Holding N.V | Gamma lactams as prostaglandin agonists and use thereof |
| JP2006505572A (ja) | 2002-10-25 | 2006-02-16 | メルク フロスト カナダ アンド カンパニー | Ep4受容体アゴニストとしての2−ピロリドン |
| EP1586564B1 (en) | 2003-01-21 | 2012-11-28 | Ono Pharmaceutical Co., Ltd. | 8-azaprostaglandin derivatives and medicinal uses thereof |
| WO2004078103A2 (en) * | 2003-03-03 | 2004-09-16 | Applied Research Systems Ars Holding N.V. | G-lactam derivatives as prostaglandin agonists |
| US7169807B2 (en) | 2004-04-09 | 2007-01-30 | Allergan, Inc. | 10-Hydroxy-11-dihydroprostaglandin analogs as selective EP4 agonists |
| EP1782830A4 (en) | 2004-08-10 | 2009-07-29 | Ono Pharmaceutical Co | PREVENTION AND / OR REMEDY FOR LOWER URINARY TRACT DISEASES CONTAINING AN EP4 AGONIST |
| JPWO2006016695A1 (ja) | 2004-08-10 | 2008-05-01 | 小野薬品工業株式会社 | Ep4アゴニストを含有してなる高カリウム血症の予防および/または治療剤 |
| TWI404529B (zh) * | 2005-06-03 | 2013-08-11 | Ono Pharmaceutical Co | 神經再生及/或保護劑 |
| US20070232660A1 (en) | 2006-04-04 | 2007-10-04 | Allergan, Inc. | Therapeutic and delivery methods of prostaglandin ep4 agonists |
| US8507545B2 (en) | 2007-05-08 | 2013-08-13 | National University Corporation, Hamamatsu University School Of Medicine | Cytotoxic T cell activator comprising EP4 agonist |
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| US20120283293A1 (en) | 2011-05-06 | 2012-11-08 | The Board Of Trustees Of The Leland Stanford Junior University | Methods of neuroprotection involving Prostaglandin E2 EP4 (PGE2 EP4) receptor activation |
| BR112014002377A2 (pt) | 2011-08-02 | 2017-02-21 | Ono Pharmaceutical Co | agente intensificador da função diastólica do ventrículo esquerdo |
| CA2879506C (en) | 2012-07-19 | 2020-10-27 | Cayman Chemical Company, Inc. | Difluorolactam compositions for ep4-mediated osteo related diseases and conditions |
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| JP6352497B2 (ja) | 2018-07-04 |
| PH12015502165A1 (en) | 2016-01-25 |
| CA2906134A1 (en) | 2014-09-18 |
| KR20150130326A (ko) | 2015-11-23 |
| EP3235817A1 (en) | 2017-10-25 |
| EP3235817B1 (en) | 2018-12-12 |
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