ZA200210099B - Thrombin receptor antagonists. - Google Patents
Thrombin receptor antagonists. Download PDFInfo
- Publication number
- ZA200210099B ZA200210099B ZA200210099A ZA200210099A ZA200210099B ZA 200210099 B ZA200210099 B ZA 200210099B ZA 200210099 A ZA200210099 A ZA 200210099A ZA 200210099 A ZA200210099 A ZA 200210099A ZA 200210099 B ZA200210099 B ZA 200210099B
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- ZA
- South Africa
- Prior art keywords
- alkyl
- group
- alkoxy
- aryl
- independently selected
- Prior art date
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Classifications
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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- C07D405/08—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing alicyclic rings
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Families Citing this family (97)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6346510B1 (en) | 1995-10-23 | 2002-02-12 | The Children's Medical Center Corporation | Therapeutic antiangiogenic endostatin compositions |
RU2293735C2 (ru) * | 2000-06-15 | 2007-02-20 | Шеринг Корпорейшн | Производные нор-секо химбацина, фармацевтическая композиция и способ ингибирования на их основе |
US20040192753A1 (en) * | 2000-06-15 | 2004-09-30 | Samuel Chackalamannil | Methods of use of thrombin receptor antagonists |
US7235567B2 (en) * | 2000-06-15 | 2007-06-26 | Schering Corporation | Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist |
US7488742B2 (en) * | 2000-06-15 | 2009-02-10 | Schering Corporation | Thrombin receptor antagonists |
KR100960170B1 (ko) | 2001-10-18 | 2010-05-26 | 쉐링 코포레이션 | 트롬빈 수용체 길항제로서의 힘바신 동족체 |
TW200407110A (en) | 2001-11-23 | 2004-05-16 | Astrazeneca Ab | New use for the treatment of gastroesophageal reflux disease |
ATE494284T1 (de) * | 2002-04-16 | 2011-01-15 | Schering Corp | Tricyclischer thrombinrezeptorantagonist |
US7105526B2 (en) | 2002-06-28 | 2006-09-12 | Banyu Pharmaceuticals Co., Ltd. | Benzimidazole derivatives |
US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
US20060172019A1 (en) * | 2003-03-07 | 2006-08-03 | Ralston Stuart H | Cannabinoid receptor inverse agonists and neutral antagonists as therapeutic agents for the treatment of bone disorders |
US20070243632A1 (en) * | 2003-07-08 | 2007-10-18 | Coller Barry S | Methods for measuring platelet reactivity of patients that have received drug eluting stents |
EP1641492B1 (en) * | 2003-07-08 | 2011-12-14 | Accumetrics, Inc. | Controlled platelet activation to monitor therapy of adp antagonists |
ATE547404T1 (de) | 2003-09-22 | 2012-03-15 | Msd Kk | Piperidinderivate |
WO2005097127A2 (en) | 2004-04-02 | 2005-10-20 | Merck & Co., Inc. | Method of treating men with metabolic and anthropometric disorders |
US7407753B2 (en) * | 2004-05-24 | 2008-08-05 | Yissum Research Development Company Of The Hebrewuniversityofjerusalem | Methods, kits and pharmaceutical compositions for diagnosing, delaying onset of, preventing and/or treating osteoporosis |
MXPA06013903A (es) * | 2004-05-28 | 2007-01-26 | Schering Corp | Analogos restringidos de himbacina como antagonistas del receptor de trombina. |
AU2005277203A1 (en) * | 2004-08-20 | 2006-03-02 | Entremed, Inc. | Compositions and methods comprising proteinase activated receptor antagonists |
CA2582353A1 (en) * | 2004-10-06 | 2006-04-20 | University Of Rochester | Treatment of pulmonary hypertension using an agent that inhibits a tissue factor pathway |
EP2075250B1 (en) * | 2004-10-08 | 2015-03-04 | Merck Sharp & Dohme Corp. | Thrombin receptor antagonists |
MX2007006069A (es) * | 2004-11-18 | 2007-07-11 | Schering Corp | Metodos para utilizar inhibidores de la fosfodiesterasa tipo v y para el tratamiento de insuficiencia cardiaca congestiva. |
US7541471B2 (en) * | 2005-01-14 | 2009-06-02 | Schering Corporation | Synthesis of himbacine analogs |
SG158884A1 (en) * | 2005-01-14 | 2010-02-26 | Schering Corp | An exo-selective synthesis of himbacine analogs |
PL2206697T3 (pl) * | 2005-01-14 | 2012-03-30 | Merck Sharp & Dohme | Egzo- oraz diastereoselektywna synteza analogów himbacyny |
EP1863778B1 (en) * | 2005-03-31 | 2015-12-30 | Merck Sharp & Dohme Corp. | Spirocyclic thrombin receptor antagonists |
US7595169B2 (en) * | 2005-04-27 | 2009-09-29 | Accumetrics, Inc. | Method for determining percent platelet aggregation |
NZ562766A (en) | 2005-05-30 | 2011-03-31 | Banyu Pharma Co Ltd | Piperidine derivatives as histamine-H3 receptor antagonists |
CA2618112A1 (en) | 2005-08-10 | 2007-02-15 | Banyu Pharmaceutical Co., Ltd. | Pyridone compound |
AU2006282260A1 (en) | 2005-08-24 | 2007-03-01 | Msd K.K. | Phenylpyridone derivative |
US20090264426A1 (en) | 2005-09-07 | 2009-10-22 | Shunji Sakuraba | Bicyclic aromatic substituted pyridone derivative |
AU2006307046A1 (en) | 2005-10-27 | 2007-05-03 | Msd K.K. | Novel benzoxathiin derivative |
BRPI0618354B8 (pt) | 2005-11-10 | 2021-05-25 | Banyu Pharma Co Ltd | composto e seu uso, composição farmacêutica, preventivo ou remédio |
WO2007075808A2 (en) * | 2005-12-20 | 2007-07-05 | Schering Corporation | Methods for preventing and/or treating a cell proliferative disorder |
WO2007075809A2 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Oxazoloisoquinoline derivatives as thrombin receptor antagonists |
US20070202140A1 (en) * | 2005-12-22 | 2007-08-30 | Veltri Enrico P | Thrombin receptor antagonists as prophylaxis to complications from cardiopulmonary surgery |
KR20080104352A (ko) * | 2006-03-29 | 2008-12-02 | 쉐링 코포레이션 | 트롬빈 수용체 길항제로서 유용한 모노사이클릭 및 비사이클릭 힘바신 유도체 |
MX2008013246A (es) * | 2006-04-13 | 2008-10-21 | Schering Corp | Antagonistas del receptor de trombina de anillo fusionado. |
CN101506198A (zh) * | 2006-06-29 | 2009-08-12 | 先灵公司 | 取代的双环和三环凝血酶受体拮抗剂 |
KR20090042779A (ko) * | 2006-06-30 | 2009-04-30 | 쉐링 코포레이션 | P53 활성을 증가시키는 치환된 피페리딘 및 이의 사용 |
TWI367112B (en) * | 2006-06-30 | 2012-07-01 | Schering Corp | Immediate-release tablet formulations of a thrombin receptor antagonist |
AR061727A1 (es) * | 2006-06-30 | 2008-09-17 | Schering Corp | Sintesis de dietil [[ 5- ( 3-fluorofenil) -piridin -2il] metil] fosfonato |
JP2009542677A (ja) * | 2006-06-30 | 2009-12-03 | シェーリング コーポレイション | トロンビン受容体拮抗薬の固形製剤 |
TWI343262B (en) * | 2006-09-26 | 2011-06-11 | Schering Corp | Rapidly disintegrating lyophilized oral formulations of a thrombin receptor antagonist |
JPWO2008038692A1 (ja) | 2006-09-28 | 2010-01-28 | 萬有製薬株式会社 | ジアリールケチミン誘導体 |
WO2008060372A2 (en) * | 2006-10-04 | 2008-05-22 | Schering Corporation | Thrombin receptor antagonists based on the modified tricyclic unit of himbacine |
JP2010505842A (ja) * | 2006-10-04 | 2010-02-25 | シェーリング コーポレイション | トロンビン受容体拮抗薬としての二環式誘導体および三環式誘導体 |
JP2010513516A (ja) * | 2006-12-22 | 2010-04-30 | シェーリング コーポレイション | 固形剤の湿式顆粒化処方物中の崩壊促進剤 |
US20080234236A1 (en) * | 2007-03-23 | 2008-09-25 | Veltri Enrico P | Reduction of adverse events after percutaneous intervention by use of a thrombin receptor antagonist |
EP2145884B1 (en) | 2007-04-02 | 2014-08-06 | Msd K.K. | Indoledione derivative |
CN101675342A (zh) * | 2007-05-03 | 2010-03-17 | 阿库米特里克斯股份有限公司 | 测量凝血酶受体拮抗剂对血小板聚集的抑制的方法 |
US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
CA3089569C (en) | 2007-06-04 | 2023-12-05 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
AU2009220605A1 (en) | 2008-03-06 | 2009-09-11 | Msd K.K. | Alkylaminopyridine derivative |
AU2009229860A1 (en) | 2008-03-28 | 2009-10-01 | Msd K.K. | Diarylmethylamide derivative having antagonistic activity on melanin-concentrating hormone receptor |
CL2009001214A1 (es) | 2008-05-19 | 2010-12-31 | Schering Corp | Compuestos derivados de heterociclo, moduladores de serina proteasas composicion fa<rmacaeutica que los comprende; y su uso en el tratamiento de trastornos tromboembolicos |
JP2011522828A (ja) | 2008-06-04 | 2011-08-04 | シナジー ファーマシューティカルズ インコーポレイテッド | 胃腸障害、炎症、癌、およびその他の障害の治療のために有用なグアニル酸シクラーゼのアゴニスト |
US20110071129A1 (en) | 2008-06-19 | 2011-03-24 | Makoto Ando | Spirodiamine-diaryl ketoxime derivative |
EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
EP2319841A1 (en) | 2008-07-30 | 2011-05-11 | Msd K.K. | (5-membered)-(5-membered) or (5-membered)-(6-membered) fused ring cycloalkylamine derivative |
MX2011004258A (es) | 2008-10-22 | 2011-06-01 | Merck Sharp & Dohme | Derivados de bencimidazol ciclicos novedosos utiles como agentes anti-diabeticos. |
JP5557845B2 (ja) | 2008-10-31 | 2014-07-23 | メルク・シャープ・アンド・ドーム・コーポレーション | 糖尿病用剤として有用な新規環状ベンゾイミダゾール誘導体 |
JP5789256B2 (ja) | 2009-06-04 | 2015-10-07 | メルク・シャープ・アンド・ドーム・コーポレーションMerck Sharp & Dohme Corp. | トロンビン受容体アンタゴニストの活性代謝物 |
US20120141586A1 (en) | 2009-06-08 | 2012-06-07 | Rubi Burlage | Thrombin receptor antagonist and clopidogrel fixed dose tablet |
EP2462123B1 (en) | 2009-08-04 | 2013-10-02 | Merck Sharp & Dohme Corp. | 4,5,6-trisubstituted pyrimidine derivatives as factor ixa inhibitors |
BR112012008849A2 (pt) | 2009-10-14 | 2015-09-22 | Schering Corp | composto, composição farmacêutica, e, uso de um composto |
EP2538784B1 (en) | 2010-02-25 | 2015-09-09 | Merck Sharp & Dohme Corp. | Benzimidazole derivatives useful anti-diabetic agents |
WO2011128420A1 (de) | 2010-04-16 | 2011-10-20 | Sanofi | Pyridyl-vinyl-pyrazolo-chinoline als par1-inhibitoren |
EP2558465B1 (de) | 2010-04-16 | 2014-12-17 | Sanofi | Trizyklische pyridyl-vinyl-pyrrole als par1-inhibitoren |
US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
KR20150075120A (ko) | 2011-02-25 | 2015-07-02 | 머크 샤프 앤드 돔 코포레이션 | 항당뇨병제로서 유용한 신규 시클릭 아자벤즈이미다졸 유도체 |
EP2771008A4 (en) | 2011-10-28 | 2015-04-08 | Merck Sharp & Dohme | MACROCYCLES INCREASING P53 ACTIVITY AND USES THEREOF |
EP2793890B1 (en) | 2011-12-21 | 2016-09-07 | Merck Sharp & Dohme Corp. | Substituted piperidines as hdm2 inhibitors |
WO2013134012A1 (en) | 2012-03-06 | 2013-09-12 | Merck Sharp & Dohme Corp. | Preparation and use of bicyclic himbacine derivatives as par-receptor antagonists |
RU2015106909A (ru) | 2012-08-02 | 2016-09-27 | Мерк Шарп И Доум Корп. | Антидиабетические трициклические соединения |
BR112015013611A2 (pt) | 2012-12-20 | 2017-11-14 | Merck Sharp & Dohme | composto, e, composição farmacêutica |
KR20150118158A (ko) | 2013-02-22 | 2015-10-21 | 머크 샤프 앤드 돔 코포레이션 | 항당뇨병 비시클릭 화합물 |
EP2970119B1 (en) | 2013-03-14 | 2021-11-03 | Merck Sharp & Dohme Corp. | Novel indole derivatives useful as anti-diabetic agents |
EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
US9486494B2 (en) | 2013-03-15 | 2016-11-08 | Synergy Pharmaceuticals, Inc. | Compositions useful for the treatment of gastrointestinal disorders |
JP6606491B2 (ja) | 2013-06-05 | 2019-11-13 | シナジー ファーマシューティカルズ インコーポレイテッド | グアニル酸シクラーゼcの超高純度アゴニスト、その作成および使用方法 |
EP3024550A4 (en) | 2013-07-22 | 2016-12-07 | Merck Sharp & Dohme | CO-CRYSTAL OF VORAPAXAR PAR-1 RECEPTOR ANTAGONIST AND ASPIRINE |
WO2015026685A1 (en) | 2013-08-22 | 2015-02-26 | Merck Sharp & Dohme Corp. | 7a-heterocycle substituted- 6, 6-difluoro bicyclic himbacine derivatives |
EP3035928B1 (en) | 2013-08-22 | 2023-10-18 | Merck Sharp & Dohme LLC | 3'-pyridyl substituted- 6,6-difluoro bicyclic himbacine derivatives |
EP3035929A4 (en) | 2013-08-22 | 2017-03-15 | Merck Sharp & Dohme Corp. | 7a-amide substituted-6,6-difluoro bicyclic himbacine derivatives |
WO2015051496A1 (en) | 2013-10-08 | 2015-04-16 | Merck Sharp & Dohme Corp. | Antidiabetic tricyclic compounds |
EP3131897B8 (en) | 2014-04-16 | 2022-08-03 | Merck Sharp & Dohme LLC | Factor ixa inhibitors |
DE102014108210A1 (de) | 2014-06-11 | 2015-12-17 | Dietrich Gulba | Rodentizid |
WO2016058144A1 (en) * | 2014-10-15 | 2016-04-21 | Merck Sharp & Dohme Corp. | Preparation and use of cyclic sulfonamide derivatives as par-1 receptor antagonists |
EP3551176A4 (en) | 2016-12-06 | 2020-06-24 | Merck Sharp & Dohme Corp. | ANTIDIABETIC HETEROCYCLIC COMPOUNDS |
CN110407819B (zh) * | 2019-08-02 | 2020-06-26 | 牡丹江医学院 | 一种作为预防外科手术并发症的凝血酶受体拮抗剂 |
CN116133660A (zh) | 2020-07-22 | 2023-05-16 | 詹森药业有限公司 | 可用作因子XIa抑制剂的化合物 |
US11919881B2 (en) | 2021-03-18 | 2024-03-05 | Janssen Pharmaceutica Nv | Substituted pyridine N-oxide derivatives useful as a factor XIa inhibitors |
US11845748B2 (en) | 2021-03-18 | 2023-12-19 | Janssen Pharmaceutica Nv | Bicyclic pyridine N-oxide derivatives useful as a factor XIa inhibitors |
US11814364B2 (en) | 2021-03-18 | 2023-11-14 | Janssen Pharmaceutica Nv | Pyridine N-oxide derivatives useful as factor XIa inhibitors |
EP4070658A1 (de) | 2021-04-06 | 2022-10-12 | BIORoxx GmbH | Verwendung von blutgerinnungshemmenden verbindungen als rodentizide |
US11897880B2 (en) | 2021-04-30 | 2024-02-13 | Janssen Pharmaceutica Nv | 7,8-dihydrobenzo[e]pyrido[3,4-c]azocine-2,5(3H,6H)-dione derivatives useful as a factor XIa inhibitors |
US11958856B2 (en) | 2021-07-22 | 2024-04-16 | Janssen Pharmaceutica Nv | Substituted 1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-ones as factor XIa inhibitors |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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IL106197A (en) | 1992-07-30 | 1999-11-30 | Cor Therapeutics Inc | Agagonists for the rhombin receptors and pharmaceutical preparations containing them |
JP2000229961A (ja) * | 1998-12-11 | 2000-08-22 | Sagami Chem Res Center | ヒドロナフト[2,3−c]フラン誘導体およびその製造方法 |
US6063847A (en) | 1997-11-25 | 2000-05-16 | Schering Corporation | Thrombin receptor antagonists |
ATE266025T1 (de) * | 1997-11-25 | 2004-05-15 | Schering Corp | Thrombin-rezeptor antagonisten |
DE19801636A1 (de) * | 1998-01-17 | 1999-07-22 | Bayer Ag | Substituierte bicyclische Lactone |
RU2293735C2 (ru) * | 2000-06-15 | 2007-02-20 | Шеринг Корпорейшн | Производные нор-секо химбацина, фармацевтическая композиция и способ ингибирования на их основе |
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