ES2558087T3 - Procesos para la preparación de moduladores del receptor S1P1 y formas cristalinas de los mismos - Google Patents
Procesos para la preparación de moduladores del receptor S1P1 y formas cristalinas de los mismos Download PDFInfo
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- ES2558087T3 ES2558087T3 ES11707330.4T ES11707330T ES2558087T3 ES 2558087 T3 ES2558087 T3 ES 2558087T3 ES 11707330 T ES11707330 T ES 11707330T ES 2558087 T3 ES2558087 T3 ES 2558087T3
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- salt
- acid
- indole
- isopropoxy
- trifluoromethyl
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- QPILZZVXGUNELN-UHFFFAOYSA-M sodium;4-amino-5-hydroxynaphthalene-2,7-disulfonate;hydron Chemical compound [Na+].OS(=O)(=O)C1=CC(O)=C2C(N)=CC(S([O-])(=O)=O)=CC2=C1 QPILZZVXGUNELN-UHFFFAOYSA-M 0.000 description 1
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- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
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- Physical Education & Sports Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33936210P | 2010-03-03 | 2010-03-03 | |
| US339362P | 2010-03-03 | ||
| PCT/US2011/026806 WO2011109471A1 (en) | 2010-03-03 | 2011-03-02 | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2558087T3 true ES2558087T3 (es) | 2016-02-01 |
Family
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| ES11707330.4T Active ES2558087T3 (es) | 2010-03-03 | 2011-03-02 | Procesos para la preparación de moduladores del receptor S1P1 y formas cristalinas de los mismos |
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| Country | Link |
|---|---|
| US (2) | US9085581B2 (https=) |
| EP (1) | EP2542554B1 (https=) |
| JP (2) | JP2013521301A (https=) |
| CN (2) | CN102884064B (https=) |
| CA (1) | CA2789480A1 (https=) |
| ES (1) | ES2558087T3 (https=) |
| SG (2) | SG183416A1 (https=) |
| WO (1) | WO2011109471A1 (https=) |
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| EA019252B1 (ru) | 2008-07-23 | 2014-02-28 | Арена Фармасьютикалз, Инк. | ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ (1,2,3,4-ТЕТРАГИДРОЦИКЛОПЕНТА[b]ИНДОЛ-3-ИЛ)УКСУСНОЙ КИСЛОТЫ, ПРИМЕНИМЫЕ В ЛЕЧЕНИИ АУТОИММУННЫХ И ВОСПАЛИТЕЛЬНЫХ РАССТРОЙСТВ |
| SI2342205T1 (sl) | 2008-08-27 | 2016-09-30 | Arena Pharmaceuticals, Inc. | Substituirani triciklični kislinski derivati kot agonisti S1P1 receptorja, uporabni v zdravljenju avtoimunskih in vnetnih obolenj |
| SG10201906876PA (en) | 2010-01-27 | 2019-09-27 | Arena Pharm Inc | Processes for the preparation of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof |
| SG183416A1 (en) * | 2010-03-03 | 2012-09-27 | Arena Pharm Inc | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
| AU2014414316B2 (en) * | 2014-10-27 | 2020-04-09 | Cellix Bio Private Limited | Three component salts of fumaric acid monomethyl ester with piperazine or ethylene diamine for the treatment of multiple sclerosis |
| MX386419B (es) | 2015-01-06 | 2025-03-18 | Arena Pharm Inc | Metodos de condiciones de tratamiento relacionadas con el receptor s1p1. |
| EP3939965A1 (en) | 2015-06-22 | 2022-01-19 | Arena Pharmaceuticals, Inc. | Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta[b]indol-3-yl)acetic acid for use in sipi receptor-associated disorders |
| MA47504A (fr) | 2017-02-16 | 2019-12-25 | Arena Pharm Inc | Composés et méthodes de traitement de l'angiocholite biliaire primitive |
| WO2018151834A1 (en) | 2017-02-16 | 2018-08-23 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of inflammatory bowel disease with extra-intestinal manifestations |
| ES2987794T3 (es) | 2018-06-06 | 2024-11-18 | Arena Pharm Inc | Procedimientos de tratamiento de afecciones relacionadas con el receptor S1P1 |
| CN112955431A (zh) | 2018-09-06 | 2021-06-11 | 艾尼纳制药公司 | 可用于治疗自身免疫性病症和炎性病症的化合物 |
| JP7504880B2 (ja) * | 2018-10-26 | 2024-06-24 | ケロス セラピューティクス インコーポレイテッド | Ａｌｋ２阻害剤の結晶形 |
Family Cites Families (150)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL293572A (https=) * | 1962-06-07 | |||
| DE2226703A1 (de) | 1972-05-25 | 1973-12-13 | Schering Ag | Neue tetrahydrocarbazolderivate und verfahren zu ihrer herstellung |
| US4057559A (en) | 1973-10-01 | 1977-11-08 | American Home Products Corporation | Carbazole acetic acid derivatives |
| US4810699A (en) | 1987-02-20 | 1989-03-07 | American Home Products Corporation | Substituted 1,3,4,9-tetrahydropyrano[3,4,-b]indole-1-acetic acids, pharmaceutical compositions containing them, and methods for treating inflammatory conditions and for analgesic purposes using them |
| US4782076A (en) | 1988-03-01 | 1988-11-01 | American Home Products Corporation | Substituted 2,3,4,9-tetrahydro-1H-carbazole-1-acetic acid derivatives, composition and use |
| PT95692A (pt) | 1989-10-27 | 1991-09-13 | American Home Prod | Processo para a preparacao de derivados de acidos indole-,indeno-,piranoindole- e tetra-hidrocarbazole-alcanoicos, ou quais sao uteis como inibidores de pla2 e da lipoxigenase |
| US5221678A (en) | 1990-07-26 | 1993-06-22 | Merck Frosst Canada, Inc. | (quinolin-2-ylmethoxy)tetrahydrocarbazoles as inhibitors of the biosynthesis of leukotrienes |
| US5998499A (en) | 1994-03-25 | 1999-12-07 | Dentsply G.M.B.H. | Liquid crystalline (meth)acrylate compounds, composition and method |
| US5776967A (en) | 1996-07-26 | 1998-07-07 | American Home Products Corporation | Pyranoindole inhibitors of COX--2 |
| US5830911A (en) | 1996-08-14 | 1998-11-03 | American Home Products Corporation | Pyranoindole and tetrahydrocarbazole inhibitors of COX-2 |
| US6861448B2 (en) | 1998-01-14 | 2005-03-01 | Virtual Drug Development, Inc. | NAD synthetase inhibitors and uses thereof |
| NZ515086A (en) | 1999-04-28 | 2003-10-31 | Aventis Pharma Gmbh | Di-aryl acid derivatives as PPAR receptor ligands |
| US6410583B1 (en) | 2000-07-25 | 2002-06-25 | Merck Frosst Canada & Co. | Cyclopentanoindoles, compositions containing such compounds and methods of treatment |
| WO2002039987A2 (en) | 2000-11-14 | 2002-05-23 | Neurosearch A/S | Use of malaria parasite anion channel blockers for treating malaria |
| US7064217B2 (en) | 2001-01-30 | 2006-06-20 | University Of Virginia Patent Foundation | Agonists and antagonists of sphingosine-1-phosphate receptors |
| EP1375463A4 (en) | 2001-03-29 | 2009-09-02 | Osaka Gas Co Ltd | OPTICALLY ACTIVE COMPOUND AND PHOTOSENSITIVE RESIN COMPOSITION |
| WO2002092068A1 (en) | 2001-05-10 | 2002-11-21 | Ono Pharmaceutical Co., Ltd. | Carboxylic acid derivatives and drugs containing the same as the active ingredient |
| MXPA04002679A (es) | 2001-09-27 | 2004-07-30 | Kyorin Seiyaku Kk | Derivados de sulfuro de diarilo, sales de los mismos y agentes inmunosupresores que utilizan los mismos. |
| WO2003059346A1 (en) | 2002-01-18 | 2003-07-24 | The Genetics Company Inc. | Beta-secretase inhibitors |
| US20050070506A1 (en) | 2002-01-18 | 2005-03-31 | Doherty George A. | Selective s1p1/edg1 receptor agonists |
| US7479504B2 (en) | 2002-01-18 | 2009-01-20 | Merck & Co., Inc. | Edg receptor agonists |
| US7309721B2 (en) | 2002-03-01 | 2007-12-18 | Merck + Co., Inc. | Aminoalkylphosphonates and related compounds as Edg receptor agonists |
| AU2003218056A1 (en) | 2002-03-01 | 2003-09-16 | Merck & Co., Inc. | Aminoalkylphosphonates and related compounds as edg receptor agonists |
| JP2005533058A (ja) | 2002-06-17 | 2005-11-04 | メルク エンド カムパニー インコーポレーテッド | Ｅｄｇ受容体アゴニストとしての１−（（５−アリール−１，２，４−オキサジアゾール−３−イル）ベンジル）アゼチジン−３−カルボキシラートおよび１−（（５−アリール−１，２，４−オキサジアゾール−３−イル）ベンジル）ピロリジン−３−カルボキシラート |
| US20060004010A1 (en) | 2002-07-10 | 2006-01-05 | Hiromu Habashita | Ccr4 antagonist and medical use thereof |
| CA2533587A1 (en) | 2002-07-30 | 2004-02-05 | University Of Virginia Patent Foundation | Compounds active in sphingosine 1-phosphate signaling |
| AU2003277576A1 (en) | 2002-11-08 | 2004-06-07 | Takeda Pharmaceutical Company Limited | Receptor function controlling agent |
| JP4516430B2 (ja) | 2002-12-20 | 2010-08-04 | メルク・シャープ・エンド・ドーム・コーポレイション | １−（アミノ）インダン並びに（１，２−ジヒドロ−３−アミノ）−ベンゾフラン、ベンゾチオフェン及びインドール |
| MXPA05008531A (es) | 2003-02-11 | 2005-11-17 | Irm Llc | Compuestos biciclicos novedosos y composiciones. |
| US7456157B2 (en) | 2003-02-18 | 2008-11-25 | Kyorin Pharmaceutical Co., Ltd. | Aminophosphonic acid derivatives, addition salts thereof and S1P receptor modulators |
| MXPA05011539A (es) | 2003-04-30 | 2006-01-23 | Inst For Pharm Discovery Inc | Acidos carboxilicos sustituidos con heterociclo como inhibidores de la proteina tirosina-fosfatasa-1b. |
| CA2523677A1 (en) | 2003-04-30 | 2004-11-11 | Novartis Ag | Aminopropanol derivatives as sphingosine-1-phosphate receptor modulators |
| EP1622860B1 (en) | 2003-04-30 | 2012-02-29 | Novartis AG | AMINO-PROPANOL DERIVATIVES AS SPHINGOSINE-1-PHOSPHATE RECEPTOR MODULATORs |
| US20060252741A1 (en) | 2003-05-15 | 2006-11-09 | Colandrea Vincent J | 3-(2-amino-1-azacyclyl)-5-aryl-1,2,4-oxadiazoles as s1p receptor agonists |
| WO2004104205A2 (en) | 2003-05-16 | 2004-12-02 | Merck & Co., Inc. | Enzymatic preparation of chiral indole esters |
| CN1791592B (zh) | 2003-05-19 | 2012-07-04 | Irm责任有限公司 | 免疫抑制剂化合物和组合物 |
| ES2558761T3 (es) | 2003-05-19 | 2016-02-08 | Novartis Ag | Compuestos y composiciones inmunosupresores |
| BRPI0410439A (pt) | 2003-05-19 | 2006-06-06 | Irm Llc | compostos e composições imunossupressoras |
| MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
| GB0313612D0 (en) | 2003-06-12 | 2003-07-16 | Novartis Ag | Organic compounds |
| EP1661879A4 (en) | 2003-08-04 | 2006-11-29 | Ono Pharmaceutical Co | A DIPHENYL ETHER COMPOUND, PROCESS FOR THE PRODUCTION AND USE THEREOF |
| CN1874996B (zh) | 2003-08-28 | 2011-05-18 | 诺瓦提斯公司 | 氨基丙醇衍生物 |
| EP1661881B1 (en) | 2003-08-29 | 2014-12-17 | Ono Pharmaceutical Co., Ltd. | Compound capable of binding s1p receptor and pharmaceutical use thereof |
| CN1874991A (zh) | 2003-08-29 | 2006-12-06 | 小野药品工业株式会社 | 能够结合s1p受体的化合物及其药物用途 |
| EP1661889A4 (en) | 2003-09-05 | 2009-08-05 | Ono Pharmaceutical Co | ANTAGONIST OF THE CHEMOKINE RECEPTOR AND ITS USE FOR MEDICAL PURPOSES |
| CN1859908A (zh) | 2003-10-01 | 2006-11-08 | 默克公司 | 作为s1p受体激动剂的3,5－芳基、杂芳基或环烷基取代的－1,2,4－噁二唑类化合物 |
| WO2005041899A2 (en) | 2003-11-03 | 2005-05-12 | University Of Virginia Patent Foundation | Orally available sphingosine 1-phosphate receptor agonists and antagonists |
| WO2005044780A1 (ja) | 2003-11-10 | 2005-05-19 | Kyorin Pharmaceutical Co., Ltd. | アミノカルボン酸誘導体とその付加塩及びｓ１ｐ受容体調節剤 |
| US7605171B2 (en) | 2003-12-17 | 2009-10-20 | Merck & Co., Inc. | (3,4-disubstituted)propanoic carboxylates as S1P (Edg) receptor agonists |
| ATE528276T1 (de) | 2003-12-19 | 2011-10-15 | Ono Pharmaceutical Co | Lysophosphatidylsäurerezeptor-antagonistische verbindungen und ihre anwendungen |
| GB0329498D0 (en) | 2003-12-19 | 2004-01-28 | Novartis Ag | Organic compounds |
| GB0401332D0 (en) | 2004-01-21 | 2004-02-25 | Novartis Ag | Organic compounds |
| JP2005272453A (ja) | 2004-02-24 | 2005-10-06 | Sankyo Co Ltd | アミノアルコール化合物 |
| TW200538433A (en) | 2004-02-24 | 2005-12-01 | Irm Llc | Immunosuppressant compounds and compositiions |
| JP4740884B2 (ja) | 2004-02-24 | 2011-08-03 | アイアールエム・リミテッド・ライアビリティ・カンパニー | 免疫抑制性化合物および組成物 |
| WO2005085214A1 (ja) | 2004-03-05 | 2005-09-15 | Banyu Pharmaceutical Co., Ltd | ジアリール置換複素５員環誘導体 |
| GB0405289D0 (en) | 2004-03-09 | 2004-04-21 | Novartis Ag | Organic compounds |
| TWI344954B (en) | 2004-04-02 | 2011-07-11 | Merck Sharp & Dohme | Asymmetric hydrogenation process |
| WO2005123677A1 (en) | 2004-06-16 | 2005-12-29 | Actelion Pharmaceuticals Ltd | 4-carbonyl substituted 1,1,2-trimethyl-1a,4,5,5a-tetrahydro-1h-4-aza-cyclopropa'a!pentalene derivatives as agonists for the g-protein-coupled receptor s1p1/edg1 and immunosuppressive agents |
| EP1760071A4 (en) | 2004-06-23 | 2008-03-05 | Ono Pharmaceutical Co | COMPOUND WITH S1P RECEPTOR BINDING ABILITY AND USE THEREOF |
| CN101014329B (zh) | 2004-07-16 | 2010-09-08 | 杏林制药株式会社 | 用于对器官或组织的移植的排异反应或骨髓移植的移植物抗宿主反应预防或治疗的药物组合物 |
| JP2007284350A (ja) | 2004-07-27 | 2007-11-01 | Takeda Chem Ind Ltd | 糖尿病治療剤 |
| TW200611687A (en) | 2004-07-29 | 2006-04-16 | Sankyo Co | Pharmaceutical compositions used for immunosuppressant |
| WO2006010379A1 (en) | 2004-07-29 | 2006-02-02 | Actelion Pharmaceuticals Ltd. | Novel thiophene derivatives as immunosuppressive agents |
| US8022225B2 (en) | 2004-08-04 | 2011-09-20 | Taisho Pharmaceutical Co., Ltd | Triazole derivative |
| US20060223866A1 (en) | 2004-08-13 | 2006-10-05 | Praecis Pharmaceuticals, Inc. | Methods and compositions for modulating sphingosine-1-phosphate (S1P) receptor activity |
| MX2007001661A (es) | 2004-08-13 | 2007-04-23 | Praecis Pharm Inc | Metodos y composiciones para modular la actividad del receptor de esfingosina -1 fosfato (sip). |
| MX2007003371A (es) | 2004-09-23 | 2007-05-07 | Wyeth Corp | Derivados de carbazol y ciclopentaindol para tratar infeccion con virus de hepatitis c. |
| MX2007004262A (es) | 2004-10-12 | 2008-03-04 | Forbes Medi Tech Res Inc | Compuestos y metodos para tratar resistencia a la insulina y cardiomiopatia. |
| AU2005299851B2 (en) | 2004-10-22 | 2011-03-17 | Merck Sharp & Dohme Corp. | 2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as S1P receptor agonists |
| ATE397582T1 (de) | 2004-10-22 | 2008-06-15 | Bioprojet Soc Civ | Neue dicarbonsäurederivate |
| AU2005307718A1 (en) | 2004-11-18 | 2006-05-26 | The Institutes For Pharmaceutical Discovery, Llc | Heterocycle substituted carboxylic acids for the treatment of diabetes |
| US20080051418A1 (en) | 2004-11-26 | 2008-02-28 | Tsuyoshi Maekawa | Arylalkanoic Acid Derivative |
| JP2008522977A (ja) | 2004-12-06 | 2008-07-03 | ユニバーシティ オブ バージニア パテント ファンデーション | スフィンゴシン＝１−リン酸のアリールアミドアナログ |
| EP2592066B1 (en) | 2004-12-13 | 2014-12-03 | Ono Pharmaceutical Co., Ltd. | Aminocarboxylic acid derivative and medical use thereof |
| WO2006079406A1 (en) | 2005-01-25 | 2006-08-03 | Merck Patent Gmbh | Mesogenic compounds, liquid crystal medium and liquid crystal display |
| AU2006214314B2 (en) | 2005-02-14 | 2012-02-09 | University Of Virginia Patent Foundation | Sphingosine 1- phos phate agonists comprising cycloalkanes and 5 -membered heterocycles substituted by amino and phenyl groups |
| KR20080002850A (ko) | 2005-03-23 | 2008-01-04 | 액테리온 파마슈티칼 리미티드 | 신규한 티오펜 유도체 |
| BRPI0609668A2 (pt) | 2005-03-23 | 2011-10-18 | Actelion Pharmaceuticals Ltd | composto, composição farmacêutica, e, uso de um composto |
| US7723378B2 (en) | 2005-03-23 | 2010-05-25 | Actelion Pharmaceuticals Ltd. | Hydrogenated benzo (C) thiophene derivatives as immunomodulators |
| BRPI0612028A2 (pt) | 2005-06-08 | 2010-10-13 | Novartis Ag | oxadiazóis ou isodiazóis policìclicos e uso dos mesmos como ligantes de receptor s1p |
| EP1896446A1 (en) | 2005-06-24 | 2008-03-12 | Actelion Pharmaceuticals Ltd. | Novel thiophene derivatives |
| TWI418350B (zh) | 2005-06-24 | 2013-12-11 | Sankyo Co | 含有ｐｐａｒ調節劑之醫藥組成物的用途 |
| US20070060573A1 (en) | 2005-08-10 | 2007-03-15 | Lars Wortmann | Acyltryptophanols |
| WO2007024922A1 (en) | 2005-08-23 | 2007-03-01 | Irm Llc | Immunosuppressant compounds and compositions |
| JPWO2007037196A1 (ja) | 2005-09-29 | 2009-04-09 | 山本化成株式会社 | インドリン系化合物及びその製造方法 |
| EP1965807A4 (en) | 2005-11-23 | 2010-10-27 | Epix Delaware Inc | S1P RECEPTOR MODULATING COMPOUNDS AND THEIR USE |
| AR057894A1 (es) | 2005-11-23 | 2007-12-26 | Actelion Pharmaceuticals Ltd | Derivados de tiofeno |
| TWI404706B (zh) | 2006-01-11 | 2013-08-11 | Actelion Pharmaceuticals Ltd | 新穎噻吩衍生物 |
| TW200736234A (en) | 2006-01-17 | 2007-10-01 | Astrazeneca Ab | Chemical compounds |
| ATE447568T1 (de) | 2006-01-24 | 2009-11-15 | Actelion Pharmaceuticals Ltd | Neue pyrinderivate |
| GB0601744D0 (en) | 2006-01-27 | 2006-03-08 | Novartis Ag | Organic compounds |
| TWI389683B (zh) | 2006-02-06 | 2013-03-21 | Kyorin Seiyaku Kk | A therapeutic agent for an inflammatory bowel disease or an inflammatory bowel disease treatment using a 2-amino-1,3-propanediol derivative as an active ingredient |
| AU2007212193A1 (en) | 2006-02-09 | 2007-08-16 | University Of Virginia Patent Foundation | Bicyclic sphingosine 1-phosphate analogs |
| TW200806611A (en) | 2006-02-09 | 2008-02-01 | Daiichi Seiyaku Co | Novel amidopropionic acid derivatives and medicine containing the same |
| US20070191371A1 (en) | 2006-02-14 | 2007-08-16 | Kalypsys, Inc. | Heterocyclic modulators of ppar |
| BRPI0707873A2 (pt) | 2006-02-15 | 2011-05-10 | Allergan Inc | compostos amida, Éster, tioamida e tiol Éster do Ácido indol-3-carboxÍlico carregando grupos arila ou heteroarila tendo atividade biolàgica antagonista de recptor de esfingosina-1-fosfato (s1p) |
| CN101460458A (zh) | 2006-02-15 | 2009-06-17 | 阿勒根公司 | 具有1－磷酸－鞘氨醇(s1p)受体拮抗剂生物活性的带芳基或者杂芳基基团的吲哚－3－羧酸的酰胺、酯、硫代酰胺和硫羟酸酯化合物 |
| BRPI0707957A2 (pt) | 2006-02-21 | 2011-05-17 | Univ Virginia Patent Found | composto, e, método para prevenção ou tratamento de uma condição ou sintoma patológico em um mamìfero |
| US7649098B2 (en) | 2006-02-24 | 2010-01-19 | Lexicon Pharmaceuticals, Inc. | Imidazole-based compounds, compositions comprising them and methods of their use |
| CA2646430A1 (en) | 2006-03-14 | 2007-09-20 | Amgen Inc. | Bicyclic carboxylic acid derivatives useful for treating metabolic disorders |
| JP2009530389A (ja) | 2006-03-21 | 2009-08-27 | エピックス デラウェア， インコーポレイテッド | Ｓ１ｐ受容体調節化合物及びその使用 |
| JP2007262009A (ja) | 2006-03-29 | 2007-10-11 | Dai Ichi Seiyaku Co Ltd | ヘテロアリール低級カルボン酸誘導体 |
| MX2008012738A (es) | 2006-04-03 | 2009-02-06 | Astellas Pharma Inc | Heterocompuesto. |
| GB0607389D0 (en) | 2006-04-12 | 2006-05-24 | Novartis Ag | Organic compounds |
| WO2007129473A1 (ja) | 2006-05-09 | 2007-11-15 | Daiichi Sankyo Company, Limited | 二環性アリール誘導体 |
| EA200802058A1 (ru) | 2006-05-09 | 2009-06-30 | Пфайзер Продактс Инк. | Производные циклоалкиламинокислот и их фармацевтические композиции |
| JPWO2007129745A1 (ja) | 2006-05-09 | 2009-09-17 | 第一三共株式会社 | ヘテロアリールアミド低級カルボン酸誘導体 |
| TW200823182A (en) | 2006-08-01 | 2008-06-01 | Praecis Pharm Inc | Chemical compounds |
| US20080070866A1 (en) | 2006-08-01 | 2008-03-20 | Praecis Pharmaceuticals Incorporated | Chemical compounds |
| JP2009545630A (ja) | 2006-08-04 | 2009-12-24 | プリーシス・ファーマシューティカルズ・インコーポレイテッド | 化合物 |
| JP5188972B2 (ja) | 2006-08-08 | 2013-04-24 | 杏林製薬株式会社 | アミノリン酸エステル誘導体及びそれらを有効成分とするｓ１ｐ受容体調節剤 |
| WO2008024196A1 (en) | 2006-08-24 | 2008-02-28 | Praecis Pharmaceuticals Incorporated | Chemical compounds |
| JP2009269819A (ja) | 2006-08-25 | 2009-11-19 | Asahi Kasei Pharma Kk | アミン化合物 |
| TWI392671B (zh) | 2006-09-07 | 2013-04-11 | Actelion Pharmaceuticals Ltd | 吡啶-４-基衍生物 |
| AU2007292347A1 (en) | 2006-09-07 | 2008-03-13 | Allergan, Inc. | Heteroaromatic compounds having sphingosine-1-phosphate (S1P) receptor agonist and/or antagonist biological activity |
| TWI408139B (zh) | 2006-09-07 | 2013-09-11 | Actelion Pharmaceuticals Ltd | 新穎噻吩衍生物 |
| PE20080769A1 (es) | 2006-09-08 | 2008-08-14 | Novartis Ag | Derivados de biaril-sulfonamida |
| MX2009002915A (es) | 2006-09-21 | 2009-03-31 | Actelion Pharmaceuticals Ltd | Derivados de fenilo y su uso como inmunomoduladores. |
| SG177221A1 (en) | 2006-12-15 | 2012-01-30 | Abbott Lab | Novel oxadiazole compounds |
| JO2701B1 (en) * | 2006-12-21 | 2013-03-03 | جلاكسو جروب ليميتد | Vehicles |
| CL2007003784A1 (es) | 2006-12-21 | 2008-06-27 | Abbott Lab | Compuestos derivados de 1-amino-3-fenilciclopentano, que son agonistas o antagonistas de uno o mas receptores de la familia s1p; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar la esclerosis multiple, artritis reumato |
| GB0625648D0 (en) | 2006-12-21 | 2007-01-31 | Glaxo Group Ltd | Compounds |
| JP2010515750A (ja) | 2007-01-11 | 2010-05-13 | アラーガン インコーポレイテッド | スフィンゴシン−１−ホスフェート（ｓ１ｐ）受容体アンタゴニスト生物活性を有する６−置換インドール−３−カルボン酸アミド化合物 |
| WO2008091967A1 (en) | 2007-01-26 | 2008-07-31 | Smithkline Beecham Corporation | Chemical compounds |
| WO2008097819A2 (en) | 2007-02-05 | 2008-08-14 | Smithkline Beecham Corporation | Chemical compounds |
| PT2125797E (pt) | 2007-03-16 | 2014-03-11 | Actelion Pharmaceuticals Ltd | Derivados aminopiridina como agonistas do receptor s1p1/edg1 |
| MX2009010060A (es) | 2007-03-21 | 2010-01-20 | Epix Pharm Inc | Compuestos moduladores del receptor de esfingosin-1-fosfato y uso de los mismos. |
| KR20090130062A (ko) | 2007-04-19 | 2009-12-17 | 글락소 그룹 리미티드 | 스핑고신 １―포스페이트 (ｓ１ｐ) 효능제로서 사용하기 위한 옥사디아졸 치환된 인다졸 유도체 |
| EP2014653A1 (en) | 2007-06-15 | 2009-01-14 | Bioprojet | Novel dicarboxylic acid derivatives as S1P1 receptor agonists |
| US20090069288A1 (en) | 2007-07-16 | 2009-03-12 | Breinlinger Eric C | Novel therapeutic compounds |
| WO2009019506A1 (en) | 2007-08-03 | 2009-02-12 | Astrazeneca Ab | Heterocyclyc sulfonamides having edg-1 antagonistic activity |
| MX2010001446A (es) | 2007-08-08 | 2010-03-01 | Merck Serono Sa | Derivados de 6-amino-pirimidina-4-carboxamida y compuestos relacionados que se enlazan a los receptores para esfingosina 1-fosfato (s1p) para el tratamiento de esclerosis multiple. |
| UY31468A1 (es) | 2007-11-15 | 2009-07-17 | Derivados bis-(sulfonilamino) en terapia 065 | |
| EP2222668B1 (en) | 2007-12-18 | 2011-11-02 | Arena Pharmaceuticals, Inc. | Tetrahydrocyclopenta[b]indol-3-yl carboxylic acid derivatives useful in the treatment of autoimmune and inflammatory disorders |
| AU2009206733A1 (en) | 2008-01-25 | 2009-07-30 | Arena Pharmaceuticals, Inc. | Dihydro- 1H- pyrrolo [1,2-a] indol-1-yl carboxylic derivatives which act as S1P1 agonists |
| AR070398A1 (es) | 2008-02-22 | 2010-03-31 | Gruenenthal Chemie | Derivados sustituidos de indol |
| SI2291080T1 (sl) | 2008-05-14 | 2015-11-30 | The Scripps Research Institute | Novi modulatorji sfingosinskih fosfatnih receptorjev |
| WO2009151621A1 (en) | 2008-06-13 | 2009-12-17 | Arena Pharmaceuticals, Inc. | Substituted (1, 2, 4-0xadiaz0l-3-yl) indolin-1-yl carboxylic acid derivatives useful as s1p1 agonists |
| WO2009151626A1 (en) | 2008-06-13 | 2009-12-17 | Arena Pharmaceuticals, Inc. | Substituted (1, 2, 4-0xadiaz0l-3-yl) indolin-1-yl carboxylic acid derivatives useful as s1p1 agonists |
| EA019252B1 (ru) | 2008-07-23 | 2014-02-28 | Арена Фармасьютикалз, Инк. | ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ (1,2,3,4-ТЕТРАГИДРОЦИКЛОПЕНТА[b]ИНДОЛ-3-ИЛ)УКСУСНОЙ КИСЛОТЫ, ПРИМЕНИМЫЕ В ЛЕЧЕНИИ АУТОИММУННЫХ И ВОСПАЛИТЕЛЬНЫХ РАССТРОЙСТВ |
| SI2342205T1 (sl) | 2008-08-27 | 2016-09-30 | Arena Pharmaceuticals, Inc. | Substituirani triciklični kislinski derivati kot agonisti S1P1 receptorja, uporabni v zdravljenju avtoimunskih in vnetnih obolenj |
| US8193378B2 (en) * | 2008-12-05 | 2012-06-05 | Astellas Pharma Inc. | 2H-chromene compound and derivative thereof |
| MX2011008450A (es) | 2009-02-10 | 2011-09-01 | Abbott Lab | Agonistas y antagonistas del receptor s1p5, y metodos de uso de los mismos. |
| WO2011005290A1 (en) | 2009-06-23 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Disubstituted oxadiazole derivatives useful in the treatment of autoimmune and inflammatory disorders |
| WO2011005295A1 (en) | 2009-06-24 | 2011-01-13 | Arena Pharmaceuticals, Inc. | Modulators of the sphingosine-1-phosphate (s1p) receptor useful for the treatment of disorders related thereto |
| JP5728487B2 (ja) | 2009-10-29 | 2015-06-03 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | 三環式ヘテロ環化合物 |
| SG10201906876PA (en) | 2010-01-27 | 2019-09-27 | Arena Pharm Inc | Processes for the preparation of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof |
| SG183416A1 (en) * | 2010-03-03 | 2012-09-27 | Arena Pharm Inc | Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof |
| EP2598126A2 (en) | 2010-07-30 | 2013-06-05 | Saint Louis University | Methods of treating pain |
-
2011
- 2011-03-02 SG SG2012061685A patent/SG183416A1/en unknown
- 2011-03-02 SG SG10201501575VA patent/SG10201501575VA/en unknown
- 2011-03-02 CA CA2789480A patent/CA2789480A1/en not_active Withdrawn
- 2011-03-02 CN CN201180022490.XA patent/CN102884064B/zh active Active
- 2011-03-02 EP EP11707330.4A patent/EP2542554B1/en active Active
- 2011-03-02 JP JP2012556199A patent/JP2013521301A/ja not_active Abandoned
- 2011-03-02 CN CN201510932844.4A patent/CN105503882B/zh active Active
- 2011-03-02 WO PCT/US2011/026806 patent/WO2011109471A1/en not_active Ceased
- 2011-03-02 US US13/581,846 patent/US9085581B2/en active Active
- 2011-03-02 ES ES11707330.4T patent/ES2558087T3/es active Active
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2015
- 2015-06-15 US US14/739,341 patent/US20150284399A1/en not_active Abandoned
- 2015-07-17 JP JP2015142650A patent/JP2015180706A/ja not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP2542554A1 (en) | 2013-01-09 |
| US9085581B2 (en) | 2015-07-21 |
| CN102884064A (zh) | 2013-01-16 |
| CN105503882A (zh) | 2016-04-20 |
| JP2013521301A (ja) | 2013-06-10 |
| WO2011109471A1 (en) | 2011-09-09 |
| US20150284399A1 (en) | 2015-10-08 |
| SG183416A1 (en) | 2012-09-27 |
| EP2542554B1 (en) | 2015-11-04 |
| CN105503882B (zh) | 2019-07-05 |
| JP2015180706A (ja) | 2015-10-15 |
| CN102884064B (zh) | 2016-01-13 |
| HK1179627A1 (zh) | 2013-10-04 |
| CA2789480A1 (en) | 2011-09-09 |
| SG10201501575VA (en) | 2015-04-29 |
| US20120329848A1 (en) | 2012-12-27 |
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