BRPI0618210A2 - compostos, composição farmacêutica, métodos de produção de um composto e de preparação de uma composição farmacêutica, uso de um composto ou de um sal farmaceuticamente aceitável do mesmo - Google Patents
compostos, composição farmacêutica, métodos de produção de um composto e de preparação de uma composição farmacêutica, uso de um composto ou de um sal farmaceuticamente aceitável do mesmo Download PDFInfo
- Publication number
- BRPI0618210A2 BRPI0618210A2 BRPI0618210-0A BRPI0618210A BRPI0618210A2 BR PI0618210 A2 BRPI0618210 A2 BR PI0618210A2 BR PI0618210 A BRPI0618210 A BR PI0618210A BR PI0618210 A2 BRPI0618210 A2 BR PI0618210A2
- Authority
- BR
- Brazil
- Prior art keywords
- compound
- formula
- group
- dioxo
- methylamino
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 106
- 150000003839 salts Chemical class 0.000 title claims abstract description 59
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- 238000011282 treatment Methods 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 23
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
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- 102000007466 Purinergic P2 Receptors Human genes 0.000 claims abstract 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 73
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 70
- -1 6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl Chemical group 0.000 claims description 64
- 239000002904 solvent Substances 0.000 claims description 52
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- WUPZRLYEGIXBNO-UHFFFAOYSA-N 1-(5-chlorothiophen-2-yl)sulfonyl-1-[4-[6-fluoro-7-(methylamino)-2,4-dioxo-1h-quinazolin-3-yl]phenyl]urea Chemical compound O=C1C=2C=C(F)C(NC)=CC=2NC(=O)N1C(C=C1)=CC=C1N(C(N)=O)S(=O)(=O)C1=CC=C(Cl)S1 WUPZRLYEGIXBNO-UHFFFAOYSA-N 0.000 claims description 25
- 238000002329 infrared spectrum Methods 0.000 claims description 24
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 24
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- WLMZTKAZJUWXCB-KQYNXXCUSA-N [(2r,3s,4r,5r)-5-(6-amino-2-methylsulfanylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphono hydrogen phosphate Chemical compound C12=NC(SC)=NC(N)=C2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O WLMZTKAZJUWXCB-KQYNXXCUSA-N 0.000 claims description 6
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 4
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 3
- KLPPUPBECAHKEF-UHFFFAOYSA-N thiophen-2-ylsulfonylurea Chemical compound NC(=O)NS(=O)(=O)C1=CC=CS1 KLPPUPBECAHKEF-UHFFFAOYSA-N 0.000 claims 3
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- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 claims 1
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- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
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- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- PPADHTVWIWCEDE-UHFFFAOYSA-M potassium;(5-chlorothiophen-2-yl)sulfonyl-[[4-[6-fluoro-7-(methylamino)-2,4-dioxo-1h-quinazolin-3-yl]phenyl]carbamoyl]azanide Chemical compound [K+].O=C1C=2C=C(F)C(NC)=CC=2NC(=O)N1C(C=C1)=CC=C1NC(=O)[N-]S(=O)(=O)C1=CC=C(Cl)S1 PPADHTVWIWCEDE-UHFFFAOYSA-M 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
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- 238000005488 sandblasting Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
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- 238000011105 stabilization Methods 0.000 description 1
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- 150000005846 sugar alcohols Chemical class 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- 230000003582 thrombocytopenic effect Effects 0.000 description 1
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- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—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
- C07D409/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Biomedical Technology (AREA)
- Neurology (AREA)
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- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (3)
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| US73365005P | 2005-11-03 | 2005-11-03 | |
| US60/733650 | 2005-11-03 | ||
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| BRPI0618210A2 true BRPI0618210A2 (pt) | 2011-08-23 |
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| JP (1) | JP5509406B2 (enExample) |
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| AU (1) | AU2006311795B2 (enExample) |
| BR (1) | BRPI0618210A2 (enExample) |
| CA (1) | CA2627719C (enExample) |
| CY (1) | CY1112826T1 (enExample) |
| DK (1) | DK1951254T3 (enExample) |
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| IL (1) | IL191193A (enExample) |
| NZ (2) | NZ567747A (enExample) |
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| BRPI0512273A (pt) | 2004-06-18 | 2008-02-19 | Millennium Pharm Inc | inibidores do fator xa |
| KR101423483B1 (ko) * | 2005-11-03 | 2014-07-28 | 포톨라 파마슈티컬스, 인코포레이티드 | 〔４-(６-할로-７-치환된-２,４-디옥소-１,４-디히드로-２ｈ-퀴나졸린-３-일)-페닐〕-５-클로로티오펜-２-일-설포닐우레아 및 이의 형태 및 이와 관련된 방법 |
| EP2016072B1 (en) | 2006-05-05 | 2014-07-16 | Millennium Pharmaceuticals, Inc. | Factor xa inhibitors |
| TW200911755A (en) | 2007-04-19 | 2009-03-16 | Astellas Pharma Inc | Bicyclic heterocyclic compounds |
| EA020045B1 (ru) * | 2007-05-02 | 2014-08-29 | Портола Фармасьютиклз, Инк. | Комбинированная терапия соединением, проявляющим активность ингибитора рецептора адф на тромбоцитах |
| US20090156620A1 (en) * | 2007-05-02 | 2009-06-18 | Portola Pharmaceuticals, Inc. | [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, forms and methods related thereto |
| CA2686221A1 (en) * | 2007-05-02 | 2008-11-13 | Portola Pharmaceuticals, Inc. | [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, forms and methods related thereto |
| KR20100029746A (ko) | 2007-05-02 | 2010-03-17 | 포톨라 파마슈티컬스, 인코포레이티드 | 직접 작용하는 가역적인 ｐ2ｙ12 억제제의 정맥내 및 경구 투여 |
| MX2009013431A (es) * | 2007-06-18 | 2010-01-15 | Sanofi Aventis | Derivados de pirrol como antagonistas de p2y12. |
| CN101654441B (zh) * | 2008-08-19 | 2012-10-03 | 信谊药厂 | 抗凝化合物、组合物及其用途 |
| CA2743639A1 (en) * | 2008-11-14 | 2010-05-20 | Patheon Inc. | Solid composition for controlled release of ionizable active agents with poor aqueous solubility at low ph and methods of use thereof |
| WO2011006169A1 (en) | 2009-07-10 | 2011-01-13 | Portola Pharmaceuticals, Inc. | Methods for diagnosis and treatment of thrombotic disorders mediated by cyp2c19*2 |
| JP5597202B2 (ja) | 2009-08-28 | 2014-10-01 | 第一三共株式会社 | ３−（ビアリールオキシ）プロピオン酸誘導体 |
| WO2011075602A1 (en) | 2009-12-17 | 2011-06-23 | Millennium Pharmaceuticals, Inc. | Methods of preparing factor xa inhibitors and salts thereof |
| JP5796872B2 (ja) | 2009-12-17 | 2015-10-21 | ミレニアム ファーマシューティカルズ， インコーポレイテッドＭｉｌｌｅｎｎｉｕｍ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． | 第Ｘａ因子阻害剤の結晶性塩 |
| US20130165459A1 (en) | 2010-01-12 | 2013-06-27 | Norvartis Pharma Ag | Pharmaceutical composition and dosage forms of elinogrel and methods of use thereof |
| WO2011137459A1 (en) | 2010-04-30 | 2011-11-03 | Portola Pharmaceuticals, Inc. | Dosage forms of elinogrel and methods of injectable administration thereof |
| EP2646434B1 (en) * | 2010-12-03 | 2019-05-15 | Portola Pharmaceuticals, Inc. | Pharmaceutical compositions, dosage forms and new forms of the compound of formula (i), and methods of use thereof |
| WO2014042176A1 (ja) * | 2012-09-14 | 2014-03-20 | キッセイ薬品工業株式会社 | 縮合複素環誘導体の製造方法およびその製造中間体 |
| RU2556198C1 (ru) * | 2014-04-10 | 2015-07-10 | Федеральное государственное бюджетное учреждение "Научно-исследовательский институт кардиологии" Сибирского отделения Российской академии медицинских наук | Способ профилактики развития постперикардиотомного синдрома у больных ишемической болезнью сердца, подвергшихся коронарному шунтированию |
| HK1255034A1 (zh) | 2015-07-01 | 2019-08-02 | Crinetics Pharmaceuticals, Inc. | 生长抑素调节剂及其用途 |
| WO2019023278A1 (en) | 2017-07-25 | 2019-01-31 | Crinetics Pharmaceuticals, Inc. | MODULATORS OF SOMATOSTATIN AND USES THEREOF |
| EP4204418A1 (en) | 2020-08-28 | 2023-07-05 | Arvinas Operations, Inc. | Rapidly accelerating fibrosarcoma protein degrading compounds and associated methods of use |
| TW202432544A (zh) | 2022-09-07 | 2024-08-16 | 美商亞文納營運公司 | 快速加速纖維肉瘤降解化合物及相關使用方法 |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE845042C (de) | 1950-07-14 | 1952-07-28 | Basf Ag | Verfahren zur Herstellung von Sulfonylurethanen, -harnstoffen oder -carbonsaeureamiden |
| US3847925A (en) * | 1971-07-15 | 1974-11-12 | En Nom Collectif Science Et Ci | Benzenesulfonyl semicarbazides |
| DE3134780A1 (de) * | 1981-09-02 | 1983-03-10 | Hoechst Ag, 6000 Frankfurt | "sulfonylharnstoffe, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung" |
| US4720450A (en) * | 1985-06-03 | 1988-01-19 | Polaroid Corporation | Thermal imaging method |
| GB9413975D0 (en) | 1994-07-11 | 1994-08-31 | Fujisawa Pharmaceutical Co | New heterobicyclic derivatives |
| US5314902A (en) * | 1993-01-27 | 1994-05-24 | Monsanto Company | Urea derivatives useful as platelet aggregation inhibitors |
| US6268380B1 (en) | 1993-02-19 | 2001-07-31 | G. D. Searle & Co. | Urea derivatives useful as platelet aggregation inhibitors |
| WO1994021602A1 (en) | 1993-03-15 | 1994-09-29 | G.D. Searle & Co. | Urea derivatives useful as platelet aggregation inhibitors |
| TW448161B (en) | 1994-07-14 | 2001-08-01 | Otsuka Pharma Co Ltd | Cyclic amide derivatives |
| JPH0881442A (ja) | 1994-07-14 | 1996-03-26 | Otsuka Pharmaceut Co Ltd | 環状アミド誘導体 |
| US6413724B1 (en) * | 1996-10-28 | 2002-07-02 | Versicor, Inc. | Solid phase and combinatorial library syntheses of fused 2,4-pyrimidinediones |
| US6160000A (en) * | 1996-12-23 | 2000-12-12 | Merck & Co., Inc. | Antidiabetic agents based on aryl and heteroarylacetic acids |
| JPH10195323A (ja) | 1997-01-09 | 1998-07-28 | Nippon Paper Ind Co Ltd | 新規なスルホニルグアニジン化合物及びそれを用いた感熱記録体 |
| SE9702774D0 (sv) | 1997-07-22 | 1997-07-22 | Astra Pharma Prod | Novel compounds |
| JP2002509152A (ja) | 1998-01-15 | 2002-03-26 | シーオーアール セラピューティクス インコーポレイテッド | 血小板ａｄｐ受容体阻害剤 |
| JP2000204081A (ja) | 1998-02-05 | 2000-07-25 | Takeda Chem Ind Ltd | スルホンアミド誘導体、その製造法及び用途 |
| US6906063B2 (en) * | 2000-02-04 | 2005-06-14 | Portola Pharmaceuticals, Inc. | Platelet ADP receptor inhibitors |
| JP4574100B2 (ja) | 2000-02-04 | 2010-11-04 | ポートラ ファーマシューティカルズ， インコーポレイテッド | 血小板ａｄｐレセプターインヒビター |
| ATE502928T1 (de) * | 2000-11-01 | 2011-04-15 | Millennium Pharm Inc | Stickstoffhaltige heterozyklische verbindungen und verfahren zu deren herstellung |
| US6824790B2 (en) * | 2002-01-09 | 2004-11-30 | Enzrel Inc. | Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds |
| US20040242658A1 (en) * | 2003-01-08 | 2004-12-02 | Dr. Reddy's Laboratories Limited | Amorphous form of rosiglitazone maleate and process for preparation thereof |
| AU2004278030C1 (en) * | 2003-10-03 | 2010-12-02 | Portola Pharmaceuticals, Inc. | 2,4-Dioxo-3-quinazolinylaryl sulfonylureas |
| KR101423483B1 (ko) | 2005-11-03 | 2014-07-28 | 포톨라 파마슈티컬스, 인코포레이티드 | 〔４-(６-할로-７-치환된-２,４-디옥소-１,４-디히드로-２ｈ-퀴나졸린-３-일)-페닐〕-５-클로로티오펜-２-일-설포닐우레아 및 이의 형태 및 이와 관련된 방법 |
| US20090156620A1 (en) * | 2007-05-02 | 2009-06-18 | Portola Pharmaceuticals, Inc. | [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, forms and methods related thereto |
| KR20100029746A (ko) * | 2007-05-02 | 2010-03-17 | 포톨라 파마슈티컬스, 인코포레이티드 | 직접 작용하는 가역적인 ｐ2ｙ12 억제제의 정맥내 및 경구 투여 |
| CA2686221A1 (en) * | 2007-05-02 | 2008-11-13 | Portola Pharmaceuticals, Inc. | [4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2h-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea salts, forms and methods related thereto |
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