BRPI0607400A2 - derivados do ácido [isoquinolin-3-(carbonil)amino]-propiÈnico como inibidores dos fatores xi e ix para o tratamento de trombose - Google Patents
derivados do ácido [isoquinolin-3-(carbonil)amino]-propiÈnico como inibidores dos fatores xi e ix para o tratamento de tromboseInfo
- Publication number
- BRPI0607400A2 BRPI0607400A2 BRPI0607400-6A BRPI0607400A BRPI0607400A2 BR PI0607400 A2 BRPI0607400 A2 BR PI0607400A2 BR PI0607400 A BRPI0607400 A BR PI0607400A BR PI0607400 A2 BRPI0607400 A2 BR PI0607400A2
- Authority
- BR
- Brazil
- Prior art keywords
- isoquinolin
- carbonyl
- inhibitors
- factors
- treatment
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title abstract 2
- YVNNJMGQURRMNF-UHFFFAOYSA-N 2-(isoquinoline-3-carbonylamino)propanoic acid Chemical class C1=CC=C2C=NC(C(=O)NC(C)C(O)=O)=CC2=C1 YVNNJMGQURRMNF-UHFFFAOYSA-N 0.000 title 1
- 208000007536 Thrombosis Diseases 0.000 title 1
- 239000005557 antagonist Substances 0.000 abstract 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical class [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 abstract 1
- 102100022641 Coagulation factor IX Human genes 0.000 abstract 1
- 108010076282 Factor IX Proteins 0.000 abstract 1
- 108010074864 Factor XI Proteins 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 230000023555 blood coagulation Effects 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- 229960004222 factor ix Drugs 0.000 abstract 1
- 125000001072 heteroaryl group Chemical group 0.000 abstract 1
- 230000006623 intrinsic pathway Effects 0.000 abstract 1
Classifications
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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
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/02—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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/02—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
- C07D405/12—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 chain containing hetero atoms as chain links
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Gynecology & Obstetrics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Pregnancy & Childbirth (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
DERIVADOS DO áCIDO [ISOQUINOLIN-3-(CARBONIL)AMINOI-PROPIÈNICO COMO INIBIDORES DOS FATORES XI E IX PARA O TRATAMENTO DE TROMBOSE. Essa invenção provê compostos de arila e heteroarua de fórmula (X) Os compostos da invenção podem ser úteis como antagonistas, ou antagonistas parciais do fator IX e/ou do fator XI e assim, podem ser usados para inibir a via intrínseca da coagulação sanguínea. A fórmula (X) em que R~ 102~ é selecionado do grupo que consiste em - C(O)OH, - C(O)OCH~ 3~, - C(O)O-t-butila, -C(O)NH-OCH~ 2~-fenila, C(O)NHOH e - C(O) NHSO~ 2~CH~ 3~; e em que R~ 101~, R~ 103~, R~ 104~ e Y são conforme aqui definido.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/069,521 US7208601B2 (en) | 2003-08-08 | 2005-03-01 | Aryl and heteroaryl compounds, compositions, and methods of use |
| PCT/US2006/006571 WO2006093823A1 (en) | 2005-03-01 | 2006-02-23 | 2- [ isoquinolin-s - carbonyl ) amino] -propionic acid derivatives as inhibitors of factors xi and ix for the treatment of thrombosis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0607400A2 true BRPI0607400A2 (pt) | 2009-09-01 |
Family
ID=36539849
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0607400-6A BRPI0607400A2 (pt) | 2005-03-01 | 2006-02-23 | derivados do ácido [isoquinolin-3-(carbonil)amino]-propiÈnico como inibidores dos fatores xi e ix para o tratamento de trombose |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US7208601B2 (pt) |
| EP (1) | EP1888566A1 (pt) |
| JP (1) | JP2008531689A (pt) |
| CN (1) | CN101137650A (pt) |
| AU (1) | AU2006218815A1 (pt) |
| BR (1) | BRPI0607400A2 (pt) |
| CA (1) | CA2599808A1 (pt) |
| IL (1) | IL185428A0 (pt) |
| MX (1) | MX2007010682A (pt) |
| WO (1) | WO2006093823A1 (pt) |
| ZA (1) | ZA200707508B (pt) |
Families Citing this family (66)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004108681A1 (en) | 2003-06-06 | 2004-12-16 | Fibrogen, Inc. | Nitrogen-containing heteroaryl compounds and their use in increasing endogenous erythropoietin |
| US7208601B2 (en) * | 2003-08-08 | 2007-04-24 | Mjalli Adnan M M | Aryl and heteroaryl compounds, compositions, and methods of use |
| US7544699B2 (en) * | 2003-08-08 | 2009-06-09 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions, and methods of use |
| EP1831225A2 (en) * | 2004-11-19 | 2007-09-12 | The Regents of the University of California | Anti-inflammatory pyrazolopyrimidines |
| PT1951718E (pt) * | 2005-11-21 | 2012-05-21 | Purdue Pharma Lp | Compostos de 4-oxadiazolil-piperidina e as suas utilizações |
| EP1957476A1 (en) * | 2005-11-23 | 2008-08-20 | AstraZeneca AB | L-alanine derivatives |
| JP2009520695A (ja) * | 2005-12-15 | 2009-05-28 | ヴィキュロン ファーマシューティカルズ インコーポレイテッド | 抗菌活性を有するn−ヒドロキシアミド誘導体 |
| BRPI0707302B8 (pt) * | 2006-01-27 | 2021-05-25 | Fibrogen Inc | compostos de cianoisoquinolina que atuam no dano tecidual associado com isquemia, hipóxia e anemia, bem como composição farmacêutica que os compreende |
| BRPI0710527B8 (pt) * | 2006-04-04 | 2021-05-25 | Fibrogen Inc | compostos de pirrolo- e tiazolo-piridina e composição farmacêutica que os compreende |
| WO2007114926A2 (en) | 2006-04-04 | 2007-10-11 | The Regents Of The University Of California | Kinase antagonists |
| JP2009539815A (ja) * | 2006-06-09 | 2009-11-19 | アストラゼネカ アクチボラグ | 固形腫瘍の治療用のa5b1アンタゴニストとしてのN−(ベンゾイル)−O−[2−(ピリジン−2−イルアミノ)エチル]−L−チロシン誘導体と関連化合物 |
| US20090062267A1 (en) * | 2007-01-29 | 2009-03-05 | Astrazeneca Ab | L-ALANINE DERIVATIVES AS a5beta1 ANTAGONISTS |
| WO2008125811A1 (en) * | 2007-04-11 | 2008-10-23 | Astrazeneca Ab | N-[HETEROARYLCARBONYL]-S-THIENYL-L-ALANINE DERIVATIVES AS α5β1 ANTAGONISTS |
| GB2467670B (en) * | 2007-10-04 | 2012-08-01 | Intellikine Inc | Chemical entities and therapeutic uses thereof |
| US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
| MX2010007419A (es) | 2008-01-04 | 2010-11-12 | Intellikine Inc | Ciertas entidades quimicas, composiciones y metodos. |
| US8993580B2 (en) | 2008-03-14 | 2015-03-31 | Intellikine Llc | Benzothiazole kinase inhibitors and methods of use |
| EP2252293B1 (en) * | 2008-03-14 | 2018-06-27 | Intellikine, LLC | Kinase inhibitors and methods of use |
| BRPI0915231A2 (pt) * | 2008-07-08 | 2018-06-12 | Intellikine Inc | compostos inibidores de quinase e métodos de uso |
| US20110224223A1 (en) * | 2008-07-08 | 2011-09-15 | The Regents Of The University Of California, A California Corporation | MTOR Modulators and Uses Thereof |
| CA2738429C (en) | 2008-09-26 | 2016-10-25 | Intellikine, Inc. | Heterocyclic kinase inhibitors |
| EP2358720B1 (en) | 2008-10-16 | 2016-03-02 | The Regents of The University of California | Fused ring heteroaryl kinase inhibitors |
| US8476431B2 (en) | 2008-11-03 | 2013-07-02 | Itellikine LLC | Benzoxazole kinase inhibitors and methods of use |
| JP5649584B2 (ja) | 2008-11-14 | 2015-01-07 | フィブロジェン インコーポレイテッド | Hifヒドロキシラーゼ阻害剤としてのチオクロメン誘導体 |
| JP5789252B2 (ja) | 2009-05-07 | 2015-10-07 | インテリカイン, エルエルシー | 複素環式化合物およびその使用 |
| UA107360C2 (en) * | 2009-08-05 | 2014-12-25 | Biogen Idec Inc | Bicyclic aryl sphingosine 1-phosphate analogs |
| WO2011047384A2 (en) | 2009-10-16 | 2011-04-21 | The Regents Of The University Of California | Methods of inhibiting ire1 |
| WO2011073845A1 (en) | 2009-12-16 | 2011-06-23 | Pfizer Inc. | N-linked hydroxamic acid derivatives useful as antibacterial agents |
| CA2799579A1 (en) | 2010-05-21 | 2011-11-24 | Intellikine, Inc. | Chemical compounds, compositions and methods for kinase modulation |
| JP2013545749A (ja) | 2010-11-10 | 2013-12-26 | インフィニティー ファーマシューティカルズ, インコーポレイテッド | 複素環化合物及びその使用 |
| ES2637113T3 (es) | 2011-01-10 | 2017-10-10 | Infinity Pharmaceuticals, Inc. | Procedimientos para preparar isoquinolinonas y formas sólidas de isoquinolinonas |
| US9295673B2 (en) | 2011-02-23 | 2016-03-29 | Intellikine Llc | Combination of mTOR inhibitors and P13-kinase inhibitors, and uses thereof |
| AR088218A1 (es) | 2011-07-19 | 2014-05-21 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos utiles como inhibidores de pi3k |
| HK1198443A1 (en) | 2011-07-19 | 2015-04-24 | 无限药品股份有限公司 | Heterocyclic compounds and uses thereof |
| JP2014525932A (ja) | 2011-08-15 | 2014-10-02 | インターミューン, インコーポレイテッド | リゾホスファチド酸レセプターアンタゴニスト |
| MX2014002542A (es) | 2011-08-29 | 2014-07-09 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos y usos de los mismos. |
| CA2846496C (en) | 2011-09-02 | 2020-07-14 | The Regents Of The University Of California | Substituted pyrazolo[3,4-d]pyrimidines and uses thereof |
| EP2766347B1 (en) * | 2011-10-14 | 2016-05-04 | Bristol-Myers Squibb Company | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
| WO2013134660A1 (en) | 2012-03-09 | 2013-09-12 | Fibrogen, Inc. | 4 -hydroxy- isoquinoline compounds as hif hydroxylase inhibitors |
| US8940742B2 (en) | 2012-04-10 | 2015-01-27 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
| EP3219706A1 (en) | 2012-07-16 | 2017-09-20 | Fibrogen, Inc. | Process for making isoquinoline compounds |
| AU2013290438C1 (en) | 2012-07-16 | 2019-01-03 | Kyntra Bio, Inc. | Crystalline forms of the prolyl hydroxylase inhibitor [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid |
| US8883823B2 (en) | 2012-07-16 | 2014-11-11 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
| JP2015532287A (ja) | 2012-09-26 | 2015-11-09 | ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア | Ire1の調節 |
| AU2013337717B2 (en) | 2012-11-01 | 2018-10-25 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using PI3 kinase isoform modulators |
| AU2014209319B2 (en) | 2013-01-24 | 2018-04-19 | Fibrogen, Inc. | Crystalline forms of {[1-cyano-5-(4-chlorophenoxy)-4-hydroxy-isoquinoline-3-carbonyl]-amino}-acetic acid |
| US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
| PT3052485T (pt) | 2013-10-04 | 2021-10-22 | Infinity Pharmaceuticals Inc | Compostos heterocíclicos e suas utilizações |
| US9751888B2 (en) | 2013-10-04 | 2017-09-05 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| MX382033B (es) | 2014-03-19 | 2025-03-13 | Infinity Pharmaceuticals Inc | Compuestos heterocíclicos para utilizarlos en el tratamiento de trastornos mediados por pi3k-gamma. |
| WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
| WO2016054491A1 (en) | 2014-10-03 | 2016-04-07 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2017048702A1 (en) | 2015-09-14 | 2017-03-23 | Infinity Pharmaceuticals, Inc. | Solid forms of isoquinolinone derivatives, process of making, compositions comprising, and methods of using the same |
| RU2757314C2 (ru) * | 2016-01-22 | 2021-10-13 | Мерк Шарп И Доум Корп. | Антитела против фактора свертывания xi |
| WO2017161116A1 (en) | 2016-03-17 | 2017-09-21 | Infinity Pharmaceuticals, Inc. | Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors |
| WO2017214269A1 (en) | 2016-06-08 | 2017-12-14 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| SG11201811237WA (en) | 2016-06-24 | 2019-01-30 | Infinity Pharmaceuticals Inc | Combination therapies |
| BR112019003557A2 (pt) | 2016-08-31 | 2019-05-21 | Jiangsu Hengrui Medicine Co., Ltd. | derivados de oxopicolinamida, método de preparação dos mesmos e uso farmacêutico dos mesmos |
| EP3822264A4 (en) | 2018-07-02 | 2021-11-10 | Jiangsu Hengrui Medicine Co., Ltd. | CRYSTALLINE FORMS OF AN OXYPYRIDINE AMIDE DERIVATIVE AND THEIR PREPARATION PROCESS |
| CA3114672A1 (en) | 2018-10-05 | 2020-04-23 | Vertex Pharmaceuticals Incorporated | Modulators of alpha-1 antitrypsin |
| CN109400528B (zh) * | 2018-12-18 | 2022-03-15 | 深圳科兴药业有限公司 | 一种可博美的合成方法 |
| US11884672B2 (en) | 2019-05-14 | 2024-01-30 | Vertex Pharmaceuticals Incorporated | Modulators of alpha-1 antitrypsin |
| JP7732999B2 (ja) | 2020-04-03 | 2025-09-02 | バーテックス ファーマシューティカルズ インコーポレイテッド | アルファ1-アンチトリプシンのモジュレーター |
| CN115697969A (zh) * | 2020-04-03 | 2023-02-03 | 弗特克斯药品有限公司 | 作为用于治疗α-1抗胰蛋白酶缺乏症(AATD)的α-1抗胰蛋白酶调节剂的7-或8-羟基-异喹啉和7-或8-羟基-喹啉衍生物 |
| US12391640B2 (en) | 2022-03-02 | 2025-08-19 | Horizon Therapeutics Ireland Dac | Process of making a crystalline EDG-2 receptor antagonist |
Family Cites Families (98)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6087380A (en) | 1949-11-24 | 2000-07-11 | Boehringer Ingelheim Pharma Kg | Disubstituted bicyclic heterocycles, the preparations and the use thereof as pharmaceutical compositions |
| AT341512B (de) | 1975-01-09 | 1978-02-10 | Thomae Gmbh Dr K | Verfahren zur herstellung von neuen biphenylathern |
| US4717736A (en) | 1984-01-23 | 1988-01-05 | Merck Frosst Canada, Inc. | Antagonists of slow reacting substances of anaphylaxis |
| CA1243322A (en) | 1984-01-23 | 1988-10-18 | Joshua Rokach | Antagonists of slow reacting substances of anaphylaxis |
| AU567460B2 (en) | 1984-03-05 | 1987-11-19 | Mitsui Toatsu Chemicals Inc. | Preparation process of n-acylphenylalanines |
| JPS61227555A (ja) | 1985-04-02 | 1986-10-09 | Mitsui Toatsu Chem Inc | N−アシルフエニルアラニン類の製造方法 |
| AU8868991A (en) | 1990-11-15 | 1992-06-11 | Pentapharm Ag | Meta-substituted phenyl alanine derivatives |
| CA2057324A1 (en) | 1990-12-18 | 1992-06-19 | Lora Louise Fitch | Benzamide and sulfonamide hypoglycemic agents |
| US5273990A (en) | 1992-09-03 | 1993-12-28 | Ciba-Geigy Corporation | Phosphono substituted tetrazole derivatives |
| FR2694288B1 (fr) | 1992-06-30 | 1994-09-09 | Rhone Poulenc Agrochimie | Phenylbenzamides fongicides et procédés pour les préparer. |
| US5354905A (en) | 1992-10-23 | 1994-10-11 | Yashima Chemical Industry Co., Ltd. | N-alkoxymethyl benzamide derivative and manufacturing method therefor, and manufacturing method for benzamide derivative using this N-alkoxymethyl benzamide derivative |
| DE4302485A1 (de) | 1993-01-29 | 1994-08-04 | Merck Patent Gmbh | Piperazinderivate |
| US6613804B2 (en) | 1993-05-20 | 2003-09-02 | Encysive Pharmaceuticals, Inc. | Biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin |
| JP3563738B2 (ja) | 1993-06-11 | 2004-09-08 | エーザイ株式会社 | アミノ酸誘導体 |
| US5780498A (en) | 1993-11-01 | 1998-07-14 | Ciba-Geigy Japan Limited | Endothelin receptor antagonists |
| GB9322976D0 (en) | 1993-11-08 | 1994-01-05 | Pfizer Ltd | Therapeutic agents |
| CA2183767A1 (en) | 1994-03-28 | 1995-10-05 | Thomas Fruh | Antagonists of endothelin receptors |
| AU732881C (en) | 1994-09-16 | 2002-11-07 | Children's Medical Center Corporation | Triaryl and diaryl compounds, their analogues and uses thereof |
| US6342504B1 (en) | 1994-12-13 | 2002-01-29 | Corvas International, Inc. | Aromatic heterocyclic derivatives as enzyme inhibitors |
| US6306840B1 (en) | 1995-01-23 | 2001-10-23 | Biogen, Inc. | Cell adhesion inhibitors |
| US6001820A (en) | 1995-03-31 | 1999-12-14 | Hamilton Civic Hospitals Research Development Inc. | Compositions and methods for inhibiting thrombogenesis |
| US5977075A (en) | 1995-04-21 | 1999-11-02 | Novartis Ag | N-aroylamino acid amides as endothelin inhibitors |
| ATE205506T1 (de) | 1995-06-12 | 2001-09-15 | Sanquin Bloedvoorziening | Faktor ix bindende peptide abgeleitet von faktor vii und ihre verwendung als inhibitoren der blutgerinnung |
| JP3640319B2 (ja) | 1995-10-26 | 2005-04-20 | 大日本インキ化学工業株式会社 | ベンズアミド誘導体の製造方法 |
| CZ195098A3 (cs) | 1995-12-22 | 1998-10-14 | Novo Nordisk A/S | Sloučeniny uvolňující růstový hormon |
| WO1997042216A1 (en) | 1996-04-24 | 1997-11-13 | Peptide Therapeutics Limited | Auto-deconvoluting combinatorial libraries |
| UA56197C2 (uk) | 1996-11-08 | 2003-05-15 | Зенека Лімітед | Гетероциклічні похідні |
| PE121699A1 (es) | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | Heterociclos biciclicos disustituidos como inhibidores de la trombina |
| JP2001517245A (ja) | 1997-05-29 | 2001-10-02 | メルク エンド カンパニー インコーポレーテッド | 細胞接着阻害薬としてのビアリールアルカン酸類 |
| US6291511B1 (en) | 1997-05-29 | 2001-09-18 | Merck & Co., Inc. | Biarylalkanoic acids as cell adhesion inhibitors |
| US6124513A (en) | 1997-06-20 | 2000-09-26 | Pennzoil-Quaker State Company | Ethylene-alpha-olefin polymers, processes and uses |
| EP1005484A1 (en) | 1997-06-20 | 2000-06-07 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| US6127341A (en) | 1997-06-20 | 2000-10-03 | Novo Nordisk A/S | Compounds with growth hormone releasing properties |
| US6191171B1 (en) | 1997-11-20 | 2001-02-20 | Merck & Co., Inc. | Para-aminomethylaryl carboxamide derivatives |
| AU1411499A (en) | 1997-11-20 | 1999-06-15 | Merck & Co., Inc. | Para-aminomethylaryl carboxamide derivatives |
| MY153569A (en) | 1998-01-20 | 2015-02-27 | Mitsubishi Tanabe Pharma Corp | Inhibitors of ?4 mediated cell adhesion |
| JP2002509881A (ja) | 1998-03-27 | 2002-04-02 | ジェネンテク・インコーポレイテッド | Cd11/cd18接着レセプター媒介疾患の治療用アンタゴニスト |
| PL343770A1 (en) | 1998-04-16 | 2001-09-10 | Texas Biotechnology Corp | N,n-disubstituted amides that inhibit the binding of integrins to their receptors |
| US6423727B1 (en) | 1998-04-23 | 2002-07-23 | Novartis Ag | Certain thiol inhibitors of endothelin-converting enzyme |
| GB9811159D0 (en) | 1998-05-22 | 1998-07-22 | Celltech Therapeutics Ltd | Chemical compounds |
| US6194458B1 (en) | 1998-10-30 | 2001-02-27 | Merck & Co., Inc. | Benzamide potassium channel inhibitors |
| US6420396B1 (en) | 1998-12-16 | 2002-07-16 | Beiersdorf Ag | Biphenyl and biphenyl-analogous compounds as integrin antagonists |
| US6677360B2 (en) | 1998-12-16 | 2004-01-13 | Bayer Aktiengesellschaft | Biphenyl and biphenyl-analogous compounds as integrin antagonists |
| DE69927050T2 (de) | 1998-12-16 | 2006-06-29 | Bayer Healthcare Ag | Biphenylverbindungen und biphenyl-analoge als intergrin-antagonisten |
| PT1144365E (pt) | 1998-12-22 | 2004-06-30 | Tanabe Seiyaku Co | Inibidores da adesao de celulas mediada por alfa4beta1 |
| US7276348B2 (en) | 1999-04-30 | 2007-10-02 | Regents Of The University Of Michigan | Compositions and methods relating to F1F0-ATPase inhibitors and targets thereof |
| US7144880B2 (en) | 1999-04-30 | 2006-12-05 | Regents Of The University Of Michigan | Compositions relating to novel compounds and targets thereof |
| US6723711B2 (en) | 1999-05-07 | 2004-04-20 | Texas Biotechnology Corporation | Propanoic acid derivatives that inhibit the binding of integrins to their receptors |
| RU2255933C9 (ru) | 1999-05-07 | 2005-11-20 | Тексэс Байотекнолоджи Копэрейшн | ПРОИЗВОДНЫЕ ПРОПИОНОВОЙ КИСЛОТЫ (ВАРИАНТЫ), ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И СПОСОБ СЕЛЕКТИВНОГО ИНГИБИРОВАНИЯ СВЯЗЫВАНИЯ α4β1 ИНТЕГРИНА |
| ATE383153T1 (de) | 1999-05-07 | 2008-01-15 | Encysive Pharmaceuticals Inc | Carbonsäurederivate die die bindung von integrinen an ihre rezeptoren hemmen |
| JP2003502314A (ja) | 1999-06-14 | 2003-01-21 | イーライ・リリー・アンド・カンパニー | 化合物 |
| DK1194425T3 (da) | 1999-06-23 | 2005-11-21 | Aventis Pharma Gmbh | Substituerede benzimidazoler |
| DE19928424A1 (de) | 1999-06-23 | 2000-12-28 | Aventis Pharma Gmbh | Substituierte Benzimidazole |
| JP3795305B2 (ja) | 1999-07-19 | 2006-07-12 | 田辺製薬株式会社 | 医薬組成物 |
| GB2354440A (en) | 1999-07-20 | 2001-03-28 | Merck & Co Inc | Aryl amides as cell adhesion inhibitors |
| EP1206446B1 (de) | 1999-08-07 | 2004-05-26 | Boehringer Ingelheim Pharma GmbH & Co.KG | Carbonsäureamide, deren herstellung und deren verwendung als arzneimittel |
| ES2288871T3 (es) | 1999-09-24 | 2008-02-01 | Genentech, Inc. | Derivados de tirosina. |
| DE60033684T2 (de) | 1999-11-18 | 2007-12-06 | Ajinomoto Co., Inc. | Phenylalaninderivate |
| CA2392576A1 (en) | 1999-11-24 | 2001-05-31 | Lingyan Wang | .beta.-amino acid-, aspartic acid- and diaminopropionic-based inhibitors of factor xa |
| US6169208B1 (en) | 1999-12-03 | 2001-01-02 | Albemarle Corporation | Process for producing a magnesium di[tetrakis(Faryl)borate] and products therefrom |
| WO2001056994A1 (en) | 2000-02-04 | 2001-08-09 | Biogen, Inc. | Integrin antagonists |
| WO2001068586A2 (en) | 2000-03-14 | 2001-09-20 | Novartis Ag | α4β1 AND α4β7 INTEGRIN INHIBITORS |
| EP1162194A1 (en) | 2000-06-06 | 2001-12-12 | Aventis Pharma Deutschland GmbH | Factor VIIa inhibitory (thio)urea derivatives, their preparation and their use |
| US6403584B1 (en) | 2000-06-22 | 2002-06-11 | Merck & Co., Inc. | Substituted nipecotyl derivatives as inhibitors of cell adhesion |
| MY129000A (en) | 2000-08-31 | 2007-03-30 | Tanabe Seiyaku Co | INHIBITORS OF a4 MEDIATED CELL ADHESION |
| CA2321348A1 (en) | 2000-09-27 | 2002-03-27 | Blaise Magloire N'zemba | Aromatic derivatives with hiv integrase inhibitory properties |
| US20020072500A1 (en) | 2000-09-27 | 2002-06-13 | Thomas Rogers | Hydroxy acid integrin antagonists |
| US20020103192A1 (en) | 2000-10-26 | 2002-08-01 | Curtin Michael L. | Inhibitors of histone deacetylase |
| PL362320A1 (en) | 2000-12-06 | 2004-10-18 | Aventis Pharma Deutschland Gmbh | Guanidine and amidine derivatives as factor xa inhibitors |
| EP1217000A1 (en) | 2000-12-23 | 2002-06-26 | Aventis Pharma Deutschland GmbH | Inhibitors of factor Xa and factor VIIa |
| JP2004517955A (ja) | 2001-02-02 | 2004-06-17 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | カルボン酸アミド、その調製及びそれらの医薬組成物としての使用 |
| US20020151595A1 (en) | 2001-02-02 | 2002-10-17 | Ries Uwe Joerg | Carboxylic acid amides having antithrombotic activity |
| DE10111164A1 (de) | 2001-03-01 | 2002-09-05 | Gruenenthal Gmbh | Neue substituierte Catecholderivate abgeleitet von mehrbasischen sekundären Aminosäuren, Verfahren zu ihrer Herstellung und ihre Anwendung |
| US6559174B2 (en) | 2001-03-20 | 2003-05-06 | Merck & Co., Inc. | N-arylsulfonyl aryl aza-bicyclic derivatives as potent cell adhesion inhibitors |
| AU2002303265A1 (en) | 2001-04-10 | 2002-10-28 | Message Pharmaceuticals, Inc. | Small molecule inhibitors of secretion of proteins encoded by are-mrnas |
| CA2446696A1 (fr) | 2001-06-07 | 2002-12-12 | Neuro3D | Inhibiteurs des phosphodiesterases des nucleotides cycliques, preparation et utilisations de ces inhibiteurs |
| AUPR604401A0 (en) | 2001-06-29 | 2001-07-26 | University Of Wollongong, The | Peptoid compounds |
| DE60206782T2 (de) | 2001-07-09 | 2006-07-13 | Aventis Pharmaceuticals Inc. | Substituierte amide, sulfonamide und harnstoffe mit kinasehemmender wirkung |
| US20030045480A1 (en) | 2001-07-09 | 2003-03-06 | Pavel Safar | Method of treating hyperresorptive bone disorders |
| CA2448737C (en) | 2001-07-20 | 2010-06-01 | Boehringer Ingelheim (Canada) Ltd. | Viral polymerase inhibitors |
| MXPA04003167A (es) | 2001-10-03 | 2004-07-08 | Pharmacia Corp | Compuestos heterociclicos insaturados de 6 miembros utiles para la inhibicion selectiva de la cascada de coagulacion. |
| JP2005508968A (ja) | 2001-10-19 | 2005-04-07 | トランス テック ファーマ,インコーポレイテッド | PTP阻害剤としてのβ−カルボリン誘導体 |
| US20040126856A1 (en) | 2002-01-23 | 2004-07-01 | Bajaj Paul S. | Factor ixa: factor Vllla interaction and methods therefor |
| JP4233353B2 (ja) | 2002-02-27 | 2009-03-04 | 田辺三菱製薬株式会社 | 医薬組成物 |
| MY140707A (en) | 2002-02-28 | 2010-01-15 | Mitsubishi Tanabe Pharma Corp | Process for preparing a phenylalanine derivative and intermediates thereof |
| AU2003265398A1 (en) | 2002-08-09 | 2004-02-25 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds and methods to modulate coagulation |
| AU2003290120A1 (en) | 2002-11-19 | 2004-06-15 | Galderma Research & Development, S.N.C. | Biaromatic compounds which activate PPAR-Gama type receptors, and use thereof in cosmetic or pharmaceutical compositions |
| FR2847251B1 (fr) | 2002-11-19 | 2006-11-17 | NOUVEAUX COMPOSES BI-AROMATIQUES ACTIVEURS DES RECEPTEURS DE TYPE PPARy ET LEUR UTILISATION DANS DES COMPOSITIONS COSMETIQUES OU PHARMACEUTIQUES | |
| DE10310278A1 (de) | 2003-03-10 | 2004-09-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue aromatische Bicyclen, deren Herstellung und deren Verwendung als Arzneimittel |
| US7109243B2 (en) | 2003-03-24 | 2006-09-19 | Irm Llc | Inhibitors of cathepsin S |
| JP2004323487A (ja) | 2003-04-30 | 2004-11-18 | Daiichi Fine Chemical Co Ltd | ビフェニルアルデヒド |
| EP1644321B1 (en) | 2003-06-13 | 2011-02-09 | Laboratorios S.A.L.V.A.T., S.A. | New benzamides as ppaty modulators |
| JP2007501189A (ja) | 2003-08-01 | 2007-01-25 | ジェネラブス テクノロジーズ,インコーポレイテッド | フラビウイルス科に対する二環式イミダゾール誘導体 |
| US7544699B2 (en) | 2003-08-08 | 2009-06-09 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions, and methods of use |
| US7501538B2 (en) | 2003-08-08 | 2009-03-10 | Transtech Pharma, Inc. | Aryl and heteroaryl compounds, compositions and methods of use |
| US7208601B2 (en) * | 2003-08-08 | 2007-04-24 | Mjalli Adnan M M | Aryl and heteroaryl compounds, compositions, and methods of use |
| US20050053600A1 (en) | 2003-09-09 | 2005-03-10 | Lane Thomas E. | Methods for treating rheumatoid arthritis |
| US20050187409A1 (en) | 2003-10-21 | 2005-08-25 | Powers Gordon D. | Inhibitors of RNase P proteins as antibacterial compounds |
-
2005
- 2005-03-01 US US11/069,521 patent/US7208601B2/en not_active Expired - Fee Related
-
2006
- 2006-02-23 AU AU2006218815A patent/AU2006218815A1/en not_active Abandoned
- 2006-02-23 WO PCT/US2006/006571 patent/WO2006093823A1/en not_active Ceased
- 2006-02-23 CN CNA2006800069585A patent/CN101137650A/zh active Pending
- 2006-02-23 CA CA002599808A patent/CA2599808A1/en not_active Abandoned
- 2006-02-23 EP EP06736003A patent/EP1888566A1/en not_active Withdrawn
- 2006-02-23 ZA ZA200707508A patent/ZA200707508B/xx unknown
- 2006-02-23 MX MX2007010682A patent/MX2007010682A/es not_active Application Discontinuation
- 2006-02-23 JP JP2007558080A patent/JP2008531689A/ja active Pending
- 2006-02-23 BR BRPI0607400-6A patent/BRPI0607400A2/pt not_active IP Right Cessation
-
2007
- 2007-03-05 US US11/714,031 patent/US20070254916A1/en not_active Abandoned
- 2007-08-21 IL IL185428A patent/IL185428A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP1888566A1 (en) | 2008-02-20 |
| JP2008531689A (ja) | 2008-08-14 |
| MX2007010682A (es) | 2007-11-07 |
| WO2006093823A1 (en) | 2006-09-08 |
| CA2599808A1 (en) | 2006-09-08 |
| CN101137650A (zh) | 2008-03-05 |
| US7208601B2 (en) | 2007-04-24 |
| US20050171148A1 (en) | 2005-08-04 |
| AU2006218815A1 (en) | 2006-09-08 |
| IL185428A0 (en) | 2008-01-06 |
| WO2006093823A9 (en) | 2006-11-02 |
| ZA200707508B (en) | 2008-12-31 |
| US20070254916A1 (en) | 2007-11-01 |
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