CA2701581C - Pyrimidine substituted purine derivatives - Google Patents
Pyrimidine substituted purine derivatives Download PDFInfo
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- CA2701581C CA2701581C CA2701581A CA2701581A CA2701581C CA 2701581 C CA2701581 C CA 2701581C CA 2701581 A CA2701581 A CA 2701581A CA 2701581 A CA2701581 A CA 2701581A CA 2701581 C CA2701581 C CA 2701581C
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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| US7553208P | 2008-06-25 | 2008-06-25 | |
| US61/075,532 | 2008-06-25 | ||
| PCT/SG2008/000379 WO2009045175A1 (en) | 2007-10-05 | 2008-10-03 | Pyrimidine substituted purine derivatives |
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Families Citing this family (41)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
| US20030133939A1 (en) | 2001-01-17 | 2003-07-17 | Genecraft, Inc. | Binding domain-immunoglobulin fusion proteins |
| RS53318B (sr) | 2005-07-25 | 2014-10-31 | Emergent Product Development Seattle, Llc | Smanjenje broja b-ćelija upotrebom cd37-specifično i cd20-specifično vezujućih molekula |
| NZ573646A (en) | 2006-06-12 | 2012-04-27 | Wyeth Llc | Single-chain multivalent binding proteins with effector function |
| EP2209786B1 (en) | 2007-10-05 | 2013-02-27 | Verastem, Inc. | Pyrimidine substituted purine derivatives |
| JP6013733B2 (ja) | 2008-04-11 | 2016-10-25 | エマージェント プロダクト デベロップメント シアトル， エルエルシー | Ｃｄ３７免疫治療薬および二機能性化学療法薬とのその組合せ |
| WO2010005558A2 (en) | 2008-07-07 | 2010-01-14 | Xcovery, Inc. | Pi3k isoform selective inhibitors |
| TWI378933B (en) | 2008-10-14 | 2012-12-11 | Daiichi Sankyo Co Ltd | Morpholinopurine derivatives |
| US8586582B2 (en) * | 2008-11-11 | 2013-11-19 | Xcovery Holding Company, Llc | PI3K/mTOR kinase inhibitors |
| JP5766177B2 (ja) | 2009-03-27 | 2015-08-19 | ベトディーシー，インコーポレイテッド | ピリミジニル及び１，３，５−トリアジニルベンゾイミダゾールスルホンアミド及びガンの療法におけるその使用 |
| BRPI0925059A2 (pt) * | 2009-04-03 | 2015-07-28 | S Bio Pte Ltd | Pirimidina substituída de compostos de purina como quinase(s) inibidoras. |
| WO2010114494A1 (en) * | 2009-04-03 | 2010-10-07 | S*Bio Pte Ltd | 8-substituted-2-morpholino purines for use as pi3k and/or mtor inhibitors in the treatment of proliferative disorders |
| EP2451802A1 (en) | 2009-07-07 | 2012-05-16 | Pathway Therapeutics, Inc. | Pyrimidinyl and 1,3,5-triazinyl benzimidazoles and their use in cancer therapy |
| DE102009049679A1 (de) * | 2009-10-19 | 2011-04-21 | Merck Patent Gmbh | Pyrazolopyrimidinderivate |
| WO2011078795A1 (en) * | 2009-12-21 | 2011-06-30 | S*Bio Pte Ltd | Bridged morpholino substituted purines |
| US9376664B2 (en) | 2010-06-14 | 2016-06-28 | The Scripps Research Institute | Reprogramming of cells to a new fate |
| BR112013024907A2 (pt) | 2011-03-28 | 2016-12-20 | Mei Pharma Inc | composto, composição farmacêutica, método para o tratamento, prevenção ou atenuação de um ou mais sintomas de um distúrbio, doença ou condição mediada por pi3k em um sujeito, método para modular a atividade enzimática de pi3k |
| WO2012172043A1 (en) | 2011-06-15 | 2012-12-20 | Laboratoire Biodim | Purine derivatives and their use as pharmaceuticals for prevention or treatment of bacterial infections |
| UY34486A (es) * | 2011-12-05 | 2013-07-31 | Novartis Ag | Anticuerpos dirigidos al receptor del factor de crecimiento epidérmico 3 (her3) dirigidos contra el dominio ii del her3 |
| US9145411B2 (en) | 2012-08-02 | 2015-09-29 | Asana Biosciences, Llc | Substituted amino-pyrimidine derivatives |
| CN106831722B (zh) * | 2013-10-16 | 2019-08-30 | 上海璎黎药业有限公司 | 稠合杂环化合物、其制备方法、药物组合物和用途 |
| GB201321737D0 (en) * | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
| EA030538B1 (ru) | 2013-12-11 | 2018-08-31 | Байоджен Ма Инк. | Биарильное соединение, применяемое при лечении заболеваний человека в онкологии, неврологии и иммунологии |
| EP3444251B1 (en) * | 2013-12-11 | 2023-06-07 | Biogen MA Inc. | Biaryl compounds useful for the treatment of human diseases in oncology, neurology and immunology |
| WO2016109426A1 (en) * | 2014-12-29 | 2016-07-07 | Verastem, Inc. | Oral dosing regimen of a dual mtor and pi3 inhibitor |
| CN105985354B (zh) * | 2015-02-09 | 2020-10-02 | 南京盖特医药技术有限公司 | 嘧啶衍生物、细胞毒性剂、药物组合物及其应用 |
| MY185268A (en) | 2015-03-30 | 2021-04-30 | Daiichi Sankyo Co Ltd | Pyrazole derivative useful as pi3k inhibitor |
| KR101589900B1 (ko) | 2015-07-30 | 2016-01-29 | 강영만 | 바닥설치용 경계구 |
| UA126278C2 (uk) | 2015-09-21 | 2022-09-14 | Аптево Рісьорч Енд Девелопмент Ллс | Поліпептиди, які зв'язують cd3 |
| AR108665A1 (es) * | 2016-06-02 | 2018-09-12 | Celgene Corp | Derivados de aminopurina como agentes anti-tripanosómicos y anti-leishmania |
| EA037871B1 (ru) * | 2016-06-16 | 2021-05-28 | Янссен Фармацевтика Нв | Производные азабензимидазола в качестве ингибиторов pi3k beta |
| US11208442B2 (en) | 2016-12-02 | 2021-12-28 | Daiichi Sankyo Company, Limited | Endo-beta-N-acetylglucosaminidase |
| EP3621604B1 (en) * | 2017-03-31 | 2025-06-04 | FTG Bio LLC | Salt forms of amino pyrazine purine based selective kinase inhibitor |
| JOP20190233A1 (ar) | 2017-04-14 | 2019-10-02 | Biogen Ma Inc | نظائر بنزوازيبين بوصفها عوامل مثبطة لتيروزين كيناز بروتون |
| CN117860758A (zh) | 2017-05-23 | 2024-04-12 | 梅制药公司 | 联合疗法 |
| SG11202001258UA (en) | 2017-08-14 | 2020-03-30 | Mei Pharma Inc | Combination therapy |
| SG11202103118PA (en) * | 2018-09-27 | 2021-04-29 | Shanghai Yingli Pharmaceutical Co Ltd | Crystal form of morpholino quinazoline compound, preparation method therefor and use thereof |
| TWI895986B (zh) * | 2018-12-20 | 2025-09-01 | 美商Ｋｓｑ治療公司 | 經取代之吡唑并嘧啶及經取代之嘌呤以及其作為泛素特異性加工蛋白酶１（ｕｓｐ１）抑制劑的用途 |
| US11718624B2 (en) | 2020-10-30 | 2023-08-08 | KSQ Therapeutics, Inc. | Solid state forms of substituted pyrazolopyrimidines and uses thereof |
| JP2024545121A (ja) * | 2021-12-08 | 2024-12-05 | キネタ・インコーポレイテッド | 二環式ヘテロアレーンおよびその使用方法 |
| WO2024041519A1 (zh) * | 2022-08-24 | 2024-02-29 | 上海璎黎药业有限公司 | 一种吗啉基喹唑啉类化合物、其药物组合物及应用 |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4617304A (en) | 1984-04-10 | 1986-10-14 | Merck & Co., Inc. | Purine derivatives |
| US4772606A (en) | 1985-08-22 | 1988-09-20 | Warner-Lambert Company | Purine derivatives |
| ATE134624T1 (de) * | 1990-02-19 | 1996-03-15 | Ciba Geigy Ag | Acylverbindungen |
| US5217996A (en) * | 1992-01-22 | 1993-06-08 | Ciba-Geigy Corporation | Biaryl substituted 4-amino-butyric acid amides |
| US6110923A (en) * | 1994-06-22 | 2000-08-29 | Biochem Pharma Inc. | Method for treating cancer using novel substituted purinyl derivatives with immunomodulating activity |
| HRP980375A2 (en) | 1997-07-03 | 1999-04-30 | Argyrios Georgios Arvanitis | Imidazopyrimidines and imidazopyridines for the treatment of neurological disorders |
| AU748178B2 (en) * | 1998-02-26 | 2002-05-30 | Aventis Holdings Inc. | 6,9-disubstituted 2-(trans-(4- aminocyclohexyl) amino)purines |
| ATE503743T1 (de) * | 2000-04-27 | 2011-04-15 | Astellas Pharma Inc | Kondensierte heteroarylderivate |
| JP3810017B2 (ja) * | 2000-04-27 | 2006-08-16 | アステラス製薬株式会社 | 縮合ヘテロアリール誘導体 |
| CN100413852C (zh) * | 2000-07-19 | 2008-08-27 | 诺瓦提斯公司 | 缬沙坦的盐 |
| GB0100623D0 (en) * | 2001-01-10 | 2001-02-21 | Vernalis Res Ltd | Chemical compounds IV |
| CA2463563A1 (en) | 2001-10-12 | 2003-04-17 | Irm Llc | Kinase inhibitor scaffolds and methods for their preparation |
| GB0219054D0 (en) | 2002-08-15 | 2002-09-25 | Cyclacel Ltd | New purine derivatives |
| WO2004021979A2 (en) | 2002-09-06 | 2004-03-18 | Smithkline Beecham Corporation | PYRROLO[2, 3-d]PYRIMIDINE-4-YL AND PURIN-6-YL UREA COMPOUNDS |
| AU2003284142A1 (en) | 2002-10-15 | 2004-05-04 | Synta Pharmaceuticals Corp | Aromatic bicyclic heterocyles to modulate 1L-12 production |
| US7129239B2 (en) | 2002-10-28 | 2006-10-31 | Pfizer Inc. | Purine compounds and uses thereof |
| CN1735607B (zh) * | 2002-11-21 | 2010-06-09 | 诺华疫苗和诊断公司 | 2,4,6-三取代的嘧啶作为磷脂酰肌醇(pi)3-激酶抑制剂及其在治疗癌症中的应用 |
| KR101052482B1 (ko) * | 2002-11-21 | 2011-07-28 | 노바티스 백신즈 앤드 다이아그노스틱스 인코포레이티드 | 포스포티딜이노시톨(ｐｉ) 3-키나제 억제제인 2,4,6-삼치환피리미딘 및 암의 치료에서 이들의 사용 |
| FR2851248B1 (fr) * | 2003-02-18 | 2005-04-08 | Aventis Pharma Sa | Nouveaux derives de la purine, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation |
| UY29177A1 (es) * | 2004-10-25 | 2006-05-31 | Astex Therapeutics Ltd | Derivados sustituidos de purina, purinona y deazapurina, composiciones que los contienen métodos para su preparación y sus usos |
| MY179032A (en) * | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
| EP1940843A4 (en) | 2005-08-11 | 2010-09-15 | Ariad Pharma Inc | UNSATURATED HETEROCYCLIC DERIVATIVES |
| TW200801003A (en) | 2005-09-16 | 2008-01-01 | Astrazeneca Ab | Novel compounds |
| GB0519245D0 (en) | 2005-09-20 | 2005-10-26 | Vernalis R&D Ltd | Purine compounds |
| US7902187B2 (en) * | 2006-10-04 | 2011-03-08 | Wyeth Llc | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
| WO2008043031A1 (en) | 2006-10-04 | 2008-04-10 | Pharmacopeia, Inc. | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
| US20080233127A1 (en) | 2007-03-21 | 2008-09-25 | Wyeth | Imidazolopyrimidine analogs and their use as pi3 kinase and mtor inhibitors |
| EP2209786B1 (en) | 2007-10-05 | 2013-02-27 | Verastem, Inc. | Pyrimidine substituted purine derivatives |
| US20110009403A1 (en) | 2007-10-05 | 2011-01-13 | S*Bio Pte Ltd. | 2-morpholinylpurines as inhibitors of pi3k |
| CL2009000241A1 (es) | 2008-02-07 | 2010-09-03 | Chugai Pharmaceutical Co Ltd | Compuestos derivados de 5-(2-morfolin-4-il-7h-pirrolo[2,3-d]pirimidin-4-il)pirimidin-2-ilamina; proceso de preparacion; composicion farmaceutica; y uso de los compuestos para tratar o prevenir una enfermedad proliferativa tal como el cancer. |
| JP2011521968A (ja) | 2008-05-30 | 2011-07-28 | ジェネンテック， インコーポレイテッド | プリンｐｉ３ｋ阻害剤化合物および使用方法 |
| EP2310391A1 (en) | 2008-06-27 | 2011-04-20 | S*BIO Pte Ltd | Pyrazine substituted purines |
| WO2010005558A2 (en) | 2008-07-07 | 2010-01-14 | Xcovery, Inc. | Pi3k isoform selective inhibitors |
| BRPI0925059A2 (pt) | 2009-04-03 | 2015-07-28 | S Bio Pte Ltd | Pirimidina substituída de compostos de purina como quinase(s) inibidoras. |
| WO2010114494A1 (en) | 2009-04-03 | 2010-10-07 | S*Bio Pte Ltd | 8-substituted-2-morpholino purines for use as pi3k and/or mtor inhibitors in the treatment of proliferative disorders |
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2008
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2010
- 2010-03-28 IL IL204804A patent/IL204804A/en active IP Right Grant
- 2010-05-04 ZA ZA2010/03118A patent/ZA201003118B/en unknown
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2012
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2013
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2014
- 2014-11-06 IL IL235555A patent/IL235555B/en active IP Right Grant
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