CN115925693B - Jak1选择性抑制剂 - Google Patents
Jak1选择性抑制剂 Download PDFInfo
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- CN115925693B CN115925693B CN202211243959.9A CN202211243959A CN115925693B CN 115925693 B CN115925693 B CN 115925693B CN 202211243959 A CN202211243959 A CN 202211243959A CN 115925693 B CN115925693 B CN 115925693B
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211243959.9A CN115925693B (zh) | 2017-01-17 | 2018-01-16 | Jak1选择性抑制剂 |
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| US201762447057P | 2017-01-17 | 2017-01-17 | |
| US62/447057 | 2017-01-17 | ||
| CN201880018044.3A CN110461830B (zh) | 2017-01-17 | 2018-01-16 | Jak1选择性抑制剂 |
| PCT/EP2018/051038 WO2018134213A1 (en) | 2017-01-17 | 2018-01-16 | Jak1 selective inhibitors |
| CN202211243959.9A CN115925693B (zh) | 2017-01-17 | 2018-01-16 | Jak1选择性抑制剂 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201880018044.3A Division CN110461830B (zh) | 2017-01-17 | 2018-01-16 | Jak1选择性抑制剂 |
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| CN115925693A CN115925693A (zh) | 2023-04-07 |
| CN115925693B true CN115925693B (zh) | 2024-11-12 |
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| CN201880018044.3A Active CN110461830B (zh) | 2017-01-17 | 2018-01-16 | Jak1选择性抑制剂 |
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| CN201880018044.3A Active CN110461830B (zh) | 2017-01-17 | 2018-01-16 | Jak1选择性抑制剂 |
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Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR102585048B1 (ko) * | 2017-01-17 | 2023-10-05 | 아스트라제네카 아베 | Jak1 선택적 억제제 |
| DK3514153T3 (da) | 2017-01-26 | 2021-09-27 | Hanmi Pharm Ind Co Ltd | Pyrimidinforbindelse og farmaceutisk anvendelse deraf |
| SG11202100240RA (en) * | 2018-07-18 | 2021-02-25 | Astrazeneca Ab | A xinafoate salt of a jak inhibiting compound |
| KR101954370B1 (ko) | 2018-07-25 | 2019-03-05 | 한미약품 주식회사 | 피리미딘 화합물 및 이를 포함하는 암의 예방 또는 치료용 약학 조성물 |
| CA3113732C (en) * | 2018-09-21 | 2023-07-11 | Shanghai Ennovabio Pharmaceuticals Co., Ltd. | Aromatic heterocyclic compound with kinase inhibitory activity |
| PH12021551985A1 (en) | 2019-02-22 | 2022-08-22 | Hanmi Pharmaceutical Co Ltd | Pharmaceutical composition comprising flt3 inhibitor and hypomethylating agent for treating acute myeloid leukemia |
| TWI910107B (zh) * | 2019-04-19 | 2026-01-01 | 大陸商迪哲（江蘇）醫藥股份有限公司 | Ｊａｋ１選擇性激酶抑制劑 |
| EA202290154A1 (ru) | 2019-06-27 | 2022-03-29 | Ханми Фарм. Ко., Лтд. | Фармацевтическая композиция для лечения острого миелоидного лейкоза, содержащая ингибитор flt3 и химиотерапевтические агенты |
| CN115916764B (zh) * | 2020-04-09 | 2024-09-20 | 达萨玛治疗公司 | 作为sarm1抑制剂的吲唑衍生物 |
| JP7613778B2 (ja) * | 2020-11-26 | 2025-01-15 | 科輝智薬（深▲セン▼）新薬研究中心有限公司 | アミド化合物、医薬組成物およびその使用 |
| BR112023016986A2 (pt) * | 2021-02-26 | 2023-11-07 | Tyra Biosciences Inc | Compostos de aminopirimidina e métodos de seu uso |
| US12240836B2 (en) | 2022-07-05 | 2025-03-04 | Dong-A St Co., Ltd. | Compounds as GCN2 inhibitors, pharmaceutical compositions and uses thereof |
| CN115260128B (zh) * | 2022-09-21 | 2022-12-09 | 苏州凯瑞医药科技有限公司 | 一种新型jak抑制剂关键中间体的制备方法 |
| EP4648776A1 (en) * | 2023-01-11 | 2025-11-19 | Pfizer Inc. | Compositions and methods for the treatment and/or prevention of type 1 diabetes |
| CN115974845B (zh) * | 2023-01-19 | 2024-09-20 | 奥锐特药业股份有限公司 | 奥希替尼中间体的制备方法 |
| TW202438061A (zh) * | 2023-03-16 | 2024-10-01 | 美商英塞特公司 | 用於治療氣喘之ｊａｋ１路徑抑制劑 |
| GB202316063D0 (en) | 2023-10-20 | 2023-12-06 | Astrazeneca Ab | Dosing regime |
| GB202403369D0 (en) | 2024-03-08 | 2024-04-24 | Astrazeneca Ab | Process and intermediates for the production of a jak1 inhibitor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101421250A (zh) * | 2006-01-30 | 2009-04-29 | 埃克塞里艾克西斯公司 | 作为jak-2调节剂的4-芳基-2-氨基-嘧啶或4-芳基-2-氨基烷基-嘧啶及包含它们的药物组合物 |
| CN103209695A (zh) * | 2010-09-15 | 2013-07-17 | 弗·哈夫曼-拉罗切有限公司 | 氮杂苯并噻唑化合物、组合物及应用方法 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2007004488A (es) * | 2004-10-13 | 2007-09-11 | Wyeth Corp | Analogos de anilino-pirimidina n-bencenosulfonilo sustituidos. |
| GB2431927B (en) * | 2005-11-04 | 2010-03-17 | Amira Pharmaceuticals Inc | 5-Lipoxygenase-activating protein (FLAP) inhibitors |
| JP2010518025A (ja) * | 2007-02-05 | 2010-05-27 | アミラ ファーマシューティカルス，インコーポレーテッド | ５−リポキシゲナーゼ活性化タンパク質（ｆｌａｐ）インヒビターとしての逆インドール |
| WO2009045700A2 (en) * | 2007-10-05 | 2009-04-09 | Amira Pharmaceuticals, Inc. | 5-lipoxygenase-activating protein (flap) inhibitors |
| WO2009046416A1 (en) * | 2007-10-05 | 2009-04-09 | Targegen Inc. | Anilinopyrimidines as jak kinase inhibitors |
| GB0805477D0 (en) * | 2008-03-26 | 2008-04-30 | Univ Nottingham | Pyrimidines triazines and their use as pharmaceutical agents |
| UA110324C2 (en) * | 2009-07-02 | 2015-12-25 | Genentech Inc | Jak inhibitory compounds based on pyrazolo pyrimidine |
| PT3354652T (pt) | 2010-03-10 | 2020-07-20 | Incyte Holdings Corp | Derivados de piperidin-4-ilazetidina como inibidores de jak1 |
| EP3060234A1 (en) | 2013-10-24 | 2016-08-31 | AbbVie Inc. | Jak1 selective inhibitor and uses thereof |
| BR112018005833B1 (pt) | 2015-09-25 | 2023-10-10 | Dizal (Jiangsu) Pharmaceutical Co., Limited | Composto, sal farmaceuticamente aceitável, composição farmacêutica e uso do composto |
| KR102585048B1 (ko) * | 2017-01-17 | 2023-10-05 | 아스트라제네카 아베 | Jak1 선택적 억제제 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101421250A (zh) * | 2006-01-30 | 2009-04-29 | 埃克塞里艾克西斯公司 | 作为jak-2调节剂的4-芳基-2-氨基-嘧啶或4-芳基-2-氨基烷基-嘧啶及包含它们的药物组合物 |
| CN103209695A (zh) * | 2010-09-15 | 2013-07-17 | 弗·哈夫曼-拉罗切有限公司 | 氮杂苯并噻唑化合物、组合物及应用方法 |
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