EA037988B1 - Замещенные производные индолина в качестве ингибиторов репликации вирусов денге - Google Patents
Замещенные производные индолина в качестве ингибиторов репликации вирусов денге Download PDFInfo
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- EA037988B1 EA037988B1 EA201892219A EA201892219A EA037988B1 EA 037988 B1 EA037988 B1 EA 037988B1 EA 201892219 A EA201892219 A EA 201892219A EA 201892219 A EA201892219 A EA 201892219A EA 037988 B1 EA037988 B1 EA 037988B1
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- EA
- Eurasian Patent Office
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
-
- 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
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16163488 | 2016-04-01 | ||
| PCT/EP2017/057661 WO2017167951A1 (en) | 2016-04-01 | 2017-03-31 | Substituted indoline derivatives as dengue viral replication inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201892219A1 EA201892219A1 (ru) | 2019-03-29 |
| EA037988B1 true EA037988B1 (ru) | 2021-06-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201892219A EA037988B1 (ru) | 2016-04-01 | 2017-03-31 | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
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| JP (1) | JP6970115B2 (OSRAM) |
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| CN (1) | CN108884037B (OSRAM) |
| AR (1) | AR108046A1 (OSRAM) |
| AU (1) | AU2017242894B2 (OSRAM) |
| CA (1) | CA3013406C (OSRAM) |
| CL (1) | CL2018002758A1 (OSRAM) |
| CO (1) | CO2018009563A2 (OSRAM) |
| CR (1) | CR20180493A (OSRAM) |
| DK (1) | DK3436437T3 (OSRAM) |
| EA (1) | EA037988B1 (OSRAM) |
| EC (1) | ECSP18073293A (OSRAM) |
| ES (1) | ES2884067T3 (OSRAM) |
| HR (1) | HRP20211278T1 (OSRAM) |
| HU (1) | HUE055577T2 (OSRAM) |
| IL (1) | IL261948B (OSRAM) |
| JO (1) | JOP20170069B1 (OSRAM) |
| LT (1) | LT3436437T (OSRAM) |
| MX (1) | MX381634B (OSRAM) |
| MY (1) | MY195194A (OSRAM) |
| PE (1) | PE20181778A1 (OSRAM) |
| PH (1) | PH12018502077A1 (OSRAM) |
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| UY (1) | UY37182A (OSRAM) |
| WO (1) | WO2017167951A1 (OSRAM) |
| ZA (1) | ZA201806482B (OSRAM) |
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| GB201116559D0 (en) | 2011-09-26 | 2011-11-09 | Univ Leuven Kath | Novel viral replication inhibitors |
| GB201305376D0 (en) | 2013-03-25 | 2013-05-08 | Univ Leuven Kath | Novel viral replication inhibitors |
| JOP20160086B1 (ar) | 2015-05-08 | 2021-08-17 | 2 Katholieke Univ Leuven Ku Leuven Research And Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20160198B1 (ar) | 2015-09-16 | 2022-03-14 | Janssen Pharmaceuticals Inc | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JO3633B1 (ar) | 2015-09-16 | 2020-08-27 | Katholieke Univ Leuven Ku Leuven Research & Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| KR102359735B1 (ko) | 2016-03-31 | 2022-02-08 | 얀센 파마슈티칼즈, 인코포레이티드 | 뎅기 바이러스 복제 억제제로서의 치환 인돌린 유도체 |
| DK3436435T3 (da) | 2016-03-31 | 2021-08-09 | Janssen Pharmaceuticals Inc | Substituerede indolderivater som inhibitorer af replikation af denguevirus |
| CA3013408A1 (en) | 2016-04-01 | 2017-10-05 | Janssen Pharmaceuticals, Inc. | Substituted indole compound derivatives as dengue viral replication inhibitors |
| JOP20170069B1 (ar) | 2016-04-01 | 2021-08-17 | 1 Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20180025B1 (ar) | 2017-03-31 | 2021-08-17 | Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20180026A1 (ar) * | 2017-03-31 | 2019-01-30 | Univ Leuven Kath | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| WO2018215315A1 (en) | 2017-05-22 | 2018-11-29 | Janssen Pharmaceuticals, Inc. | Substituted indoline derivatives as dengue viral replication inhibitors |
| HUE054379T2 (hu) * | 2017-05-22 | 2021-09-28 | Janssen Pharmaceuticals Inc | Helyettesített indolin-származékok mint a dengue vírus szaporodásának inhibitorai |
| CA3161338A1 (en) | 2019-11-15 | 2021-05-20 | Janssen Pharmaceuticals, Inc. | Treatment and prevention of dengue disease |
| WO2025253267A1 (en) | 2024-06-06 | 2025-12-11 | Janssen Pharmaceuticals, Inc. | Combination of mosnodenvir and close analogs with nitd-688 for use in the treatment and prevention of dengue disease |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010021878A1 (en) * | 2008-08-19 | 2010-02-25 | Janssen Pharmaceutica Nv | Cold menthol receptor antagonists |
| WO2013045516A1 (en) * | 2011-09-26 | 2013-04-04 | Katholieke Universiteit Leuven | Viral replication inhibitors |
Family Cites Families (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999021559A1 (en) | 1997-10-27 | 1999-05-06 | Eli Lilly And Company | MORPHOLINO-N-ETHYL ESTER PRODRUGS OF INDOLE sPLA2 INHIBITORS |
| GB0110832D0 (en) | 2001-05-03 | 2001-06-27 | Virogen Ltd | Antiviral compounds |
| JP2005520795A (ja) | 2001-12-12 | 2005-07-14 | コンフォーマ・セラピューティクス・コーポレイション | Ｈｓｐ９０阻害活性を有するプリン類似体 |
| GB0215293D0 (en) | 2002-07-03 | 2002-08-14 | Rega Foundation | Viral inhibitors |
| AU2006204917A1 (en) | 2005-01-14 | 2006-07-20 | Smithkline Beecham Corporation | Indole derivatives for treating viral infections |
| WO2006096285A2 (en) | 2005-02-09 | 2006-09-14 | Migenix Inc. | Compositions and methods for treating or preventing flaviviridae infections |
| BRPI0909985A2 (pt) | 2008-06-03 | 2015-08-25 | Siga Technologies Inc | Composição farmacêutica e método para o tratamento ou profilaxia de uma infecção viral ou doença associada à mesma |
| TWI453207B (zh) | 2008-09-08 | 2014-09-21 | Signal Pharm Llc | 胺基三唑并吡啶，其組合物及使用其之治療方法 |
| EP2393359A4 (en) | 2009-02-09 | 2012-10-03 | Enanta Pharm Inc | COMPOUND DIBENZIMIDAZOLE DERIVATIVES |
| GB0910003D0 (en) | 2009-06-11 | 2009-07-22 | Univ Leuven Kath | Novel compounds for the treatment of neurodegenerative diseases |
| US8993604B2 (en) | 2009-06-30 | 2015-03-31 | Siga Technologies, Inc. | Treatment and prevention of dengue virus infections |
| KR20120123678A (ko) | 2010-01-15 | 2012-11-09 | 길리애드 사이언시즈, 인코포레이티드 | 플라비비리다에 바이러스의 억제제 |
| US20130023532A1 (en) | 2010-03-26 | 2013-01-24 | Casillas Linda N | Indazolyl-pyrimidines as kinase inhibitors |
| JP5716205B2 (ja) | 2011-03-29 | 2015-05-13 | 学校法人日本大学 | グルコシダーゼ活性阻害用組成物及びそのスクリーニング方法 |
| GB201305376D0 (en) | 2013-03-25 | 2013-05-08 | Univ Leuven Kath | Novel viral replication inhibitors |
| NZ717629A (en) | 2013-10-23 | 2021-12-24 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
| SG10201908467RA (en) | 2014-01-31 | 2019-10-30 | Bristol Myers Squibb Co | Macrocycles with hetrocyclic p2' groups as factor xia inhibitors |
| NO2721243T3 (OSRAM) | 2014-10-01 | 2018-10-20 | ||
| EP3201177B1 (en) | 2014-10-01 | 2018-11-21 | Janssen Pharmaceuticals, Inc. | Mono- or di-substituted indoles as dengue viral replication inhibitors |
| JP6732736B2 (ja) | 2014-10-01 | 2020-07-29 | ヤンセン ファーマシューティカルズ，インコーポレーテッド | デングウィルス複製阻害剤としての一または二置換インドール誘導体 |
| PH12017501272B1 (en) * | 2015-01-16 | 2023-01-11 | Janssen Pharmaceuticals Inc | Indole derivatives as dengue viral replication inhibitors |
| AR103680A1 (es) | 2015-02-23 | 2017-05-24 | Lilly Co Eli | Inhibidores selectivos de bace1 |
| JOP20160086B1 (ar) | 2015-05-08 | 2021-08-17 | 2 Katholieke Univ Leuven Ku Leuven Research And Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JO3633B1 (ar) | 2015-09-16 | 2020-08-27 | Katholieke Univ Leuven Ku Leuven Research & Development | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20160198B1 (ar) | 2015-09-16 | 2022-03-14 | Janssen Pharmaceuticals Inc | مشتقات اندول مستبدلة احاديا او ثنائيا بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| BR112018009010B1 (pt) | 2015-11-03 | 2023-09-26 | Zoetis Services Llc | Uso de um compósito polimérico de sol-gel para prevenir ou tratar mastite em um mamífero não humano fêmea que tem um período de lactação e sistema para formar uma barreira física no canal ou cisterna da teta do dito mamífero |
| KR102359735B1 (ko) | 2016-03-31 | 2022-02-08 | 얀센 파마슈티칼즈, 인코포레이티드 | 뎅기 바이러스 복제 억제제로서의 치환 인돌린 유도체 |
| CN109715613B (zh) | 2016-03-31 | 2021-07-30 | 武田药品工业株式会社 | 杂环化合物 |
| DK3436435T3 (da) | 2016-03-31 | 2021-08-09 | Janssen Pharmaceuticals Inc | Substituerede indolderivater som inhibitorer af replikation af denguevirus |
| JOP20170069B1 (ar) | 2016-04-01 | 2021-08-17 | 1 Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| CA3177398A1 (en) | 2016-04-01 | 2017-10-05 | Kite Pharma, Inc. | Chimeric receptors and methods of use thereof |
| EP3436018A4 (en) | 2016-04-01 | 2019-11-13 | Signal Pharmaceuticals, LLC | SUBSTITUTED AMINOPURINE COMPOUNDS, COMPOSITIONS AND METHOD FOR TREATING THEREOF |
| JP2019516352A (ja) | 2016-04-01 | 2019-06-20 | アムジエン・インコーポレーテツド | Ｆｌｔ３に対するキメラ受容体及びその使用方法 |
| CN109328074A (zh) | 2016-04-01 | 2019-02-12 | 凯德药业股份有限公司 | 嵌合抗原和t细胞受体及使用的方法 |
| UA123912C2 (uk) | 2016-04-01 | 2021-06-23 | Басф Се | Біциклічні сполуки |
| CA3013408A1 (en) | 2016-04-01 | 2017-10-05 | Janssen Pharmaceuticals, Inc. | Substituted indole compound derivatives as dengue viral replication inhibitors |
| JOP20180026A1 (ar) | 2017-03-31 | 2019-01-30 | Univ Leuven Kath | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| JOP20180025B1 (ar) | 2017-03-31 | 2021-08-17 | Janssen Pharmaceuticals Inc | مشتقات اندولين مستبدلة بصفتها مانعات للتكاثر الفيروسي لحمى الفنك |
| HUE054379T2 (hu) | 2017-05-22 | 2021-09-28 | Janssen Pharmaceuticals Inc | Helyettesített indolin-származékok mint a dengue vírus szaporodásának inhibitorai |
| WO2018215315A1 (en) | 2017-05-22 | 2018-11-29 | Janssen Pharmaceuticals, Inc. | Substituted indoline derivatives as dengue viral replication inhibitors |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010021878A1 (en) * | 2008-08-19 | 2010-02-25 | Janssen Pharmaceutica Nv | Cold menthol receptor antagonists |
| WO2013045516A1 (en) * | 2011-09-26 | 2013-04-04 | Katholieke Universiteit Leuven | Viral replication inhibitors |
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