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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- 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 That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (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)
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|---|---|
| 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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| CN (1) | CN108884037B (enExample) |
| AR (1) | AR108046A1 (enExample) |
| AU (1) | AU2017242894B2 (enExample) |
| CA (1) | CA3013406C (enExample) |
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| CR (1) | CR20180493A (enExample) |
| DK (1) | DK3436437T3 (enExample) |
| EA (1) | EA037988B1 (enExample) |
| EC (1) | ECSP18073293A (enExample) |
| ES (1) | ES2884067T3 (enExample) |
| HR (1) | HRP20211278T1 (enExample) |
| HU (1) | HUE055577T2 (enExample) |
| IL (1) | IL261948B (enExample) |
| JO (1) | JOP20170069B1 (enExample) |
| LT (1) | LT3436437T (enExample) |
| MX (1) | MX381634B (enExample) |
| MY (1) | MY195194A (enExample) |
| PE (1) | PE20181778A1 (enExample) |
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| SI (1) | SI3436437T1 (enExample) |
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| UY (1) | UY37182A (enExample) |
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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 |
| 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 |
| HUE054936T2 (hu) | 2016-03-31 | 2021-10-28 | Janssen Pharmaceuticals Inc | Helyettesített indol-származékok mint a dengue-vírus replikációjának inhibitorai |
| CA3013407A1 (en) | 2016-03-31 | 2017-10-05 | Janssen Pharmaceuticals, Inc. | Substituted indoline 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 |
| EP3436004B1 (en) | 2016-04-01 | 2024-12-11 | Janssen Pharmaceuticals, Inc. | Substituted indole compound derivatives as dengue viral replication inhibitors |
| 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 |
| EA039702B1 (ru) * | 2017-05-22 | 2022-03-01 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
| EA201992782A1 (ru) * | 2017-05-22 | 2020-03-24 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
| IL292970A (en) | 2019-11-15 | 2022-07-01 | Janssen Pharmaceuticals Inc | 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 |
|---|---|---|---|---|
| AU1200899A (en) | 1997-10-27 | 1999-05-17 | 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 |
| AU2002364566B2 (en) | 2001-12-12 | 2009-03-26 | Conforma Therapeutics Corporation | Assays and implements for determining and modulating HSP90 binding activity |
| GB0215293D0 (en) | 2002-07-03 | 2002-08-14 | Rega Foundation | Viral inhibitors |
| CA2593450A1 (en) | 2005-01-14 | 2006-07-20 | Genelabs Technologies, Inc. | Indole derivatives for treating viral infections |
| US20060194835A1 (en) | 2005-02-09 | 2006-08-31 | Migenix Inc. | Compositions and methods for treating or preventing flaviviridae infections |
| US9029376B2 (en) | 2008-06-03 | 2015-05-12 | Siga Technologies, Inc. | Small molecule inhibitors for the treatment or prevention of dengue virus infection |
| 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 |
| WO2011088303A1 (en) | 2010-01-15 | 2011-07-21 | Gilead Sciences , Inc. | Inhibitors of flaviviridae viruses |
| EP2552211A4 (en) | 2010-03-26 | 2013-10-23 | Glaxo Group Ltd | INDAZOLYL-PYRIMIDINE AS KINASEHEMMER |
| 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 |
| DK3060547T3 (en) | 2013-10-23 | 2018-01-15 | Janssen Sciences Ireland Uc | CARBOXAMIDE DERIVATIVES AND USE THEREOF AS MEDICINES FOR TREATMENT OF HEPATITS B |
| UY35971A (es) | 2014-01-31 | 2015-07-31 | Bristol Myers Squibb Company Una Corporación Del Estado De Delaware | Macrociclos con grupos p2? aromáticos como inhibidores del factor xia |
| BR112017006299A2 (pt) | 2014-10-01 | 2018-01-16 | Janssen Pharmaceuticals, Inc. | derivados indol mono- ou dissubstituídos como inibidores da replicação viral da dengue |
| ME03344B (me) * | 2014-10-01 | 2019-10-20 | Janssen Pharmaceuticals Inc | Mono- ili di-supstituisani indoli kao inнibitori replikacije denga virusa |
| NO2721243T3 (enExample) | 2014-10-01 | 2018-10-20 | ||
| 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 |
| CN108601723B (zh) | 2015-11-03 | 2022-05-17 | 硕腾服务有限责任公司 | 溶胶-凝胶聚合物复合材料及其用途 |
| SG11201807539UA (en) | 2016-03-31 | 2018-09-27 | Takeda Pharmaceuticals Co | Heterocyclic compound |
| CA3013407A1 (en) | 2016-03-31 | 2017-10-05 | Janssen Pharmaceuticals, Inc. | Substituted indoline derivatives as dengue viral replication inhibitors |
| HUE054936T2 (hu) | 2016-03-31 | 2021-10-28 | Janssen Pharmaceuticals Inc | Helyettesített indol-származékok mint a dengue-vírus replikációjának inhibitorai |
| CN109069512B (zh) | 2016-04-01 | 2022-06-14 | 西格诺药品有限公司 | 取代的氨基嘌呤化合物、其组合物以及相关治疗方法 |
| KR20210089262A (ko) | 2016-04-01 | 2021-07-15 | 카이트 파마 인코포레이티드 | 키메라 수용체 및 그의 사용 방법 |
| KR102411744B1 (ko) | 2016-04-01 | 2022-06-21 | 바스프 에스이 | 바이시클릭 화합물 |
| EP3436004B1 (en) | 2016-04-01 | 2024-12-11 | Janssen Pharmaceuticals, Inc. | Substituted indole compound derivatives as dengue viral replication inhibitors |
| SG11201808411RA (en) | 2016-04-01 | 2018-10-30 | Kite Pharma Inc | Chimeric antigen and t cell receptors and methods of use |
| UA128326C2 (uk) | 2016-04-01 | 2024-06-12 | Амджен Інк. | Химерний рецептор до flt3 та спосіб його застосування |
| 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 |
| EA201992782A1 (ru) | 2017-05-22 | 2020-03-24 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
| EA039702B1 (ru) | 2017-05-22 | 2022-03-01 | Янссен Фармасьютикалз, Инк. | Замещенные производные индолина в качестве ингибиторов репликации вирусов денге |
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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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