AU2015236982B2 - Dihydropyrimidine compounds and their application in pharmaceuticals - Google Patents
Dihydropyrimidine compounds and their application in pharmaceuticals Download PDFInfo
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- AU2015236982B2 AU2015236982B2 AU2015236982A AU2015236982A AU2015236982B2 AU 2015236982 B2 AU2015236982 B2 AU 2015236982B2 AU 2015236982 A AU2015236982 A AU 2015236982A AU 2015236982 A AU2015236982 A AU 2015236982A AU 2015236982 B2 AU2015236982 B2 AU 2015236982B2
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- methyl
- thiazol
- title compound
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- 239000003814 drug Substances 0.000 title claims description 35
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 571
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 87
- 201000010099 disease Diseases 0.000 claims abstract description 83
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 239000012453 solvate Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims description 134
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 83
- -1 phosphazid Chemical compound 0.000 claims description 59
- 239000008194 pharmaceutical composition Substances 0.000 claims description 39
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- 108010050904 Interferons Proteins 0.000 claims description 31
- 102000014150 Interferons Human genes 0.000 claims description 31
- 229940079322 interferon Drugs 0.000 claims description 31
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 239000000651 prodrug Substances 0.000 claims description 16
- 229940002612 prodrug Drugs 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
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- 230000007882 cirrhosis Effects 0.000 claims description 11
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
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- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- WDQLRUYAYXDIFW-RWKIJVEZSA-N (2r,3r,4s,5r,6r)-4-[(2s,3r,4s,5r,6r)-3,5-dihydroxy-4-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,5-triol Chemical compound O[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)O1 WDQLRUYAYXDIFW-RWKIJVEZSA-N 0.000 claims description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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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
- A61K31/495—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
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- 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
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- 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
- A61P31/20—Antivirals for DNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Virology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Biotechnology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410126202 | 2014-03-28 | ||
| CN201410126202.0 | 2014-03-28 | ||
| CN201410596489.3 | 2014-10-29 | ||
| CN201410596489 | 2014-10-29 | ||
| PCT/CN2015/075299 WO2015144093A1 (en) | 2014-03-28 | 2015-03-27 | Dihydropyrimidine compounds and their application in pharmaceuticals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2015236982A1 AU2015236982A1 (en) | 2016-08-11 |
| AU2015236982B2 true AU2015236982B2 (en) | 2017-12-14 |
Family
ID=54160517
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2015236982A Active AU2015236982B2 (en) | 2014-03-28 | 2015-03-27 | Dihydropyrimidine compounds and their application in pharmaceuticals |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US9771358B2 (enExample) |
| EP (1) | EP3122747B1 (enExample) |
| JP (1) | JP2017512789A (enExample) |
| KR (1) | KR20160133563A (enExample) |
| CN (1) | CN104945395B (enExample) |
| AU (1) | AU2015236982B2 (enExample) |
| CA (1) | CA2938050A1 (enExample) |
| MX (1) | MX2016012573A (enExample) |
| MY (1) | MY196243A (enExample) |
| RU (1) | RU2682672C2 (enExample) |
| SG (1) | SG11201605896WA (enExample) |
| WO (1) | WO2015144093A1 (enExample) |
Families Citing this family (66)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5977837B2 (ja) | 2011-12-21 | 2016-08-24 | ノヴィラ・セラピューティクス・インコーポレイテッド | Ｂ型肝炎抗ウイルス剤 |
| MX373711B (es) | 2012-08-28 | 2020-05-08 | Janssen Sciences Ireland Uc | Sulfamoilarilamidas y su uso como medicamentos para el tratamiento de la hepatitis b. |
| DK2961732T3 (en) | 2013-02-28 | 2017-07-10 | Janssen Sciences Ireland Uc | SULFAMOYLARYLAMIDS AND USE THEREOF AS MEDICINES TO TREAT HEPATITIS B |
| CN105102451B (zh) | 2013-04-03 | 2018-09-18 | 爱尔兰詹森科学公司 | N-苯基-氨甲酰衍生物及其作为药物用于治疗乙型肝炎的用途 |
| DK2997019T3 (en) | 2013-05-17 | 2018-12-03 | Janssen Sciences Ireland Uc | SULFAMOYLTHIOPHENAMIDE DERIVATIVES AND USE THEREOF AS MEDICINES FOR TREATING HEPATITIS B |
| JO3603B1 (ar) | 2013-05-17 | 2020-07-05 | Janssen Sciences Ireland Uc | مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي |
| KR102244937B1 (ko) | 2013-07-25 | 2021-04-27 | 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 | 글리옥사미드 치환된 피롤아미드 유도체 및 ｂ형 간염 치료용 의약으로서의 이의 용도 |
| DK3060547T3 (en) | 2013-10-23 | 2018-01-15 | Janssen Sciences Ireland Uc | CARBOXAMIDE DERIVATIVES AND USE THEREOF AS MEDICINES FOR TREATMENT OF HEPATITS B |
| AU2014356984B2 (en) | 2013-11-27 | 2018-01-04 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
| US9169212B2 (en) | 2014-01-16 | 2015-10-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
| US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
| EP3102225B1 (en) | 2014-02-05 | 2020-03-25 | Novira Therapeutics Inc. | Combination therapy for treatment of hbv infections |
| US11078193B2 (en) | 2014-02-06 | 2021-08-03 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
| US9884831B2 (en) | 2015-03-19 | 2018-02-06 | Novira Therapeutics, Inc. | Azocane and azonane derivatives and methods of treating hepatitis B infections |
| WO2016161268A1 (en) | 2015-04-01 | 2016-10-06 | Enanta Pharmaceuticals, Inc. | Hepatitis b antviral agents |
| US10738035B2 (en) | 2015-05-13 | 2020-08-11 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
| WO2017011552A1 (en) * | 2015-07-13 | 2017-01-19 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| US10301255B2 (en) | 2015-07-22 | 2019-05-28 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| TW201718496A (zh) | 2015-09-29 | 2017-06-01 | 諾維拉治療公司 | B型肝炎抗病毒劑之晶型 |
| WO2017136403A1 (en) | 2016-02-02 | 2017-08-10 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| CN109069488B (zh) | 2016-03-07 | 2021-09-07 | 英安塔制药有限公司 | 乙型肝炎抗病毒剂 |
| CN109640980A (zh) | 2016-04-15 | 2019-04-16 | 诺维拉治疗公司 | 包含壳体装配抑制剂的组合和方法 |
| WO2017198201A1 (en) * | 2016-05-19 | 2017-11-23 | Sunshine Lake Pharma Co., Ltd. | Crystalline form, salt and complex of dihydropyrimidine derivative, and uses thereof in medicine |
| KR20190027814A (ko) | 2016-06-10 | 2019-03-15 | 이난타 파마슈티칼스, 인코포레이티드 | B형 간염 항바이러스제 |
| CN107674072B (zh) * | 2016-08-01 | 2020-11-24 | 广东东阳光药业有限公司 | 二氢嘧啶衍生物及其酸加成物的制备方法 |
| US11166954B2 (en) | 2016-11-18 | 2021-11-09 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Dihydropyrimidine compound and preparation method and use thereof |
| CN109790145B (zh) | 2016-11-18 | 2020-09-22 | 四川科伦博泰生物医药股份有限公司 | 二氢嘧啶类化合物及其制备方法和用途 |
| WO2019001396A1 (en) * | 2017-06-26 | 2019-01-03 | Sunshine Lake Pharma Co., Ltd. | DIHYDROPYRIMIDINE COMPOUNDS AND USES THEREOF IN MEDICINE |
| JP2020525490A (ja) | 2017-06-27 | 2020-08-27 | ヤンセン ファーマシューティカ エヌ．ベー． | ヘテロアリールジヒドロピリミジン誘導体及びｂ型肝炎感染を治療する方法 |
| TWI811236B (zh) | 2017-08-28 | 2023-08-11 | 美商因那塔製藥公司 | B型肝炎抗病毒試劑 |
| MX2020004839A (es) | 2017-11-02 | 2020-10-16 | Aicuris Gmbh & Co Kg | Nuevas indol-2-carboxamidas sustituidas con amino-tiazol, de alta actividad, activas contra el virus de la hepatitis b (vhb). |
| AR115131A1 (es) | 2017-11-02 | 2020-12-02 | Aicuris Gmbh & Co Kg | Altamente activas indolo-2-carboxamidas sustituidas con pirazolo-pirimidina activas contra el virus de la hepatitis b (vhb) |
| TW201927789A (zh) | 2017-12-06 | 2019-07-16 | 美商因那塔製藥公司 | B型肝炎抗病毒試劑 |
| WO2019113175A1 (en) | 2017-12-06 | 2019-06-13 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| WO2019143902A2 (en) | 2018-01-22 | 2019-07-25 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
| JP2021515769A (ja) | 2018-03-14 | 2021-06-24 | ヤンセン・サイエンシズ・アイルランド・アンリミテッド・カンパニー | カプシド集合調節剤の投薬レジメン |
| WO2019191166A1 (en) | 2018-03-29 | 2019-10-03 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| CN108329308B (zh) | 2018-05-16 | 2022-11-01 | 四川科伦博泰生物医药股份有限公司 | 一种二氢嘧啶类化合物的固体形式及其制备方法 |
| CN109021015B (zh) * | 2018-07-12 | 2019-12-03 | 山东大学 | 二氢嘧啶-磷酰胺类衍生物及其制备方法与应用 |
| US11053235B2 (en) | 2018-08-09 | 2021-07-06 | Janssen Sciences Ireland Unlimited Company | Substituted 1,4-dihydropyrimidines for the treatment of HBV infection or HBV-induced diseases |
| US10865211B2 (en) | 2018-09-21 | 2020-12-15 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| EP3873913A1 (en) | 2018-11-02 | 2021-09-08 | AiCuris GmbH & Co. KG | Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (hbv) |
| AR117188A1 (es) | 2018-11-02 | 2021-07-21 | Aicuris Gmbh & Co Kg | Derivados de urea 6,7-dihidro-4h-pirazolo[1,5-a]pirazinas activas contra el virus de la hepatitis b (vhb) |
| AR116947A1 (es) | 2018-11-02 | 2021-06-30 | Aicuris Gmbh & Co Kg | Derivados de urea 6,7-dihidro-4h-pirazolo[1,5-a]pirazinas-indol-2-carboxamidas activas contra el virus de la hepatitis b (vhb) |
| UY38434A (es) | 2018-11-02 | 2020-05-29 | Aicuris Gmbh & Co Kg | Nuevas 6,7-dihidro-4h-pirazolo[1,5-a]pirazin indol-2-carboxamidas activas contra el virus de la hepatitis b (hbv) |
| AR116948A1 (es) | 2018-11-02 | 2021-06-30 | Aicuris Gmbh & Co Kg | Derivados de urea 6,7-dihidro-4h-pirazolo[1,5-a]pirazinas activas contra el virus de la hepatitis b (vhb) |
| UY38439A (es) | 2018-11-02 | 2020-05-29 | Aicuris Gmbh & Co Kg | Novedosas urea 6,7-dihidro-4h-pirazolo[4,3-c]piridinas activas contra el virus de la hepatitis b (vhb) |
| US11198693B2 (en) | 2018-11-21 | 2021-12-14 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| TW202035412A (zh) * | 2018-12-20 | 2020-10-01 | 比利時商健生藥品公司 | 雜芳基二氫嘧啶衍生物和治療ｂ型肝炎感染之方法 |
| MA55020A (fr) | 2019-02-22 | 2021-12-29 | Janssen Sciences Ireland Unlimited Co | Dérivés d'amide utiles dans le traitement d'une infection par le virus de l'hépatite b ou de maladies induites par le virus de l'hépatite b |
| CN113767102A (zh) | 2019-04-30 | 2021-12-07 | 艾库里斯有限及两合公司 | 具有抗乙型肝炎病毒(hbv)活性的新的苯基和吡啶基脲类化合物 |
| CN113767101A (zh) | 2019-04-30 | 2021-12-07 | 艾库里斯有限及两合公司 | 具有抗乙型肝炎病毒(hbv)活性的新的吲哚-2-甲酰胺类化合物 |
| AU2020265392A1 (en) | 2019-04-30 | 2021-12-23 | Aicuris Gmbh & Co. Kg | Novel indolizine-2-carboxamides active against the hepatitis B virus (HBV) |
| WO2020221811A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel oxalyl piperazines active against the hepatitis b virus (hbv) |
| AR119732A1 (es) | 2019-05-06 | 2022-01-05 | Janssen Sciences Ireland Unlimited Co | Derivados de amida útiles en el tratamiento de la infección por vhb o de enfermedades inducidas por vhb |
| US11236111B2 (en) | 2019-06-03 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| WO2020247561A1 (en) | 2019-06-04 | 2020-12-10 | Enanta Pharmaceuticals, Inc, | Hepatitis b antiviral agents |
| US11472808B2 (en) | 2019-06-04 | 2022-10-18 | Enanta Pharmaceuticals, Inc. | Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents |
| US20220249647A1 (en) * | 2019-06-18 | 2022-08-11 | Janssen Sciences Ireland Unlimited Company | Combination of hepatitis b virus (hbv) vaccines and dihydropyrimidine derivatives as capsid assembly modulators |
| US11738019B2 (en) | 2019-07-11 | 2023-08-29 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
| US11236108B2 (en) | 2019-09-17 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Functionalized heterocycles as antiviral agents |
| CN110615797A (zh) * | 2019-10-11 | 2019-12-27 | 李丽丽 | 用于治疗乙型肝炎的化合物及其用途 |
| US11802125B2 (en) | 2020-03-16 | 2023-10-31 | Enanta Pharmaceuticals, Inc. | Functionalized heterocyclic compounds as antiviral agents |
| UY39569A (es) | 2020-12-17 | 2022-07-29 | Astrazeneca Ab | N-(2-(4-cianotiazolidin-3-il)-2-oxoetil)- quinolin-4-carboxamidas |
| US20240246978A1 (en) | 2021-02-05 | 2024-07-25 | Hepagene Therapeutics (HK) Limited | Phenyldihydropyrimidine compound and use thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014029193A1 (en) * | 2012-08-24 | 2014-02-27 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and their application in pharmaceuticals |
| WO2015078391A1 (en) * | 2013-11-27 | 2015-06-04 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
Family Cites Families (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61271278A (ja) | 1985-05-20 | 1986-12-01 | イ− ア−ル スクイブ アンド サンズ インコ−ポレ−テツド | ２−置換チオまたはオキソ−４−アリ−ルまたはヘテロシクロ−５−カルボキシ−１，４−ジヒドロピリミジン |
| GB8906168D0 (en) | 1989-03-17 | 1989-05-04 | Pfizer Ltd | Therapeutic agents |
| SE9702563D0 (sv) | 1997-07-02 | 1997-07-02 | Astra Ab | Compounds |
| SE9702564D0 (sv) | 1997-07-02 | 1997-07-02 | Astra Ab | New compounds |
| DE19817262A1 (de) | 1998-04-18 | 1999-10-21 | Bayer Ag | Neue 2-heterocyclisch substituierte Dihydropyrimidine |
| DE19817264A1 (de) | 1998-04-18 | 1999-10-21 | Bayer Ag | Neue Dihydropyrimidine |
| DE19817265A1 (de) | 1998-04-18 | 1999-10-21 | Bayer Ag | Verwendung von Dihydropyrimidinen als Arzneimittel und neue Stoffe |
| WO2000058302A1 (de) | 1999-03-25 | 2000-10-05 | Bayer Aktiengesellschaft | Dihydropyrimidine und ihre verwendung zur behandlung von hepatitis b |
| DE10012549A1 (de) | 2000-03-15 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10012823A1 (de) | 2000-03-16 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10012824A1 (de) | 2000-03-16 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10013126A1 (de) | 2000-03-17 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10013125A1 (de) | 2000-03-17 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| US7157461B2 (en) | 2003-07-23 | 2007-01-02 | Bristol-Myers Squibb Co. | Substituted dihydropyrimidine inhibitors of calcium channel function |
| CN101104617B (zh) | 2006-07-10 | 2010-06-23 | 北京摩力克科技有限公司 | 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 |
| CN101104604B (zh) | 2006-07-10 | 2011-03-02 | 北京摩力克科技有限公司 | 光学纯二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 |
| CN101225084A (zh) | 2007-01-16 | 2008-07-23 | 北京摩力克科技有限公司 | 二氢嘧啶类化合物及其用于制备治疗和预防病毒性疾病的药物的用途 |
| CN101328168B (zh) | 2007-06-18 | 2011-09-07 | 张中能 | 一种乙氧碳酰基-取代噻唑二氢嘧啶 |
| WO2008154818A1 (fr) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Thiazolyl-dihydropyrimidines à substitution fluorophényle |
| KR101173892B1 (ko) | 2007-06-18 | 2012-08-16 | 선샤인 레이크 파르마 컴퍼니 리미티드 | 브로모-페닐 치환된 티아졸릴 디하이드로피리미딘 |
| WO2008154819A1 (fr) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Thiazolyl-dihydropyrimidines à substitution carbéthoxy |
| WO2010069147A1 (zh) | 2008-12-17 | 2010-06-24 | 张中能 | 二氢嘧啶类化合物、其组合物及其应用 |
| CN101744823B (zh) | 2008-12-17 | 2013-06-19 | 广东东阳光药业有限公司 | 一种二氢嘧啶类化合物的固体分散体及其药用制剂 |
| CN101575318B (zh) | 2009-06-25 | 2012-02-08 | 中国人民解放军军事医学科学院毒物药物研究所 | 二氢嘧啶类化合物及其用于制备治疗和/或预防病毒性疾病的药物的用途 |
| US9487534B2 (en) | 2011-08-02 | 2016-11-08 | Scripps Research Institute, A Not-For-Profit Public Benefit Corporation Of California | Modulators of virus assembly as antiviral agents |
| CN104302626B (zh) | 2012-01-06 | 2016-09-07 | 爱尔兰詹森科学公司 | 4,4-二取代的-1,4-二氢嘧啶及其作为治疗乙型肝炎的药物的用途 |
| US20130267517A1 (en) | 2012-03-31 | 2013-10-10 | Hoffmann-La Roche Inc. | Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
| CN103664897B (zh) | 2012-09-01 | 2018-04-03 | 广东东阳光药业有限公司 | 二氢嘧啶类化合物及其在药物中的应用 |
| CN103664925B (zh) | 2012-09-07 | 2018-01-23 | 广东东阳光药业有限公司 | 杂芳基取代的二氢嘧啶类化合物及其在药物中的应用 |
| KR20150054795A (ko) | 2012-09-10 | 2015-05-20 | 에프. 호프만-라 로슈 아게 | B형 간염 바이러스 감염의 치료 및 예방을 위한 6-아미노산 헤테로아릴다이하이드로피리미딘 |
| CN103664899B (zh) | 2012-09-11 | 2017-06-16 | 广东东阳光药业有限公司 | 杂芳基取代的二氢嘧啶类化合物及其在药物中的应用 |
| WO2014074906A1 (en) | 2012-11-09 | 2014-05-15 | Indiana University Research And Technology Corporation | Alternative uses for hbv assembly effectors |
| EP2976083A4 (en) | 2013-03-20 | 2016-11-23 | Univ Indiana Res & Tech Corp | FLUORESCENCE HAP: DIAGNOSTIC STAINING FOR HBV CROPS IN CELLS |
| US9266904B2 (en) | 2013-05-17 | 2016-02-23 | Hoffmann-La Roche Inc. | 6-bridged heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis B virus infection |
| JP6524081B2 (ja) | 2013-11-19 | 2019-06-05 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． | ジヒドロピリミジン化合物及び医薬におけるその適用 |
| CN104650069B (zh) | 2013-11-19 | 2019-04-19 | 广东东阳光药业有限公司 | 4-甲基二氢嘧啶类化合物及其在药物中的应用 |
| CN104650070B (zh) | 2013-11-25 | 2018-09-14 | 广东东阳光药业有限公司 | 二氢嘧啶类化合物及其在药物中的应用 |
| RS58384B1 (sr) | 2014-03-07 | 2019-04-30 | Hoffmann La Roche | Novi 6-fuzionisani heteroarildihidropirimidini za lečenje i profilaksu infekcije virusom hepatitisa b |
| ES2687606T3 (es) | 2014-05-30 | 2018-10-26 | Qilu Pharmaceutical Co., Ltd. | Derivado de bucle de dihidropirimido como inhibidor de HBV |
-
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- 2015-03-27 SG SG11201605896WA patent/SG11201605896WA/en unknown
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014029193A1 (en) * | 2012-08-24 | 2014-02-27 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and their application in pharmaceuticals |
| WO2015078391A1 (en) * | 2013-11-27 | 2015-06-04 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
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| KR20160133563A (ko) | 2016-11-22 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) | ||
| PC | Assignment registered |
Owner name: NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY Free format text: FORMER OWNER(S): SUNSHINE LAKE PHARMA CO., LTD. |
|
| PC | Assignment registered |
Owner name: SUNSHINE LAKE PHARMA CO., LTD. Free format text: FORMER OWNER(S): NORTH & SOUTH BROTHER PHARMACY INVESTMENT COMPANY LIMITED |