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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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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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
-
- 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
-
- 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
-
- 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 (cg-RX-API-DMAC7.html) |
| EP (1) | EP3122747B1 (cg-RX-API-DMAC7.html) |
| JP (1) | JP2017512789A (cg-RX-API-DMAC7.html) |
| KR (1) | KR20160133563A (cg-RX-API-DMAC7.html) |
| CN (1) | CN104945395B (cg-RX-API-DMAC7.html) |
| AU (1) | AU2015236982B2 (cg-RX-API-DMAC7.html) |
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Families Citing this family (66)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20190007106A (ko) | 2011-12-21 | 2019-01-21 | 노비라 테라퓨틱스, 인코포레이티드 | B형 간염의 항바이러스성 제제 |
| KR102271574B1 (ko) | 2012-08-28 | 2021-07-01 | 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 | 설파모일-아릴아미드 및 b형 간염 치료제로서의 그 용도 |
| SI2961732T1 (sl) | 2013-02-28 | 2017-07-31 | Janssen Sciences Ireland Uc | Sulfamoil-arilamidi in njihova uporaba kot zdravila za zdravljenje hepatitisa B |
| PT2981536T (pt) | 2013-04-03 | 2017-08-09 | Janssen Sciences Ireland Uc | Derivados de n-fenil-carboxamida e sua utilização como medicamentos para o tratamento da hepatite b |
| JO3603B1 (ar) | 2013-05-17 | 2020-07-05 | Janssen Sciences Ireland Uc | مشتقات سلفامويل بيرولاميد واستخدامها كادوية لمعالجة التهاب الكبد نوع بي |
| US10160743B2 (en) | 2013-05-17 | 2018-12-25 | Janssen Sciences Ireland Uc | Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
| SG11201600522UA (en) | 2013-07-25 | 2016-02-26 | Janssen Sciences Ireland Uc | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis b |
| 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 |
| CA2927373C (en) | 2013-11-27 | 2021-07-13 | Sunshine Lake Pharma Co., Ltd. | Processes for preparing dihydropyrimidine derivatives and intermediates thereof |
| US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
| US9169212B2 (en) | 2014-01-16 | 2015-10-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
| KR20160128305A (ko) | 2014-02-05 | 2016-11-07 | 노비라 테라퓨틱스, 인코포레이티드 | Hbv 감염의 치료를 위한 병용 요법 |
| CN110483484A (zh) | 2014-02-06 | 2019-11-22 | 爱尔兰詹森科学公司 | 氨磺酰基吡咯酰胺衍生物及其作为药物用于治疗乙型肝炎的用途 |
| EA201792069A1 (ru) | 2015-03-19 | 2018-04-30 | Новира Терапьютикс, Инк. | Производные азокана и азонана и способы лечения инфекций гепатита в |
| US10442788B2 (en) | 2015-04-01 | 2019-10-15 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| WO2016183266A1 (en) | 2015-05-13 | 2016-11-17 | Enanta Pharmaceuticals, Inc. | Ehpatitis 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 |
| HK1259410A1 (zh) | 2015-09-29 | 2019-11-29 | 诺维拉治疗公司 | 乙型肝炎抗病毒剂的晶体形式 |
| WO2017136403A1 (en) | 2016-02-02 | 2017-08-10 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| EP3426245B1 (en) | 2016-03-07 | 2022-12-14 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| CA3021068A1 (en) | 2016-04-15 | 2017-10-19 | Novira Therapeutics, Inc. | Combinations and methods comprising a capsid assembly inhibitor |
| 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 |
| EP3468561A4 (en) | 2016-06-10 | 2019-12-04 | Enanta Pharmaceuticals, Inc. | ANTIVIRAL AGENTS AGAINST HEPATITIS B |
| 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 |
| CA3037218A1 (en) | 2016-11-18 | 2018-05-24 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Dihydropyrimidine compound and preparation method and use thereof |
| WO2019001396A1 (en) * | 2017-06-26 | 2019-01-03 | Sunshine Lake Pharma Co., Ltd. | DIHYDROPYRIMIDINE COMPOUNDS AND USES THEREOF IN MEDICINE |
| AU2018291688B2 (en) | 2017-06-27 | 2022-02-03 | Janssen Pharmaceutica Nv | Heteroaryldihydropyrimidine derivatives and methods of treating hepatitis B infections |
| UY37861A (es) | 2017-08-28 | 2019-03-29 | Enanta Pharm Inc | Agentes antivirales contra la hepatitis b |
| MA50524A (fr) | 2017-11-02 | 2020-09-09 | Aicuris Gmbh & Co Kg | Nouveaux indole-2-carboxamides à substitution amino-thiazole hautement actifs agissant contre le virus de l'hépatite b (vhb) |
| BR112020008765A2 (pt) | 2017-11-02 | 2020-10-20 | Aicuris Gmbh & Co. Kg | indol-2-carboxamidas pirazolo-piperidina substituídas altamente ativas inovadoras ativas contra o vírus da hepatite b (hbv) |
| US10428070B2 (en) | 2017-12-06 | 2019-10-01 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| TW201936192A (zh) | 2017-12-06 | 2019-09-16 | 美商因那塔製藥公司 | B 型肝炎抗病毒試劑 |
| US11058678B2 (en) | 2018-01-22 | 2021-07-13 | Enanta Pharmaceuticals, Inc. | Substituted heterocycles as antiviral agents |
| KR20200131816A (ko) | 2018-03-14 | 2020-11-24 | 얀센 사이언시즈 아일랜드 언리미티드 컴퍼니 | 캡시드 조립 조절제 투약 요법 |
| 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 |
| UY38383A (es) | 2018-09-21 | 2020-04-30 | Enanta Pharm Inc | Heterociclos funcionalizados como agentes antivirales |
| 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) |
| AR116946A1 (es) | 2018-11-02 | 2021-06-30 | Aicuris Gmbh & Co Kg | Derivados de urea 6,7-dihidro-4h-pirazolo[4,3-c]piridinas 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) |
| WO2020089460A1 (en) | 2018-11-02 | 2020-05-07 | Aicuris Gmbh & Co. Kg | Novel urea 6,7-dihydro-4h-thiazolo[5,4-c]pyridines active against the hepatitis b virus (hbv) |
| UY38437A (es) | 2018-11-02 | 2020-05-29 | Aicuris Gmbh & Co Kg | Nuevas urea 6,7-dihidro-4h-pirazolo[1,5-a]pirazinas activas contra el virus de la hepatitis b (hbv) |
| KR102819704B1 (ko) | 2018-11-21 | 2025-06-11 | 이난타 파마슈티칼스, 인코포레이티드 | 항바이러스제로서의 작용화된 헤테로사이클 |
| 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 |
| BR112021015618A2 (pt) | 2019-02-22 | 2021-10-05 | Janssen Sciences Ireland Unlimited Company | Derivados de amida úteis no tratamento da infecção pelo hbv ou doenças induzidas pelo hbv |
| MX2021013086A (es) | 2019-04-30 | 2021-11-17 | Aicuris Gmbh & Co Kg | Nuevas fenil y piridil ureas activas contra el virus de la hepatitis b (vhb). |
| WO2020221811A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel oxalyl piperazines active against the hepatitis b virus (hbv) |
| KR20220004131A (ko) | 2019-04-30 | 2022-01-11 | 아이쿠리스 게엠베하 운트 코. 카게 | B형 간염 바이러스 (hbv)에 대해 활성인 신규 인돌-2-카르복스아미드 |
| WO2020221824A1 (en) | 2019-04-30 | 2020-11-05 | Aicuris Gmbh & Co. Kg | Novel indolizine-2-carboxamides active against the hepatitis b virus (hbv) |
| TW202108576A (zh) | 2019-05-06 | 2021-03-01 | 愛爾蘭商健生科學愛爾蘭無限公司 | 用於治療ｈｂｖ感染或ｈｂｖ誘發的疾病之醯胺衍生物 |
| US11236111B2 (en) | 2019-06-03 | 2022-02-01 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| US11760755B2 (en) | 2019-06-04 | 2023-09-19 | Enanta Pharmaceuticals, Inc. | Hepatitis B antiviral agents |
| WO2020247575A1 (en) | 2019-06-04 | 2020-12-10 | Enanta Pharmaceuticals, Inc. | Hepatitis b antiviral agents |
| WO2020255015A1 (en) * | 2019-06-18 | 2020-12-24 | 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 |
| AU2021403827B2 (en) | 2020-12-17 | 2024-07-25 | Astrazeneca Ab | N-(2-(4-cyanothiazolidin-3-yl)-2-oxoethyl)- quinoline-4-carboxamides |
| EP4289842A4 (en) | 2021-02-05 | 2025-01-08 | 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 |
|---|---|---|---|---|
| EP0202654A3 (en) | 1985-05-20 | 1987-12-16 | E.R. Squibb & Sons, Inc. | 5-carboxy-1,4-dihydropyrimidine derivatives |
| GB8906168D0 (en) | 1989-03-17 | 1989-05-04 | Pfizer Ltd | Therapeutic agents |
| SE9702564D0 (sv) | 1997-07-02 | 1997-07-02 | Astra Ab | New compounds |
| SE9702563D0 (sv) | 1997-07-02 | 1997-07-02 | Astra Ab | Compounds |
| 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 |
| DE19817262A1 (de) | 1998-04-18 | 1999-10-21 | Bayer Ag | Neue 2-heterocyclisch substituierte Dihydropyrimidine |
| 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 |
| DE10012824A1 (de) | 2000-03-16 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10012823A1 (de) | 2000-03-16 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10013125A1 (de) | 2000-03-17 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| DE10013126A1 (de) | 2000-03-17 | 2001-09-20 | Bayer Ag | Arzneimittel gegen virale Erkrankungen |
| WO2005007124A2 (en) | 2003-07-23 | 2005-01-27 | Bristol-Myers Squibb Company | 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 |
| WO2008154818A1 (fr) | 2007-06-18 | 2008-12-24 | Zhang, Zhongneng | Thiazolyl-dihydropyrimidines à substitution fluorophényle |
| CN101328169B (zh) | 2007-06-18 | 2011-05-25 | 张中能 | 一种乙氧碳酰基-取代噻唑二氢嘧啶 |
| PT2159224E (pt) * | 2007-06-18 | 2012-10-24 | Sunshine Lake Pharma Co Ltd | Tiazolil dihidropirimidinas substituídas com bromo-fenilo |
| 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 |
| 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 |
| WO2014037480A1 (en) | 2012-09-10 | 2014-03-13 | F. Hoffmann-La Roche Ag | 6-amino acid heteroaryldihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection |
| 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 |
| US20150292045A1 (en) | 2012-11-09 | 2015-10-15 | Indiana University Research And Technology Corporation | Alternative uses for hbv assembly effectors |
| WO2014153459A2 (en) | 2013-03-20 | 2014-09-25 | Indiana University Research And Technology Corporation | Fluorescent-hap: a diagnostic stain for hbv cores in cells |
| PE20151951A1 (es) | 2013-05-17 | 2015-12-26 | Hoffmann La Roche | Heteroarildihidropirimidinas unidas por puentes en 6 para el tratamiento y la profilaxis de infeccion por el virus de la hepatitis b |
| CA2920415A1 (en) | 2013-11-19 | 2015-05-28 | Sunshine Lake Pharma Co., Ltd. | Dihydropyrimidine compounds and their application in pharmaceuticals |
| 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 |
-
2015
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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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| RU2016138735A3 (cg-RX-API-DMAC7.html) | 2018-05-03 |
| WO2015144093A1 (en) | 2015-10-01 |
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