AU2012312485B2 - Novel betulinic acid derivatives with antiviral activity - Google Patents
Novel betulinic acid derivatives with antiviral activity Download PDFInfo
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- AU2012312485B2 AU2012312485B2 AU2012312485A AU2012312485A AU2012312485B2 AU 2012312485 B2 AU2012312485 B2 AU 2012312485B2 AU 2012312485 A AU2012312485 A AU 2012312485A AU 2012312485 A AU2012312485 A AU 2012312485A AU 2012312485 B2 AU2012312485 B2 AU 2012312485B2
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- Prior art keywords
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- aids
- hiv
- alkyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 230000000840 anti-viral effect Effects 0.000 title claims abstract description 18
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 title description 13
- 208000030507 AIDS Diseases 0.000 claims abstract description 87
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 33
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 7
- 229960005475 antiinfective agent Drugs 0.000 claims description 6
- 239000002955 immunomodulating agent Substances 0.000 claims description 6
- 229940121354 immunomodulator Drugs 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 230000002584 immunomodulator Effects 0.000 claims description 3
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 3
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- -1 heteroalicyclic Chemical group 0.000 description 38
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 27
- 229960002555 zidovudine Drugs 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 125000001072 heteroaryl group Chemical group 0.000 description 19
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 13
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 11
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
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- 125000004432 carbon atom Chemical group C* 0.000 description 10
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 10
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical class OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- 102100034343 Integrase Human genes 0.000 description 8
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 8
- 238000011161 development Methods 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229960001936 indinavir Drugs 0.000 description 7
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 108010010369 HIV Protease Proteins 0.000 description 6
- 108010002350 Interleukin-2 Proteins 0.000 description 6
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- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 6
- 125000004104 aryloxy group Chemical group 0.000 description 6
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 6
- 210000000234 capsid Anatomy 0.000 description 6
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 description 6
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- 125000005296 thioaryloxy group Chemical group 0.000 description 6
- 125000005404 thioheteroaryloxy group Chemical group 0.000 description 6
- 125000005190 thiohydroxy group Chemical group 0.000 description 6
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 5
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 5
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- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 5
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- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 5
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- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical compound [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- 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
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Tropical Medicine & Parasitology (AREA)
- AIDS & HIV (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
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| US201161537099P | 2011-09-21 | 2011-09-21 | |
| US61/537,099 | 2011-09-21 | ||
| PCT/US2012/056186 WO2013043778A1 (en) | 2011-09-21 | 2012-09-20 | Novel betulinic acid derivatives with antiviral activity |
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| AU2012312485A1 AU2012312485A1 (en) | 2014-05-08 |
| AU2012312485B2 true AU2012312485B2 (en) | 2016-09-01 |
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| AU2012312485A Ceased AU2012312485B2 (en) | 2011-09-21 | 2012-09-20 | Novel betulinic acid derivatives with antiviral activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8906889B2 (en) * | 2012-02-15 | 2014-12-09 | Bristol-Myers Squibb Company | C-3 cycloalkenyl triterpenoids with HIV maturation inhibitory activity |
| US8889854B2 (en) | 2012-05-07 | 2014-11-18 | Bristol-Myers Squibb Company | C-17 bicyclic amines of triterpenoids with HIV maturation inhibitory activity |
| US20180094019A1 (en) * | 2015-04-14 | 2018-04-05 | ViiV Healthcare UK (No.4) Limited | Crystalline forms of modified triterpenoid hydrochloride salts with hiv maturation inhibitor activity |
| AU2016298667A1 (en) | 2015-07-28 | 2018-02-22 | Glaxosmithkline Intellectual Property (No.2) Limited | Betuin derivatives for preventing or treating HIV infections |
| CN108026140A (zh) | 2015-07-28 | 2018-05-11 | 葛兰素史克知识产权第二有限公司 | 用于预防或治疗hiv感染的白桦脂醇衍生物 |
| CN108368071A (zh) | 2015-09-24 | 2018-08-03 | 葛兰素史克知识产权第二有限公司 | 具有hiv成熟抑制活性的化合物 |
| BR112018014622A2 (pt) | 2016-01-20 | 2018-12-11 | Glaxosmithkline Ip No 2 Ltd | ?composto ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, métodos para tratar uma infecção por hiv e para prevenir uma infecção por hiv, e, uso de um composto ou sal? |
| JP2019519571A (ja) * | 2016-06-30 | 2019-07-11 | ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド | ヒト免疫不全ウイルス複製のアザ置換阻害剤 |
| EP4321164A3 (en) | 2018-04-24 | 2024-04-17 | ViiV Healthcare UK (No.5) Limited | Compounds with hiv maturation inhibitory activity |
| AU2019292599B2 (en) * | 2018-06-29 | 2022-03-03 | Dfh Therapeutics | Triterpene amine derivatives |
| RS64915B1 (sr) | 2019-02-11 | 2023-12-29 | Hetero Labs Ltd | Novi derivati triterpena kao inhibitori hiv-a |
| CN115380040A (zh) * | 2020-02-11 | 2022-11-22 | 熙德隆制药有限公司 | 作为hiv抑制剂的新型三萜衍生物 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009100532A1 (en) * | 2008-02-14 | 2009-08-20 | Virochem Pharma Inc. | NOVEL 17ß LUPANE DERIVATIVES |
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|---|---|---|---|---|
| US5413999A (en) | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
| US5869535A (en) | 1995-03-21 | 1999-02-09 | The Board Of Trustees Of The University Of Illinois | Method and composition for selectively inhibiting melanoma |
| US5962527A (en) | 1995-03-21 | 1999-10-05 | The Board Of Trustees Of The University Of Illinois | Method and composition for treating cancers |
| US5679828A (en) | 1995-06-05 | 1997-10-21 | Biotech Research Labs, Inc. | Betulinic acid and dihydrobetulinic acid derivatives and uses therefor |
| US20040110785A1 (en) | 2001-02-02 | 2004-06-10 | Tao Wang | Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives |
| US7365221B2 (en) | 2002-09-26 | 2008-04-29 | Panacos Pharmaceuticals, Inc. | Monoacylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof |
| WO2004089357A2 (en) | 2003-04-02 | 2004-10-21 | Regents Of The University Of Minnesota | Anti-fungal formulation of triterpene and essential oil |
| US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
| WO2005090380A1 (en) | 2004-03-17 | 2005-09-29 | Panacos Pharmaceuticals, Inc. | Pharmaceuticals salts of 3-o-(3',3'-dimethylsuccinyl) betulinic acid |
| TW200628161A (en) * | 2004-11-12 | 2006-08-16 | Panacos Pharmaceuticals Inc | Novel betulin derivatives, preparation thereof and use thereof |
| WO2008127364A2 (en) | 2006-10-13 | 2008-10-23 | Myriad Genetics, Inc. | Antiviral compounds and use thereof |
| US20090105203A1 (en) | 2006-10-16 | 2009-04-23 | Myriad Genetics, Incorporated | Compounds for treating viral infections |
| US9067966B2 (en) | 2009-07-14 | 2015-06-30 | Hetero Research Foundation, Hetero Drugs Ltd. | Lupeol-type triterpene derivatives as antivirals |
| EP2576586B1 (en) | 2010-06-04 | 2015-08-12 | Bristol-Myers Squibb Company | C-28 amides of modified c-3 betulinic acid derivatives as hiv maturation inhibitors |
| CN103038245B (zh) | 2010-06-04 | 2015-03-25 | 百时美施贵宝公司 | 作为hiv成熟抑制剂的c-3经修饰的桦木酸衍生物 |
| EP2670765B1 (en) | 2011-01-31 | 2017-10-18 | Viiv Healthcare Uk (No. 4) Limited | C-17 and c-3 modified triterpenoids with hiv maturation inhibitory activity |
| ES2552512T3 (es) | 2011-01-31 | 2015-11-30 | Bristol-Myers Squibb Company | Aminas C-28 de derivados de ácido betulínico modificado en C-3 como inhibidores de la maduracion del virus de inmunodeficiencia humana |
-
2012
- 2012-09-20 CN CN201280046037.7A patent/CN103814042B/zh not_active Expired - Fee Related
- 2012-09-20 EA EA201490643A patent/EA023463B1/ru not_active IP Right Cessation
- 2012-09-20 SG SG11201400331WA patent/SG11201400331WA/en unknown
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- 2012-09-20 US US13/623,165 patent/US8754069B2/en not_active Expired - Fee Related
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- 2012-09-20 KR KR1020147010087A patent/KR20140069167A/ko not_active Ceased
- 2012-09-20 TW TW101134558A patent/TW201317255A/zh unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009100532A1 (en) * | 2008-02-14 | 2009-08-20 | Virochem Pharma Inc. | NOVEL 17ß LUPANE DERIVATIVES |
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| IL231421A0 (en) | 2014-04-30 |
| EA201490643A1 (ru) | 2014-06-30 |
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| JP6100786B2 (ja) | 2017-03-22 |
| EA023463B1 (ru) | 2016-06-30 |
| EP2758419A1 (en) | 2014-07-30 |
| CN103814042B (zh) | 2015-08-19 |
| JP2014526554A (ja) | 2014-10-06 |
| EP2758419B8 (en) | 2017-04-19 |
| WO2013043778A1 (en) | 2013-03-28 |
| ES2611727T3 (es) | 2017-05-10 |
| AU2012312485A1 (en) | 2014-05-08 |
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| EP2758419B1 (en) | 2016-10-19 |
| SG11201400331WA (en) | 2014-08-28 |
| US20130072465A1 (en) | 2013-03-21 |
| TW201317255A (zh) | 2013-05-01 |
| CA2849475A1 (en) | 2013-03-28 |
| US8754069B2 (en) | 2014-06-17 |
| IL231421A (en) | 2015-11-30 |
| CN103814042A (zh) | 2014-05-21 |
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