ES2548905T3 - Amidas C-28 de derivados del ácido betulínico C-3 modificados como inhibidores de la maduración del VIH - Google Patents
Amidas C-28 de derivados del ácido betulínico C-3 modificados como inhibidores de la maduración del VIH Download PDFInfo
- Publication number
- ES2548905T3 ES2548905T3 ES11726564.5T ES11726564T ES2548905T3 ES 2548905 T3 ES2548905 T3 ES 2548905T3 ES 11726564 T ES11726564 T ES 11726564T ES 2548905 T3 ES2548905 T3 ES 2548905T3
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- Prior art keywords
- alkyl
- group
- substituted
- prop
- pentamethyl
- Prior art date
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- 150000001408 amides Chemical class 0.000 title description 121
- 239000003112 inhibitor Substances 0.000 title description 31
- 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 19
- 230000035800 maturation Effects 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 272
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims abstract description 208
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 49
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 39
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 35
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 16
- 229910006069 SO3H Inorganic materials 0.000 claims abstract description 10
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims abstract description 10
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims abstract description 4
- 208000030507 AIDS Diseases 0.000 claims description 98
- 208000031886 HIV Infections Diseases 0.000 claims description 61
- 208000037357 HIV infectious disease Diseases 0.000 claims description 60
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 60
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 50
- 238000011282 treatment Methods 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 230000000840 anti-viral effect Effects 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 239000003443 antiviral agent Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 5
- 239000002955 immunomodulating agent Substances 0.000 claims description 5
- 229940121354 immunomodulator Drugs 0.000 claims description 5
- 229960005475 antiinfective agent Drugs 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 229930192474 thiophene Natural products 0.000 claims description 4
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 230000002584 immunomodulator Effects 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
- 229940126154 HIV entry inhibitor Drugs 0.000 claims 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims 1
- -1 s Chemical compound 0.000 description 381
- 238000000034 method Methods 0.000 description 333
- 238000002360 preparation method Methods 0.000 description 223
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 171
- 239000000047 product Substances 0.000 description 171
- 239000007787 solid Substances 0.000 description 164
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 158
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 144
- 238000005160 1H NMR spectroscopy Methods 0.000 description 139
- 239000002253 acid Substances 0.000 description 134
- 230000015572 biosynthetic process Effects 0.000 description 131
- 150000001412 amines Chemical class 0.000 description 120
- 230000007062 hydrolysis Effects 0.000 description 105
- 238000006460 hydrolysis reaction Methods 0.000 description 105
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 84
- 239000000203 mixture Substances 0.000 description 80
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- QTBSBXVTEAMEQO-GUEYOVJQSA-N acetic acid-d4 Chemical compound [2H]OC(=O)C([2H])([2H])[2H] QTBSBXVTEAMEQO-GUEYOVJQSA-N 0.000 description 56
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 55
- 230000002829 reductive effect Effects 0.000 description 54
- 239000000243 solution Substances 0.000 description 47
- 229940095102 methyl benzoate Drugs 0.000 description 42
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- 239000000543 intermediate Substances 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 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 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 31
- 229910052938 sodium sulfate Inorganic materials 0.000 description 30
- 235000011152 sodium sulphate Nutrition 0.000 description 30
- 239000007858 starting material Substances 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 239000002904 solvent Substances 0.000 description 22
- 229960002555 zidovudine Drugs 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 238000006069 Suzuki reaction reaction Methods 0.000 description 19
- 239000000284 extract Substances 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 16
- 229910052796 boron Inorganic materials 0.000 description 16
- 239000012153 distilled water Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000002953 preparative HPLC Methods 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 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 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 12
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 11
- 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 11
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 241000700605 Viruses Species 0.000 description 10
- 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- 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 9
- 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 9
- 239000005711 Benzoic acid Substances 0.000 description 9
- 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 9
- 208000007766 Kaposi sarcoma Diseases 0.000 description 9
- 235000010233 benzoic acid Nutrition 0.000 description 9
- 239000002274 desiccant Substances 0.000 description 9
- 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 9
- 230000000694 effects Effects 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 9
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 9
- 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 9
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 8
- 239000005695 Ammonium acetate Substances 0.000 description 8
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 8
- 102100034343 Integrase Human genes 0.000 description 8
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 235000019257 ammonium acetate Nutrition 0.000 description 8
- 229940043376 ammonium acetate Drugs 0.000 description 8
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000011161 development Methods 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
- 239000002777 nucleoside Substances 0.000 description 7
- 150000003833 nucleoside derivatives Chemical class 0.000 description 7
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 7
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- 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
- 235000011054 acetic acid Nutrition 0.000 description 6
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- 238000005804 alkylation reaction Methods 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
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- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
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- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
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- 229960000885 rifabutin Drugs 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940076133 sodium carbonate monohydrate Drugs 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 235000019372 spiramycin Nutrition 0.000 description 1
- 229960001294 spiramycin Drugs 0.000 description 1
- 229930191512 spiramycin Natural products 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- 229940066769 systemic antihistamines substituted alkylamines Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 description 1
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 1
- QSYTWBKZNNEKPN-UHFFFAOYSA-N tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(CCN)CC1 QSYTWBKZNNEKPN-UHFFFAOYSA-N 0.000 description 1
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- POHWAQLZBIMPRN-UHFFFAOYSA-N tert-butyl n-(3-aminopropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCN POHWAQLZBIMPRN-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- HJZYBDPHAHGHAZ-UHFFFAOYSA-N thiadiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSN=N1 HJZYBDPHAHGHAZ-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
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- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- GLQWRXYOTXRDNH-UHFFFAOYSA-N thiophen-2-amine Chemical compound NC1=CC=CS1 GLQWRXYOTXRDNH-UHFFFAOYSA-N 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N trans-aconitic acid Natural products OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 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
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 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
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Virology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Immunology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35133210P | 2010-06-04 | 2010-06-04 | |
| US351332P | 2010-06-04 | ||
| PCT/US2011/038884 WO2011153319A1 (en) | 2010-06-04 | 2011-06-02 | C-28 amides of modified c-3 betulinic acid derivatives as hiv maturation inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2548905T3 true ES2548905T3 (es) | 2015-10-21 |
Family
ID=44627254
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES11726564.5T Active ES2548905T3 (es) | 2010-06-04 | 2011-06-02 | Amidas C-28 de derivados del ácido betulínico C-3 modificados como inhibidores de la maduración del VIH |
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| US (1) | US8802661B2 (enExample) |
| EP (1) | EP2576586B1 (enExample) |
| JP (1) | JP5755731B2 (enExample) |
| CN (1) | CN102985438B (enExample) |
| AR (1) | AR081638A1 (enExample) |
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| CA (1) | CA2801491C (enExample) |
| DK (1) | DK2576586T3 (enExample) |
| EA (1) | EA026140B1 (enExample) |
| ES (1) | ES2548905T3 (enExample) |
| HR (1) | HRP20150977T1 (enExample) |
| HU (1) | HUE026662T2 (enExample) |
| MX (1) | MX2012013628A (enExample) |
| PL (1) | PL2576586T3 (enExample) |
| PT (1) | PT2576586E (enExample) |
| RS (1) | RS54239B1 (enExample) |
| SI (1) | SI2576586T1 (enExample) |
| SM (1) | SMT201500272B (enExample) |
| TW (1) | TW201201792A (enExample) |
| WO (1) | WO2011153319A1 (enExample) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012106190A1 (en) * | 2011-01-31 | 2012-08-09 | Bristol-Myers Squibb Company | C-17 and c-3 modified triterpenoids with hiv maturation inhibitory activity |
| HRP20151212T1 (hr) * | 2011-01-31 | 2015-12-04 | Bristol-Myers Squibb Company | C-28 AMINI C-3 MODIFICIRANIH DERIVATA BETULINSKE KISELINE KAO INHIBITORI SAZRIJEVANJA HIV-a P |
| EP2758419B8 (en) | 2011-09-21 | 2017-04-19 | VIIV Healthcare UK (No.5) Limited | Novel betulinic acid derivatives with antiviral activity |
| 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 |
| US9637516B2 (en) | 2012-12-31 | 2017-05-02 | Hetero Research Foundation | Betulinic acid proline derivatives as HIV inhibitors |
| EA027371B1 (ru) * | 2013-02-06 | 2017-07-31 | Бристол-Майерс Сквибб Компани | C-19 модифицированные тритерпеноиды с ингибиторной активностью созревания вич |
| BR112015019590A2 (pt) * | 2013-02-25 | 2017-07-18 | Bristol Myers Squibb Co | derivados de ácido betulínico modificado com c-3 alquila e alquenila úteis no tratamento de hiv |
| MX374543B (es) | 2014-04-11 | 2025-03-06 | Viiv Healthcare Uk No 4 Ltd | Triterpenoides con actividad inhibidora de la maduración del virus de inmunodeficiencia humana, sustituidos en la posición 3 con un anillo no aromático que lleva un sustituyente haloalquilo. |
| US9920090B2 (en) | 2014-06-19 | 2018-03-20 | VIIV Healthcare UK (No.5) Limited | Betulinic acid derivatives with HIV maturation inhibitory activity |
| WO2015198263A2 (en) * | 2014-06-26 | 2015-12-30 | Hetero Research Foundation | Novel betulinic proline substituted derivatives as hiv inhibitors |
| US20170129916A1 (en) | 2014-06-26 | 2017-05-11 | Hetero Research Foundation | Novel betulinic proline imidazole derivatives as hiv inhibitors |
| AU2015346303B2 (en) * | 2014-11-14 | 2018-03-15 | VIIV Healthcare UK (No.5) Limited | Oxolupene derivatives |
| RU2017118576A (ru) | 2014-11-14 | 2018-12-14 | ВАЙВ ХЕЛТКЕР ЮКей (N5) ЛИМИТЕД | C-17-арил-замещённые аналоги бетулиновой кислоты |
| MA40886B1 (fr) | 2015-02-09 | 2020-03-31 | Hetero Research Foundation | Nouveau triterpénone en c-3 avec des dérivés d'amide inverse en c-28 en tant qu'inhibiteurs du vih |
| WO2016147099A2 (en) | 2015-03-16 | 2016-09-22 | Hetero Research Foundation | C-3 novel triterpenone with c-28 amide derivatives as hiv inhibitors |
| RU2018105352A (ru) | 2015-07-28 | 2019-08-29 | ГлаксоСмитКлайн Интеллекчуал Проперти (N2) Лимитед | Производные бетулина для предупреждения или лечения ВИЧ-инфекций |
| KR20180028534A (ko) | 2015-07-28 | 2018-03-16 | 글락소스미스클라인 인털렉츄얼 프로퍼티 (넘버 2) 리미티드 | Hiv 감염을 예방하거나 치료하기 위한 베투인 유도체 |
| RU2018112958A (ru) * | 2015-09-24 | 2019-10-28 | ГлаксоСмитКлайн Интеллекчуал Проперти (N2) Лимитед | Соединения с ингибирующей созревание ВИЧ активностью |
| CN108699103A (zh) | 2016-01-20 | 2018-10-23 | 葛兰素史克知识产权第二有限公司 | 具有hiv成熟抑制活性的羽扇烷类的胺衍生物 |
| AR107512A1 (es) | 2016-02-04 | 2018-05-09 | VIIV HEALTHCARE UK Nº 5 LTD | Triterpenoides modificados en c-3 y c-17 como inhibidores del vih-1 |
| EP3478703A1 (en) * | 2016-06-30 | 2019-05-08 | ViiV Healthcare UK (No.5) Limited | Triterpenoid inhibitors of human immunodeficiency virus replication |
| JP7436385B2 (ja) | 2018-04-24 | 2024-02-21 | ヴィーブ ヘルスケア ユーケー（ナンバー５）リミテッド | Ｈｉｖ成熟阻害活性を有する化合物 |
| PL237998B1 (pl) | 2018-05-28 | 2021-06-28 | Narodowy Inst Lekow | Fosfonowe pochodne kwasu 3-karboksyacylobetulinowego, sposób ich otrzymywania oraz ich zastosowanie |
| US10343997B1 (en) | 2018-12-04 | 2019-07-09 | King Saud University | Ursolic acid 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 |
| NZ506623A (en) * | 1998-03-02 | 2002-10-25 | Univ North Carolina | Acylated betulin and dihydrobetulin derivatives, preparation thereof and use in treatment of retroviral infections |
| 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 |
| WO2004028455A2 (en) * | 2002-09-26 | 2004-04-08 | Panacos Pharmaceuticals, Inc. | Monoacylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof |
| US20050014730A1 (en) | 2003-04-02 | 2005-01-20 | Carlson Robert M. | 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 |
| EP1730163A4 (en) | 2004-03-17 | 2009-12-30 | Panacos Pharmaceuticals Inc | Pharmaceutical salts of 3-O- (3,3-dimethylsuccinyl) betulinic acid |
| WO2005112929A2 (en) * | 2004-05-20 | 2005-12-01 | Cornell Research Foundation, Inc. | Anti-hiv-1 activity of betulinol derivatives |
| US7282521B2 (en) * | 2004-05-24 | 2007-10-16 | University Of North Carolina At Chapel Hill | Anti-retroviral moronic acid derivatives |
| TW200628161A (en) * | 2004-11-12 | 2006-08-16 | Panacos Pharmaceuticals Inc | Novel betulin derivatives, preparation thereof and use thereof |
| JP2009527563A (ja) * | 2006-02-21 | 2009-07-30 | アキリオン ファーマシューティカルズ，インコーポレーテッド | ウイルス感染症を治療するのに有用な置換タラキサスタン |
| WO2008097341A2 (en) * | 2006-07-26 | 2008-08-14 | Myriad Genetics, Inc. | Antiviral compounds and use thereof |
| WO2008127364A2 (en) * | 2006-10-13 | 2008-10-23 | Myriad Genetics, Inc. | Antiviral compounds and use thereof |
| WO2008115281A2 (en) * | 2006-10-16 | 2008-09-25 | Myriad Genetics, Inc. | Compounds for treating viral infections |
| WO2009020732A1 (en) * | 2007-08-03 | 2009-02-12 | Advanced Life Sciences, Inc. | Lupane-type triterpenoids modified at 30-position and analogues thereof |
| WO2009042166A1 (en) | 2007-09-25 | 2009-04-02 | Panacos Pharmaceuticals, Inc. | Liquid bevirimat dosage forms for oral administration |
| JP2011511812A (ja) | 2008-02-14 | 2011-04-14 | バイロケム ファーマ インコーポレイテッド | 新規１７βルパン誘導体 |
| WO2009114083A2 (en) | 2008-03-03 | 2009-09-17 | Panacos Pharmaceuticals, Inc. | Determinants of antiviral response |
| HUE033288T2 (en) * | 2008-04-18 | 2017-11-28 | Reata Pharmaceuticals Inc | Antioxidant inflammation modulators: C-17 homologated oleic acid derivatives |
| SG182769A1 (en) * | 2010-02-11 | 2012-09-27 | Glaxosmithkline Llc | Derivatives of betulin |
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2011
- 2011-06-02 BR BR112012030810A patent/BR112012030810A2/pt not_active IP Right Cessation
- 2011-06-02 SI SI201130604T patent/SI2576586T1/sl unknown
- 2011-06-02 WO PCT/US2011/038884 patent/WO2011153319A1/en not_active Ceased
- 2011-06-02 EA EA201270800A patent/EA026140B1/ru not_active IP Right Cessation
- 2011-06-02 ES ES11726564.5T patent/ES2548905T3/es active Active
- 2011-06-02 DK DK11726564.5T patent/DK2576586T3/en active
- 2011-06-02 CN CN201180035812.4A patent/CN102985438B/zh not_active Expired - Fee Related
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- 2011-06-02 MX MX2012013628A patent/MX2012013628A/es active IP Right Grant
- 2011-06-02 CA CA2801491A patent/CA2801491C/en not_active Expired - Fee Related
- 2011-06-02 US US13/151,722 patent/US8802661B2/en not_active Expired - Fee Related
- 2011-06-02 JP JP2013513340A patent/JP5755731B2/ja not_active Expired - Fee Related
- 2011-06-02 PL PL11726564T patent/PL2576586T3/pl unknown
- 2011-06-02 EP EP11726564.5A patent/EP2576586B1/en active Active
- 2011-06-02 HR HRP20150977TT patent/HRP20150977T1/hr unknown
- 2011-06-02 HU HUE11726564A patent/HUE026662T2/en unknown
- 2011-06-02 PT PT117265645T patent/PT2576586E/pt unknown
- 2011-06-03 AR ARP110101945A patent/AR081638A1/es not_active Application Discontinuation
- 2011-06-03 TW TW100119710A patent/TW201201792A/zh unknown
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2015
- 2015-10-30 SM SM201500272T patent/SMT201500272B/it unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US8802661B2 (en) | 2014-08-12 |
| DK2576586T3 (en) | 2015-11-23 |
| WO2011153319A1 (en) | 2011-12-08 |
| JP5755731B2 (ja) | 2015-07-29 |
| CN102985438A (zh) | 2013-03-20 |
| CA2801491C (en) | 2018-01-23 |
| EP2576586B1 (en) | 2015-08-12 |
| CN102985438B (zh) | 2016-05-18 |
| JP2013527243A (ja) | 2013-06-27 |
| PT2576586E (pt) | 2015-10-23 |
| HRP20150977T1 (hr) | 2015-10-09 |
| CA2801491A1 (en) | 2011-12-08 |
| US20120142653A1 (en) | 2012-06-07 |
| TW201201792A (en) | 2012-01-16 |
| HUE026662T2 (en) | 2016-06-28 |
| EP2576586A1 (en) | 2013-04-10 |
| EA026140B1 (ru) | 2017-03-31 |
| MX2012013628A (es) | 2012-12-17 |
| AR081638A1 (es) | 2012-10-10 |
| PL2576586T3 (pl) | 2016-01-29 |
| RS54239B1 (sr) | 2015-12-31 |
| BR112012030810A2 (pt) | 2019-09-24 |
| SI2576586T1 (sl) | 2015-11-30 |
| EA201270800A1 (ru) | 2013-04-30 |
| SMT201500272B (it) | 2016-01-08 |
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