KR20150121712A - Hiv의 치료에 유용한 c-3 알킬 및 알케닐 개질된 베툴린산 유도체 - Google Patents
Hiv의 치료에 유용한 c-3 알킬 및 알케닐 개질된 베툴린산 유도체 Download PDFInfo
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- KR20150121712A KR20150121712A KR1020157026070A KR20157026070A KR20150121712A KR 20150121712 A KR20150121712 A KR 20150121712A KR 1020157026070 A KR1020157026070 A KR 1020157026070A KR 20157026070 A KR20157026070 A KR 20157026070A KR 20150121712 A KR20150121712 A KR 20150121712A
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- South Korea
- Prior art keywords
- alkyl
- group
- mmol
- substituted
- cycloalkyl
- 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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- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 121
- -1 alkenyl modified betulinic acid derivatives Chemical class 0.000 title claims description 160
- 238000000034 method Methods 0.000 claims abstract description 124
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 208000030507 AIDS Diseases 0.000 claims abstract description 21
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 claims description 78
- 125000001072 heteroaryl group Chemical group 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 9
- 239000003443 antiviral agent Substances 0.000 claims description 8
- 239000002835 hiv fusion inhibitor Substances 0.000 claims description 8
- 125000001475 halogen functional group Chemical group 0.000 claims description 6
- 230000002924 anti-infective effect Effects 0.000 claims description 5
- 239000002955 immunomodulating agent Substances 0.000 claims description 5
- 230000002584 immunomodulator Effects 0.000 claims description 5
- 229940121354 immunomodulator Drugs 0.000 claims description 5
- 239000012678 infectious agent Substances 0.000 claims description 5
- 229940126154 HIV entry inhibitor Drugs 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 29
- 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 abstract description 17
- 230000035800 maturation Effects 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 9
- 125000003342 alkenyl group Chemical group 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 242
- 239000000203 mixture Substances 0.000 description 144
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 129
- 239000000243 solution Substances 0.000 description 120
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 109
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- 235000019439 ethyl acetate Nutrition 0.000 description 89
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
- 230000002829 reductive effect Effects 0.000 description 68
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 53
- 229910052796 boron Inorganic materials 0.000 description 50
- 239000000741 silica gel Substances 0.000 description 50
- 229910002027 silica gel Inorganic materials 0.000 description 50
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 238000002360 preparation method Methods 0.000 description 44
- 239000012044 organic layer Substances 0.000 description 43
- 239000002904 solvent Substances 0.000 description 42
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 41
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 40
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 39
- 239000007787 solid Substances 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 34
- 239000000047 product Substances 0.000 description 34
- 238000004949 mass spectrometry Methods 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 31
- 230000015572 biosynthetic process Effects 0.000 description 30
- 238000003818 flash chromatography Methods 0.000 description 30
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 29
- 239000012267 brine Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 24
- 235000019341 magnesium sulphate Nutrition 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 238000002953 preparative HPLC Methods 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 19
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 18
- 239000006260 foam Substances 0.000 description 18
- 238000000746 purification Methods 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- 238000004811 liquid chromatography Methods 0.000 description 16
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 15
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 14
- 239000005695 Ammonium acetate Substances 0.000 description 14
- 229940043376 ammonium acetate Drugs 0.000 description 14
- 235000019257 ammonium acetate Nutrition 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 12
- AMKGKYQBASDDJB-UHFFFAOYSA-N 9$l^{2}-borabicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1[B]2 AMKGKYQBASDDJB-UHFFFAOYSA-N 0.000 description 11
- FEJUGLKDZJDVFY-UHFFFAOYSA-N 9-borabicyclo[3.3.1]nonane Substances C1CCC2CCCC1B2 FEJUGLKDZJDVFY-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- NZNMSOFKMUBTKW-UHFFFAOYSA-M cyclohexanecarboxylate Chemical compound [O-]C(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-M 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 10
- 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 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 9
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- KWGFISNERABFPJ-UHFFFAOYSA-N 4-(2-chloroethyl)-1,4-thiazinane 1,1-dioxide Chemical compound ClCCN1CCS(=O)(=O)CC1 KWGFISNERABFPJ-UHFFFAOYSA-N 0.000 description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 8
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 8
- 229920002554 vinyl polymer Polymers 0.000 description 8
- 239000003643 water by type Substances 0.000 description 8
- 229960002555 zidovudine Drugs 0.000 description 8
- KXZDNQWPXJXOGY-UHFFFAOYSA-N CC(=C)C1(CCC2C1C3CCC4C(C3(CC2)C)(CCC5C4(CC=C(C5(C)C)OS(=O)(=O)C(F)(F)F)C)C)N Chemical compound CC(=C)C1(CCC2C1C3CCC4C(C3(CC2)C)(CCC5C4(CC=C(C5(C)C)OS(=O)(=O)C(F)(F)F)C)C)N KXZDNQWPXJXOGY-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 239000002274 desiccant Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 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 6
- 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 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 0 CC[C@@](CCC1)(CC2)[C@]1[C@@](CC1)[C@]2(C)[C@](C)(CC2)[C@]1[C@]1(C)[C@@]2C(C)(C)C(**)=CC1 Chemical compound CC[C@@](CCC1)(CC2)[C@]1[C@@](CC1)[C@]2(C)[C@](C)(CC2)[C@]1[C@]1(C)[C@@]2C(C)(C)C(**)=CC1 0.000 description 6
- 108010010369 HIV Protease Proteins 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000004104 aryloxy group Chemical group 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- JLFGTHGNDLLJDF-UHFFFAOYSA-N chrysen-3-yl trifluoromethanesulfonate Chemical compound C1=CC=CC2=CC=C(C=3C(=CC=C(C=3)OS(=O)(=O)C(F)(F)F)C=C3)C3=C21 JLFGTHGNDLLJDF-UHFFFAOYSA-N 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 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 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 125000005553 heteroaryloxy group Chemical group 0.000 description 6
- 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 6
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 6
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 239000007821 HATU Substances 0.000 description 5
- 208000031886 HIV Infections Diseases 0.000 description 5
- 208000037357 HIV infectious disease Diseases 0.000 description 5
- 108060001084 Luciferase Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
- FVWJYYTZTCVBKE-ROUWMTJPSA-N betulin Chemical class C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(CO)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C FVWJYYTZTCVBKE-ROUWMTJPSA-N 0.000 description 5
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 5
- DLVGFWIRQAUWDC-UHFFFAOYSA-N ethyl 4-methylidenecyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(=C)CC1 DLVGFWIRQAUWDC-UHFFFAOYSA-N 0.000 description 5
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 5
- 229960001936 indinavir Drugs 0.000 description 5
- 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 5
- 230000014759 maintenance of location Effects 0.000 description 5
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 5
- 239000002777 nucleoside Substances 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 150000003648 triterpenes Chemical class 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- BYWDDGGTLKBPKO-UHFFFAOYSA-N 1h-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate Chemical compound C=1C(OS(=O)(=O)C(F)(F)F)=CC=C(C2=CC=C34)C=1C=CC2=C3C=CC1=C4CC=C1 BYWDDGGTLKBPKO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 4
- 239000005089 Luciferase Substances 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- 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
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229940111527 trizivir Drugs 0.000 description 1
- 229940008349 truvada Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229940098802 viramune Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229940087450 zerit Drugs 0.000 description 1
- 229940052255 ziagen Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
- C07J53/002—Carbocyclic rings fused
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201361768630P | 2013-02-25 | 2013-02-25 | |
| US61/768,630 | 2013-02-25 | ||
| PCT/US2014/017688 WO2014130810A1 (en) | 2013-02-25 | 2014-02-21 | C-3 alkyl and alkenyl modified betulinic acid derivatives useful in the treatment of hiv |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20150121712A true KR20150121712A (ko) | 2015-10-29 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020157026070A Withdrawn KR20150121712A (ko) | 2013-02-25 | 2014-02-21 | Hiv의 치료에 유용한 c-3 알킬 및 알케닐 개질된 베툴린산 유도체 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US9249180B2 (enExample) |
| EP (1) | EP2958930A1 (enExample) |
| JP (1) | JP6186012B2 (enExample) |
| KR (1) | KR20150121712A (enExample) |
| CN (1) | CN105102468A (enExample) |
| AR (1) | AR094876A1 (enExample) |
| AU (1) | AU2014218754B2 (enExample) |
| BR (1) | BR112015019590A2 (enExample) |
| CA (1) | CA2902513A1 (enExample) |
| EA (1) | EA027861B1 (enExample) |
| IL (1) | IL240739A0 (enExample) |
| MX (1) | MX2015010354A (enExample) |
| SG (1) | SG11201506445PA (enExample) |
| TW (1) | TW201444862A (enExample) |
| WO (1) | WO2014130810A1 (enExample) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016127074A1 (en) | 2015-02-06 | 2016-08-11 | Blueprint Medicines Corporation | 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors |
| WO2016168447A1 (en) * | 2015-04-14 | 2016-10-20 | VIIV HEALTHCARE (No.4) LIMITED | Methods of producing an hiv maturation inhibitor |
| EP3371171B1 (en) | 2015-11-02 | 2023-10-25 | Blueprint Medicines Corporation | Inhibitors of ret |
| 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 |
| WO2017161269A1 (en) | 2016-03-17 | 2017-09-21 | Blueprint Medicines Corporation | Inhibitors of ret receptor tyrosine kinases |
| US10227329B2 (en) | 2016-07-22 | 2019-03-12 | Blueprint Medicines Corporation | Compounds useful for treating disorders related to RET |
| US10035789B2 (en) | 2016-07-27 | 2018-07-31 | Blueprint Medicines Corporation | Compounds useful for treating disorders related to RET |
| WO2018044838A1 (en) * | 2016-08-31 | 2018-03-08 | Viiv Healthcare Company | Combinations and uses and treatments thereof |
| WO2019055119A1 (en) | 2017-09-14 | 2019-03-21 | Phoenix Biotechnology, Inc. | METHOD AND COMPOSITION FOR TREATING VIRAL INFECTION |
| CN106749486A (zh) * | 2016-11-30 | 2017-05-31 | 沈阳化工大学 | 一种以乙二胺为连接臂的齐墩果酸衍生物及其应用 |
| MX2020002884A (es) | 2017-09-14 | 2020-10-05 | Phoenix Biotechnology Inc | Método y composición neuroprotectora mejorada para tratar afecciones neurológicas. |
| BR112020020273A2 (pt) | 2018-04-03 | 2021-04-06 | Blueprint Medicines Corporation | Inibidor de ret para uso no tratamento de câncer tendo uma alteração de ret |
| US12275712B2 (en) | 2019-02-11 | 2025-04-15 | Hetero Labs Limited | Triterpene derivatives as HIV inhibitors |
| CN111362923A (zh) * | 2020-03-25 | 2020-07-03 | 魏威 | 制备ret抑制剂普拉塞替尼的方法、以及普拉塞替尼的中间体及其制备方法 |
| CN111440151A (zh) * | 2020-03-25 | 2020-07-24 | 魏威 | 制备抗肿瘤药普拉赛替尼的方法 |
| RU2020130238A (ru) | 2020-03-31 | 2022-03-14 | Феникс Байотекнолоджи, Инк. | Способ и композиции для лечения коронавирусной инфекции |
| EP4009981B1 (en) | 2020-03-31 | 2023-08-16 | Phoenix Biotechnology, Inc. | Method and compositions for treating coronavirus infection |
| EP4157829A1 (en) | 2020-05-29 | 2023-04-05 | Blueprint Medicines Corporation | Solid forms of pralsetinib |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5413999A (en) | 1991-11-08 | 1995-05-09 | Merck & Co., Inc. | HIV protease inhibitors useful for the treatment of AIDS |
| US5679828A (en) | 1995-06-05 | 1997-10-21 | Biotech Research Labs, Inc. | Betulinic acid and dihydrobetulinic acid derivatives and uses therefor |
| US6369101B1 (en) * | 1999-02-26 | 2002-04-09 | Regents Of The University Of Minnesota | Therapeutic method to treat herpes virus infection |
| US20020137755A1 (en) | 2000-12-04 | 2002-09-26 | Bilodeau Mark T. | Tyrosine kinase inhibitors |
| 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 |
| US7745625B2 (en) | 2004-03-15 | 2010-06-29 | Bristol-Myers Squibb Company | Prodrugs of piperazine and substituted piperidine antiviral agents |
| AU2005224260A1 (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 |
| US20110144069A1 (en) | 2006-10-16 | 2011-06-16 | Myriad Genetics, Incorporated | Compounds for treating viral infections |
| AU2009214779A1 (en) | 2008-02-14 | 2009-08-20 | Virochem Pharma Inc. | Novel 17beta lupane derivatives |
| US9067966B2 (en) | 2009-07-14 | 2015-06-30 | Hetero Research Foundation, Hetero Drugs Ltd. | Lupeol-type triterpene derivatives as antivirals |
| ES2548905T3 (es) | 2010-06-04 | 2015-10-21 | Bristol-Myers Squibb Company | Amidas C-28 de derivados del ácido betulínico C-3 modificados como inhibidores de la maduración del VIH |
| EP2576585B8 (en) | 2010-06-04 | 2016-12-21 | VIIV Healthcare UK (No.5) Limited | Modified c-3 betulinic acid derivatives as hiv maturation inhibitors |
| SI2670764T1 (sl) | 2011-01-31 | 2016-03-31 | Bristol-Myers Squibb Company | C-28 amini derivatov c-3 modificirane betulinske kisline inhibitorjev zorenja hiv |
| CA2826113C (en) | 2011-01-31 | 2018-09-04 | Bristol-Myers Squibb Company | C-17 and c-3 modified 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 |
-
2014
- 2014-02-21 CN CN201480010426.3A patent/CN105102468A/zh active Pending
- 2014-02-21 SG SG11201506445PA patent/SG11201506445PA/en unknown
- 2014-02-21 CA CA2902513A patent/CA2902513A1/en not_active Abandoned
- 2014-02-21 BR BR112015019590A patent/BR112015019590A2/pt not_active Application Discontinuation
- 2014-02-21 JP JP2015558996A patent/JP6186012B2/ja not_active Expired - Fee Related
- 2014-02-21 MX MX2015010354A patent/MX2015010354A/es unknown
- 2014-02-21 US US14/186,533 patent/US9249180B2/en not_active Expired - Fee Related
- 2014-02-21 AU AU2014218754A patent/AU2014218754B2/en not_active Ceased
- 2014-02-21 KR KR1020157026070A patent/KR20150121712A/ko not_active Withdrawn
- 2014-02-21 WO PCT/US2014/017688 patent/WO2014130810A1/en not_active Ceased
- 2014-02-21 EP EP14710687.6A patent/EP2958930A1/en not_active Withdrawn
- 2014-02-21 EA EA201591545A patent/EA027861B1/ru not_active IP Right Cessation
- 2014-02-24 AR ARP140100580A patent/AR094876A1/es unknown
- 2014-02-24 TW TW103106131A patent/TW201444862A/zh unknown
-
2015
- 2015-08-20 IL IL240739A patent/IL240739A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US20140243298A1 (en) | 2014-08-28 |
| JP2016509062A (ja) | 2016-03-24 |
| AU2014218754A1 (en) | 2015-10-15 |
| EP2958930A1 (en) | 2015-12-30 |
| WO2014130810A1 (en) | 2014-08-28 |
| IL240739A0 (en) | 2015-10-29 |
| US9249180B2 (en) | 2016-02-02 |
| AU2014218754B2 (en) | 2017-04-20 |
| TW201444862A (zh) | 2014-12-01 |
| BR112015019590A2 (pt) | 2017-07-18 |
| CN105102468A (zh) | 2015-11-25 |
| AR094876A1 (es) | 2015-09-02 |
| SG11201506445PA (en) | 2015-09-29 |
| MX2015010354A (es) | 2015-10-09 |
| JP6186012B2 (ja) | 2017-08-23 |
| EA027861B1 (ru) | 2017-09-29 |
| EA201591545A1 (ru) | 2015-12-30 |
| CA2902513A1 (en) | 2014-08-28 |
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Legal Events
| Date | Code | Title | Description |
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| PA0105 | International application |
Patent event date: 20150922 Patent event code: PA01051R01D Comment text: International Patent Application |
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| PG1501 | Laying open of application | ||
| N231 | Notification of change of applicant | ||
| PN2301 | Change of applicant |
Patent event date: 20171220 Comment text: Notification of Change of Applicant Patent event code: PN23011R01D |
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| PC1203 | Withdrawal of no request for examination | ||
| WITN | Application deemed withdrawn, e.g. because no request for examination was filed or no examination fee was paid |