CN100462103C - Cholesterol phosphononucleoside analogue - Google Patents
Cholesterol phosphononucleoside analogue Download PDFInfo
- Publication number
- CN100462103C CN100462103C CNB2006101122957A CN200610112295A CN100462103C CN 100462103 C CN100462103 C CN 100462103C CN B2006101122957 A CNB2006101122957 A CN B2006101122957A CN 200610112295 A CN200610112295 A CN 200610112295A CN 100462103 C CN100462103 C CN 100462103C
- Authority
- CN
- China
- Prior art keywords
- cholesterol
- analogue
- phosphononucleoside
- transmission system
- phosphinylidyne
- 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.)
- Expired - Fee Related
Links
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 245
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 86
- 239000002777 nucleoside Substances 0.000 claims abstract description 36
- 239000002502 liposome Substances 0.000 claims abstract description 31
- 239000002105 nanoparticle Substances 0.000 claims abstract description 14
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 12
- 230000005540 biological transmission Effects 0.000 claims description 37
- 239000003814 drug Substances 0.000 claims description 33
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 33
- 239000006185 dispersion Substances 0.000 claims description 29
- 229960002555 zidovudine Drugs 0.000 claims description 26
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 25
- 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 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 229960001627 lamivudine Drugs 0.000 claims description 19
- 238000001338 self-assembly Methods 0.000 claims description 19
- 229960004150 aciclovir Drugs 0.000 claims description 18
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 18
- 239000004094 surface-active agent Substances 0.000 claims description 17
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 15
- 229960002656 didanosine Drugs 0.000 claims description 15
- 229960005277 gemcitabine Drugs 0.000 claims description 14
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims description 14
- 239000000654 additive Substances 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 11
- 230000000996 additive effect Effects 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 9
- 230000000840 anti-viral effect Effects 0.000 claims description 7
- 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 claims description 6
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 6
- 229960004748 abacavir Drugs 0.000 claims description 6
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 229960001203 stavudine Drugs 0.000 claims description 6
- 229960000523 zalcitabine Drugs 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 5
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 claims description 4
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 claims description 4
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 229960004117 capecitabine Drugs 0.000 claims description 4
- 229950005454 doxifluridine Drugs 0.000 claims description 4
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims description 4
- 229960000390 fludarabine Drugs 0.000 claims description 4
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 4
- 229960000329 ribavirin Drugs 0.000 claims description 4
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 4
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 claims description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 3
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 3
- GCQYYIHYQMVWLT-HQNLTJAPSA-N Sorivudine Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 GCQYYIHYQMVWLT-HQNLTJAPSA-N 0.000 claims description 3
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 claims description 3
- 229960000724 cidofovir Drugs 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 229960004396 famciclovir Drugs 0.000 claims description 3
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 claims description 3
- 229960002963 ganciclovir Drugs 0.000 claims description 3
- 229960001179 penciclovir Drugs 0.000 claims description 3
- 229950009279 sorivudine Drugs 0.000 claims description 3
- 229960003636 vidarabine Drugs 0.000 claims description 3
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- HDOVUKNUBWVHOX-QMMMGPOBSA-N Valacyclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCOC(=O)[C@@H](N)C(C)C)C=N2 HDOVUKNUBWVHOX-QMMMGPOBSA-N 0.000 claims description 2
- 229960002756 azacitidine Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 229940093257 valacyclovir Drugs 0.000 claims description 2
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims 1
- 125000003835 nucleoside group Chemical class 0.000 abstract description 7
- 239000002353 niosome Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 31
- 239000000047 product Substances 0.000 description 22
- 238000000034 method Methods 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 229940067631 phospholipid Drugs 0.000 description 18
- 150000003904 phospholipids Chemical class 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 230000006837 decompression Effects 0.000 description 16
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 208000035126 Facies Diseases 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- -1 amine salt Chemical class 0.000 description 14
- 239000000126 substance Substances 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000010408 film Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 239000002047 solid lipid nanoparticle Substances 0.000 description 9
- 241000725303 Human immunodeficiency virus Species 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000700605 Viruses Species 0.000 description 6
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 230000008685 targeting Effects 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 150000001263 acyl chlorides Chemical class 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 229940127073 nucleoside analogue Drugs 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 238000005538 encapsulation Methods 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 description 4
- 230000006320 pegylation Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- HVUMOYIDDBPOLL-UHFFFAOYSA-N 2-(3,4-Dihydroxyoxolan-2-yl)-2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)C1OCC(O)C1O HVUMOYIDDBPOLL-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 150000001447 alkali salts Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000002155 anti-virotic effect Effects 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 229940000635 beta-alanine Drugs 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 230000004700 cellular uptake Effects 0.000 description 3
- 235000015165 citric acid Nutrition 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 235000011167 hydrochloric acid Nutrition 0.000 description 3
- 159000000003 magnesium salts Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 description 3
- 229960000502 poloxamer Drugs 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000010415 tropism Effects 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 239000007957 coemulsifier Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000002751 lymph Anatomy 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000002972 pentoses Chemical class 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229950008882 polysorbate Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 229960002668 sodium chloride Drugs 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- XDTLRYHUHKZMKH-HNPMAXIBSA-M sodium;1-[(2r,4s,5s)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-2-oxopyrimidin-4-olate Chemical class [Na+].O=C1N=C([O-])C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 XDTLRYHUHKZMKH-HNPMAXIBSA-M 0.000 description 2
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- LVNGJLRDBYCPGB-LDLOPFEMSA-N (R)-1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-LDLOPFEMSA-N 0.000 description 1
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- CKTSBUTUHBMZGZ-SHYZEUOFSA-N 2'‐deoxycytidine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKTSBUTUHBMZGZ-SHYZEUOFSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 201000006082 Chickenpox Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 229940123014 DNA polymerase inhibitor Drugs 0.000 description 1
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- KVTYWCNXFMGNFZ-AXYOXNHISA-N P(=O)(OCC)(O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@@H](CCCC(C)C)C)[C@]4(CC[C@@H]3[C@]2(CC1)C)C)O Chemical compound P(=O)(OCC)(O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@@H](CCCC(C)C)C)[C@]4(CC[C@@H]3[C@]2(CC1)C)C)O KVTYWCNXFMGNFZ-AXYOXNHISA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 1
- 229940123056 Thymidine kinase inhibitor Drugs 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 206010046980 Varicella Diseases 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- PQETVFPNRLSAAJ-PXBBAZSNSA-N [(3S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] methyl hydrogen phosphate Chemical compound COP(O)(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@H](CC[C@H]4[C@@H]3CC=C2C1)[C@H](C)CCCC(C)C PQETVFPNRLSAAJ-PXBBAZSNSA-N 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940124522 antiretrovirals Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000005452 bending Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical class C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003118 drug derivative Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 206010014599 encephalitis Diseases 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 235000004554 glutamine Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 150000002433 hydrophilic molecules Chemical class 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 238000002356 laser light scattering Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- CAAULPUQFIIOTL-UHFFFAOYSA-M methyl hydrogen phosphate Chemical compound COP(O)([O-])=O CAAULPUQFIIOTL-UHFFFAOYSA-M 0.000 description 1
- 238000000593 microemulsion method Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229940093430 polyethylene glycol 1500 Drugs 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000013930 proline Nutrition 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000011067 sorbitan monolaureate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 239000003803 thymidine kinase inhibitor Substances 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A cholesterol-based phosphonucleoside analog has a Nu-L-Ch structure, where Nu is nucleoside analog group, L is phospho radical and Ch is cholesterol group. It can form the high-dispersit transfer system including liposome, non-ionic surfactant vesicle, nanoparticle or microemulsion or the self-assembled transfer system.
Description
Technical field
The present invention relates to chemistry and biomedicine field, be particularly related to a kind of cholesterol phosphononucleoside analogue, the transmission system of high degree of dispersion be can prepare by this chemical compound, liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion and self assembly transmission system comprised.
Background technology
Nucleoside (Nucleosides) is biological intravital important chemical constituent, by its carrier that the nucleotide that obtains and nucleic acid is hereditary information of deriving.Most important hereditary material DNA and RNA are assembled by nucleotide exactly.Nucleoside and nucleotide also participate in many important reactions in the organism.The nucleoside of occurring in nature is by a purine or pyrimidine bases and a pentose be combined into.Base comprises adenine, guanine, cytosine, uracil, thymus pyrimidine, and pentose is ribose and deoxyribose, and forms adenosine, guanosine, cytidine and uridnine respectively by them, and deoxyadenosine, deoxyguanosine, deoxycytidine and deoxyribosylthymine.
(Nucleoside analogues Nu) is the important chemical substance of a class to nucleoside analog.Its architectural feature and nucleoside analogues.People have synthesized multiple nucleoside analog, find wherein to have many pharmacologically actives that have, for example antivirus action, cytotoxicity, immunosuppressive action etc.Active examination mainly concentrates on antiviral and anticancer aspect to nucleoside analog at present.Through forming the phosphorylated nucleosides analog after the tyrosine phosphorylation effect of virus and human body cell, the latter can suppress virus to antiviral nucleoside analogs by all means in vivo.According to different action functions position, they can be divided into archaeal dna polymerase inhibitor, DNA reductase inhibitor, thymidine kinase inhibitor, RNA enzyme inhibitor, reverse transcriptase inhibitors etc., are used for the treatment of infection such as herpesvirus, cytomegalovirus, chickenpox virus, influenza virus, hepatitis virus, SARS virus, HIV (human immunodeficiency virus) (HIV), encephalitis clinically.Because being replicated in the cell of virus finished,, great majority need enter competence exertion antivirus action in the cell so suppressing the antiviral drugs of virus replication birth process.The water solublity of nucleoside analog is generally stronger, makes intracellular nucleosides material be difficult for oozing out, and this is by earn a bare living instinct decision of cell.Extraneous simultaneously nucleoside analog cell interior also more difficult to get access, promptly the cell membrane permeability of many nucleoside analogs is bad.Therefore many nucleoside analog drug oral bioavailability are poor, IC is little, influenced the performance of antivirus action, and medicine keeps low concentration also might make virus produce drug resistance (Yang Daofeng for a long time in cell, Deng. the antiviral nucleoside analogue brief introduction. medical Leader, 2001,20 (2): 122; Fructus Pruni salicinae becomes, etc. the progress of ucleosides antiviral drugs. chemical research and application, 2002,14 (1): 15).HIV (human immunodeficiency virus) (HIV) just often entered in lymphsystem and the brain, and has further infected other position at the initial stage of infecting human body.And nucleoside analog is generally water solublity, it is all difficult to enter lymph and brain, this also is one of reason of acquired immune deficiency syndrome (AIDS) refractory (Yazdanlan M, et al.Blood-brain barrier properties of humanimmunodeficiency virus antiretrovirals.J Pharm Sci, 1999,88:950).Anticancer nucleoside analog generally is a kind of antimetabolite, by suppressing the synthetic performance cytotoxicity (Galmarini of nucleic acid, et al.Nucleoside analogues and nucleobase in cancer treatment.Lancet, 2002,3:415).They also need to enter competence exertion effect in the cell equally.Therefore anticancer nucleoside analog also exist bioavailability lower, pass through cell membrane and blood brain barrier than problems such as difficulties.
People have designed bioavailability and the cellular uptake problem that a lot of methods solve nucleoside analog, for example synthetic prodrug and the special drug delivery system of design, and wherein fat-soluble prodrug and liposome administration system are more noticeable.
The biomembrane permeability of medicine is except outside the Pass having with the character of biomembrane own and drug molecule amount, and the physicochemical properties of medicine are major influence factors.It is generally acknowledged, suitably increase the fat-soluble of medicine and can strengthen the biomembrane permeability.The method that people have attempted the fat-soluble prodrug of synthesis of nucleoside analogue increases its bioavailability and cellular uptake.Because nucleoside analog is connected with hydroxyl or amino usually on the aliphatic chain of non-aromatic ring or ring, people often utilize these hydroxyls or aminoly link to each other with the aliphatic chain group and obtain fat-soluble prodrug.The many bioavailability of fat-soluble enhanced nucleoside analog and cellular uptakes of studies have shown that increase, and the concentration in lymphsystem and brain generally also can improve.These prodrugs can the effect through enzyme discharge former medicine and bring into play antiviral or antitumaous effect (Yatvin MB in cell, et al.Improveduptake and retention of lipophilic prodrug to improve treatment of HIV.Adv DrugDel Rev, 1999,39:165).
Though these fat-soluble prodrugs have increased the fat-soluble of nucleoside analog, fat-soluble stronger drug administration has certain difficulty.Because fat-soluble medicine is insoluble or be insoluble in water, make its general preparation, can't solve its dispersion and problems of dissolution in aqueous solution as tablet and injection.Medicine generally need could absorb and enter cell with the molecule aggregate form of molecule or high degree of dispersion state.The intravital environment of people is the aqueous solution form, and it is fat-soluble that biomembrane is, and medicine or drug delivery system need can transmit in vivo, and repeatedly pass through biomembrane, just can reach effect target sites such as cell.If insoluble fat-soluble medicine can't dissolve or high degree of dispersion, that just can't transmit medicine effectively.
Liposome (Liposomes) is a kind of vesicle that is made of phospholipid bilayer (Vesicles), is a kind ofly can be used as the carrier of a variety of medicines in the dispersive transmission system of aqueous solution camber.Its high dispersion makes it have effects such as targeting, slow release in vivo, oral have a lymph tropism, more portable medicine passes through blood brain barrier, enter (Lasic DDand Papahadjopoulos D.Liposomes revisited.Science in the cell by approach such as fusion, endocytosis easily, 1995,267:1275).The liposome that phospholipid after the modification is formed can also have functions such as long circulation in the body, temperature targeting, pH targeting, magnetic targeting, active targeting.The part of liposome (eye, nose, skin) administration has good biocompatibility, promotes the effect of drug osmotic.Liposome still is a kind of transfection reagent that often uses in biochemistry and the molecular biology research field, present still a kind of important carrier (Kikuchi H of gene therapy, et al.Genedelivery using liposome technology.J Control Release, 1999,62:269).
The phospholipid bilayer film of liposome vesicle separates the water and the outside water of internal package, is hydrophobicity in the bilayer.Medicine is wrapped in respectively in interior water or the film according to the difference of its physicochemical properties.Usually, water soluble drug is at interior aqueous phase; Fat-soluble medicine is in rete.The preparation of liposome is the process of phospholipid molecule self assembly in water, and the volume ratio of inside and outside water can not be very big.These factors have determined the encapsulation ratio of most of water soluble drug lower (＜50%), sometimes also can very low (5%), and the medicine of parcel has the possibility that leaks into outer water.If proper fat-soluble group (as aliphatic chain) is arranged, the fat-soluble medicine molecule just can be inserted in the phospholipid bilayer, and binding ratio is more firm, and drug molecule is not easy to take off, so the encapsulation ratio of medicine is higher.Therefore in order to increase the encapsulation ratio of some water soluble drug in liposome, people have often adopted mode (the Gulati M that is prepared into the fat-soluble prodrug that has long aliphatic chain, et al.Lipophilic drug derivatives in liposomes.Int J Pharm, 1998,165:129).
Present synthetic nucleoside analog water solublity is generally stronger, fat-soluble relatively poor, medicine that has even water solublity and fat-soluble all bad.Therefore their liposome rate is lower, often can't reach administration concentration.If on the basis for preparing the fat-soluble prodrug of nucleoside analog, refabrication becomes liposome, can increase encapsulation ratio, also had liposome aqueous solution camber dispersibility and fat-soluble prodrug simultaneously and easily penetrated into characteristics (the Tong P of cell, et al.Preparation and in viro antiviral activity ofliposomes of lipophilic esters of acyclovir. Acta Pharmaceutica Sinica, 1991,27:15).
Non-ionic surface active agent vesicle (Niosomes) is meant that some non-ionic surface active agent (as sorbester p18) is self-assembled into vesicle structure, similar liposome under certain condition in water.It can be used as pharmaceutical carrier equally, has some inside and outside features of similar liposome.It is nanoscale dispersed solids particle that nanoparticle (Nanoparticles) refers generally to, because its high dispersion, it has characteristics such as the drug bioavailability of raising, intensifier target tropism as pharmaceutical carrier.Solid lipid nanoparticle (SLN) adopts the compatible matrix material of human body to form nanoparticle as main adjuvant, has the characteristics of common nanoparticle and the characteristics of good biocompatibility, and Recent study is more.Microemulsion (Microemulsions) is meant the system that the emulsion droplet of particle diameter below 100 nanometers formed, and fat-soluble medicine can be wrapped in the emulsion droplet.Because its high dispersion, it has characteristics such as the drug bioavailability of raising, intensifier target tropism equally as pharmaceutical carrier.
In sum, nucleoside analog is prepared into fat-soluble prodrug, and further is prepared into the dispersive preparations of aqueous solution camber such as liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion, help bringing into play drug effect.
Summary of the invention
The inventor has invented a kind of cholesterol phosphononucleoside analogue; it is characterized in that nucleoside analog is connected by phosphoryl with the cholesterol molecule, and the inventor finds can be prepared easily by above-mentioned cholesterol phosphononucleoside analogue the transmission system of high degree of dispersion unexpectedly.According to noted earlier, have the high degree of dispersion state and fat-soluble stronger medicine transmits easily in vivo, and the biomembrane good penetrability, have targeting.Therefore the present invention designs first and has prepared the cholesterol phosphononucleoside analogue that possesses above-mentioned functions, and has prepared the transmission system of its high degree of dispersion.
The invention provides a kind of cholesterol phosphononucleoside analogue, it is characterized in that its structure is:
Nu-L-Ch
Wherein Nu is the nucleoside analog group, and L is a phosphoryl, and Ch is the cholesterol group.
The cholesterol that the present invention relates to (Cholesterol) molecule can derive from and extract and route of synthesis.
Contain a free hydroxyl in the cholesterol molecule, generally adopt certain suitable reaction, obtain cholesterol phosphononucleoside analogue cholesterol, phosphoryl, nucleoside analog triplicity.Reaction can combine phosphoryl earlier with cholesterol, combine with nucleoside analog again, can certainly be with reversed order.
The present invention is the connected mode between Nu, L and the Ch in the restricted cholesterol phosphononucleoside analogue not, but preferably connects with ester bond or amido link.
The prototype molecule of Nu among the present invention is a nucleoside analog, aspect molecular characterization, generally contain reactive group, as free hydroxyl or amino, preferably on the aliphatic chain of its non-aromatic ring or ring, be connected with hydroxyl or amido, more preferably on the aliphatic chain of the non-aromatic ring in the nucleoside analog molecule or the ring more than one hydroxyl is arranged, further preferably on the aliphatic chain of non-aromatic ring or the ring hydroxyl is arranged.Nucleoside analog of the present invention does not require it to have special role, but preferably has the medicine of pharmacologically active aspect effect, more preferably has the medicine of antiviral or antitumaous effect.Antiviral drug can be selected from acyclovir, ganciclovir, famciclovir, penciclovir, valaciclovir, Abacavir, ribavirin, Sorivudine, ribavirin, vidarabine, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, cidofovir, acyclovir preferably, ganciclovir, famciclovir, penciclovir, Abacavir, ribavirin, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, more preferably acyclovir, Abacavir, zidovudine, lamivudine, didanosine, zalcitabine, stavudine.Anticancer medicine can be selected from methotrexate, gemcitabine, capecitabine, fludarabine, doxifluridine, cytosine arabinoside, azacitidine.
Cholesterol phosphononucleoside analogue among the present invention can be by being converted into nucleoside analog or phosphinylidyne nucleoside analog performance drug effect in vivo.
Phosphoryl L among the present invention except that with claim 1 in Nu become with Ch ester or the amide, hydroxyl of its residue can keep or continue acidylate and becomes ester or amide; Wherein the branch subobject that continues acidylate with phosphoryl without limits, but preferably from molecular weight less than 500 molecular radical, more preferably molecular weight is less than 200 molecular radical; In addition on these molecular radical structures without limits, preferably from short chain fatty alcohol or fatty amine, more preferably aminoacid; Wherein aminoacid can be selected from isoleucine, leucine, lysine, order propylhomoserin, phenylalanine, threonine, tryptophan, valine, arginine, histidine, glycine, alanine, proline, aspartic acid, agedoite, glutamine, cysteine, glutamic acid, ornithine, serine, tyrosine, Beta-alanine, γ-An Jidingsuan again; Can continue to also have hydroxyurea with the molecule of phosphoryl acidylate.
Cholesterol phosphononucleoside analogue among the present invention, concrete molecular structure can be selected from cholesteryl phosphinylidyne acyclovir, cholesteryl phosphinylidyne Abacavir, cholesteryl phosphinylidyne Sorivudine, cholesteryl phosphinylidyne vidarabine, cholesteryl phosphinylidyne zidovudine, cholesteryl phosphinylidyne lamivudine, cholesteryl phosphinylidyne didanosine, cholesteryl phosphinylidyne zalcitabine, cholesteryl phosphinylidyne stavudine, cholesteryl phosphinylidyne cidofovir, cholesteryl phosphinylidyne gemcitabine, cholesteryl phosphinylidyne capecitabine, cholesteryl phosphinylidyne fludarabine, cholesteryl phosphinylidyne doxifluridine, cholesteryl phosphinylidyne cytosine arabinoside, and continue the situation that acidylate becomes ester or amide at phosphoryl accordingly; More preferably cholesteryl phosphinylidyne Abacavir, cholesteryl phosphinylidyne zidovudine, cholesteryl phosphinylidyne lamivudine, cholesteryl phosphinylidyne didanosine, cholesteryl phosphinylidyne zalcitabine, cholesteryl phosphinylidyne stavudine, cholesteryl phosphinylidyne gemcitabine, cholesteryl phosphinylidyne capecitabine, cholesteryl phosphinylidyne fludarabine, cholesteryl phosphinylidyne doxifluridine, and continue the situation that acidylate becomes ester or amide at phosphoryl accordingly.
The synthesis step of the cholesterol phosphononucleoside analogue among the present invention generally is divided into two stages.At first cholesterol or nucleoside analog are connected with phosphoryl by acylation reaction, and then with another reactant reaction, obtain end-product at last.In above-mentioned acylation reaction, can adopt acyl chlorides and hydroxyl or amino acidylate; Or directly and hydroxyl or amino acidylate by acid.By reference pertinent literature method and utilize general professional technique just can obtain highly purified cholesterol phosphononucleoside analogue.
After obtaining the cholesterol phosphononucleoside analogue among the present invention, can also it be prepared salify according to instructions for use.The salify position generally in the remaining free hydroxyl group of phosphoryl position, can be selected from sodium salt, potassium salt, calcium salt, magnesium salt, ammonia salt, organic amine salt.Nucleoside group position also can salify, comprises alkali salt and hydrochlorate.Alkali salt can be selected from sodium salt, potassium salt, calcium salt, magnesium salt, ammonia salt, organic amine salt.Acid in the hydrochlorate can be selected from maleic acid, fumaric acid, succinic acid, benzoic acid, benzenesulfonic acid, formic acid, acetic acid, propanoic acid, oxalic acid, aminoacid, citric acid, tartaric acid, nitric acid, phosphoric acid, hydrochloric acid, sulphuric acid, preferably acetic acid, citric acid, tartaric acid, benzoic acid, hydrochloric acid, sulphuric acid.The method of the salt of preparation cholesterol phosphononucleoside analogue generally can be dissolved in identical or different organic solvent respectively with cholesterol phosphononucleoside analogue and corresponding acid or alkali earlier, organic solvent solution with them mixes according to their molecule molal quantity significant proportions again, through suitably handling, at last mixed solution is volatilized, carry out suitable purification and separate, obtain the salt of cholesterol phosphononucleoside analogue; Also can directly add excessive acid or alkali salify in the preparation.
Cholesterol phosphononucleoside analogue among the present invention or its salt have fat-soluble stronger cholesterol group, they can be prepared into liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion or the dispersive preparation of self assembly transmission system equal altitudes.The preparation of these high degree of dispersion can exist with the form of aqueous suspension and administration.These particle diameters that contain the high degree of dispersion transmission system of cholesterol phosphononucleoside analogue are generally less than 1 micron, preferably less than 0.5 micron, more preferably less than 0.2 micron.Preparation method can be with reference to pertinent literature method and professional technique (New RRC ed.Liposome:apractical approach.Oxford:Oxford University Press, 1990; Uchegbu IF and VyasSP.Non-ionic surfactant based vesicles (niosomes) in drug delivery.Int J Pharm, 1998,172:33, Cavalli R, et al.Sterilization and freeze-drying of drug-free anddrug-loaded solid lipid nanoparticles.Int J Pharm, 1997,148:47; Lu Bin, Zhang Zhengquan. study the formation condition of medicinal microemulsion with triangle phasor method. Acta Pharmaceutica Sinica, 2001,36:58).
Usually, if adopt film dispersion method to prepare liposome, film materials such as cholesterol phosphononucleoside analogue and phospholipid can be dissolved in organic solvent jointly, contain in the flask, the decompression rotary evaporation obtains thin film, adds entry or suitable buffer then, vibrate with ultrasonic, until forming uniform suspension.If ultrasonic time prolongs, also may obtain the nanoscale disperse system.If adopt reverse phase evaporation to prepare liposome, film materials such as cholesterol phosphononucleoside analogue and phospholipid can be dissolved in organic solvent jointly, add entry or buffer, high-speed stirred or the ultrasonic Emulsion that is prepared into, the rotary evaporation that reduces pressure then obtains the gel state material, adds entry or suitable buffer or do not add then, continue the decompression rotary evaporation, until forming uniform liposome turbid liquor.Liposome turbid liquor can also be selected suitably to write out a prescription and carry out lyophilization or spray drying under proper condition, forms solid powdery, can guarantee stability of formulation like this, faces with the jolting of preceding adding aqueous solution to obtain liposome turbid liquor.Use same technology can obtain the non-ionic surface active agent vesicle of cholesterol phosphononucleoside analogue.
Solid lipid nanoparticle in the nano particle preparations is suitable for the cholesterol phosphononucleoside analogue among the present invention.Usually, cholesterol phosphononucleoside analogue and room temperature are solid-state lipid down, as phospholipid, fatty acid, glyceride, common heating and melting adds entry or suitable buffer then, under heating state in high pressure dispersing emulsification machine cocycle emulsifying repeatedly, form the emulsion droplet of nano-dispersed, cooling rapidly makes it to solidify, and promptly obtains the cholesterol phosphononucleoside analogue solid lipid nanoparticle.Also can make the cholesterol phosphononucleoside analogue solid lipid nanoparticle with the microemulsion method.Cholesterol phosphononucleoside analogue nanoparticle suspension can also be selected suitably, and prescription also carries out lyophilization or spray drying under proper condition; form solid powdery; can guarantee stability of formulation like this, face with the jolting of preceding adding aqueous solution and can obtain the nanoparticle suspension.
The preparation of cholesterol phosphononucleoside analogue microemulsion can generally comprise emulsifying agent, co-emulsifier, cosolvent, oil phase, water with reference to common prescription.Generally after selecting suitable prescription, can easily form microemulsion.If select suitable prescription, generally comprise emulsifying agent, co-emulsifier, cosolvent, oil phase, can also form the self-emulsifying microemulsion system, after adding suitable quantity of water solution, system can be dispersed into microemulsion voluntarily.
Except the transmission system of the high degree of dispersion of the above-mentioned cholesterol phosphononucleoside analogue that can obtain easily, the inventor also finds unexpectedly because the cholesterol phosphononucleoside analogue among the present invention has special physicochemical character, particularly amphipathic, by it self or add an amount of additive after can self assembly in aqueous solution, form the transmission system of high degree of dispersion.Therefore contain fat-soluble strong cholesterol group and the bigger nucleoside group of polarity in the cholesterol phosphononucleoside analogue molecule, have amphipathicly, this physicochemical properties are similar to phospholipid and some surfactant.If the molecular structure of amphipathic molecule satisfies certain condition, can in water, be self-assembled into the ordered aggregation of high degree of dispersion by itself, for example the nanoparticle that obtains of the vesicle that obtains of bilayer, bilayer bending and bilayer stack.Cholesterol phosphononucleoside analogue among the present invention has long and fat-soluble stronger cholesterol group and hydrophilic nucleoside group, be easier to form bilayer, and further obtain vesicle or nanoparticle, but need to add certain quantity of additive under some condition.Therefore the present invention designs first and has prepared the self assembly transmission system of being formed or added the high degree of dispersion of an amount of additive by the cholesterol phosphononucleoside analogue among the present invention.
The preparation method of the self assembly transmission system of the high degree of dispersion of being made up of cholesterol phosphononucleoside analogue among the present invention and the preparation method of liposome equal altitudes disperse system are similar.Normally cholesterol phosphononucleoside analogue is dissolved in certain organic solvent, suitable additives can be added in the organic solvent solution of cholesterol phosphononucleoside analogue as required or treat to disperse then in the disperse medium (generally being water or aqueous solution).Method comprises film dispersion method, reverse phase evaporation, injection method, multi-emulsion method etc.In some cases, additive is optional, and this moment, transmission system all was made up of cholesterol phosphononucleoside analogue.In some cases, can not form good high degree of dispersion particle with cholesterol phosphononucleoside analogue separately, need this moment to add suitable additives, help it to form ordered structure.Whether need to add the physicochemical properties decision of additive, generally can infer by preliminary experiment according to cholesterol phosphononucleoside analogue.
The molecule molar ratio that the amount of cholesterol phosphononucleoside analogue accounts for whole constituents in the self assembly transmission system of the high degree of dispersion among the present invention between 50～100%, preferably 70～100%, more preferably 85～100%, all the other are additive.Additive can be selected from lipid molecular, surfactant.Fat molecule can be selected from fatty acid, aliphatic alcohol, fatty amine, cholesterol, fatty amine such as stearylamine.Surfactant can be selected from cholate, deoxycholate, phospholipid, polyhydric alcohol esters surfactant, polyoxyethylene surfactant, polyethyleneglycol lipid derivates, polysaccharide lipid derivate, polyamino acid lipid derivate, double hexadecyl phosphatidic acid.Phospholipid comprises synthetic phospholipid, semi-synthetic phospholipid, natural phospholipid.Wherein synthetic phospholipid comprises the phospholipid of modification such as Pegylation phospholipid again, connects the phospholipid of monoclonal antibody.Polyhydric alcohol esters surfactant is sorbitan fatty acid ester preferably, and is concrete as sorbester p18, span 40, span 20.The polyoxyethylene surfactant is polyoxyethylene polyoxypropylene block copolymer (also claiming poloxamer) preferably, Polysorbate, polyoxyethylene aliphatic alcohol ether and polyoxyethylene aliphatic alcohol ester, concrete as poloxamer P188, Tween 80, polysorbate60, polysorbate40, polysorbas20, Brij35.Additive also can be selected from some derivant of cholesterol such as cholesterol fatty acid ester, Pegylation cholesterol, and the former is as the cholesterol monomester succinate, the latter such as polyethylene glycol 1500 cholesterol succinate.
The transmission system of high degree of dispersion comprises the self assembly transmission system; if its composition or surface adsorption have the molecule or the molecule segment of highly-hydrophilic; owing to can form the hydrophilic protective layer at external environment or internal milieu, can block interparticle polymerization or in vivo the retardance conditioning turn into and obtain long circulating effect.Hydrophilic molecule or molecule segment commonly used are Polyethylene Glycol (PEG).In the present invention, the transmission system of high degree of dispersion that can adopt the method for adding the fats derivant have polyglycol chain such as Pegylation phospholipid, Pegylation cholesterol, Polysorbate to prepare the cholesterol phosphononucleoside analogue of surface hydrophilic comprises its self assembly transmission system.
The method of the transmission system of the high degree of dispersion of above-mentioned preparation cholesterol phosphononucleoside analogue is without changing or through after adjusting a little, all applicable to the salt of cholesterol phosphononucleoside analogue.
The specific embodiment
The preparation of embodiment 1. cholesteryl phosphinylidyne acyclovirs
This product be phosphoryl respectively with the product of acyclovir aliphatic chain hydroxyl and cholesterol acylated hydroxy; English chemical name 2-[(2-amino-6-oxo-1; 6-dihydro-9H-purin-9-yl) methoxy] ethyl (3b)-cholest-5-en-3-yl hydrogen phosphate; be abbreviated as CPA, molecular formula C
35H
56N
5O
6P, molecular weight 673.82.Synthetic cholesterol base phosphoryl chloride phosphorus oxychloride (CPC, C at first
27ClH
45O
2P), concrete steps are as follows.Get phosphorus oxychloride 6ml in flask, add ether 80ml, ice bath, under agitation drip gradually cholesterol (7.73g, 0.02mol) and triethylamine (TEA, diethyl ether solution 3ml) (80ml), after dropwising, continuation is reacted 2h under condition of ice bath, pressure reducing and steaming solvent and residual reactant get CPC then.(1.5g 3mmol) is dissolved in the 10ml dichloromethane to get CPC.Other get acyclovir (ACV, 0.675g, 3mmol) and TEA (0.45ml, 3mmol) be dissolved in 25ml dimethyl sulfoxide (DMSO), be added drop-wise to gradually in the above-mentioned CPC solution, room temperature reaction 2h is in the reactant liquor impouring water, add the 10ml dichloromethane extraction, collect organic facies, re-extract secondary, organic facies anhydrous sodium sulfate drying, sucking filtration, volatilize behind the solvent cholesteryl phosphoryl chloride phosphorus oxychloride acyclovir (CPCA).CPCA adds 1ml water after adding 30ml oxolane (THF) dissolving, 70 ℃ of backflow 2h, most of solvent is flung in decompression, add water 20ml, divide three extractions with dichloromethane 60ml, collect the organic facies anhydrous sodium sulfate drying, sucking filtration, after volatilizing solvent, solid is used to such an extent that obtain cholesteryl phosphinylidyne acyclovir (CPA) off-white powder behind the isopropyl alcohol recrystallization.The product thin layer chromatography shows a speckle.
1H NMR shows, chemical shift 0.65-2.48 (Cholesterol-H), 3.70,3.59 (OCH
2CH
2O), 5.50 (2H, NCH
2O), 6.79 (3H, NH
2, POH), 7.81 (NCHN), 10.5 (NH).Elementary analysis value C (62.55%) H (8.78%) N (10.49%) is close with theoretical value C (62.39%) H (8.38%) N (10.39%).
Combine earlier with phosphoryl with acyclovir, and then with the bonded method of cholesterol, also can obtain cholesteryl phosphinylidyne acyclovir.
The preparation of embodiment 2. cholesteryl phosphinylidyne didanosines
This product be phosphoryl respectively with the product of didanosine aliphatic chain hydroxyl and cholesterol acylated hydroxy; English chemical name (3b)-cholest-5-en-3-yl[(2R; 5S)-5-(6-oxo-1; 6-dihydro-9H-purin-9-yl) tetrahydrofuran-2-yl] methyl hydrogen phosphate; be abbreviated as CPD, molecular formula C
37H
57N
4O
6P, molecular weight 648.85.Identical with embodiment 1, first synthetic cholesterol base phosphoryl chloride phosphorus oxychloride (CPC) then with the didanosine acidylate, at last the hydrolysis of phosphoric residue acyl chlorides is obtained end-product.Concrete operations are as follows: (1.5g 3mmol) is dissolved in the 20ml dichloromethane to get CPC.Other removes hydroxyl inosine (DDI, 0.7g, 3mmol) and TEA (0.45ml 3mmol) is dissolved in the 10ml dimethyl formamide (DMF), be added drop-wise to gradually in the above-mentioned CPC solution, room temperature reaction 1h in reactant liquor impouring 5% sodium-chloride water solution, collects organic facies, and with 20ml dichloromethane re-extract secondary, the organic facies anhydrous sodium sulfate drying, sucking filtration, volatilize behind the solvent cholesteryl phosphoryl chloride phosphorus oxychloride didanosine (CPCD).CPCD adds 1ml water after adding 30ml oxolane (THF), 70 ℃ of backflow 1h, most of solvent is flung in decompression, add water 20ml, divide three extractions with dichloromethane 60ml, collect the organic facies anhydrous sodium sulfate drying, sucking filtration, after volatilizing solvent, solid is used to such an extent that obtain cholesteryl phosphinylidyne didanosine off-white powder behind the isopropyl alcohol recrystallization.The product thin layer chromatography shows a speckle.
1H NMR shows, chemical shift 0.65-2.42 (Cholesterol-H), 3.93,3.78 (H
2COP), 4.35 (OCH), 6.26 (NCHO), 7.56 (POH), 8.07,8.16 (NCHN, NCHNH), 12.40 (NH).Elementary analysis value C (64.55%) H (8.40%) N (8.23%) is close with theoretical value C (64.89%) H (8.39%) N (8.18%).
Combine earlier with phosphoryl with didanosine, and then with the bonded method of cholesterol, also can obtain cholesteryl phosphinylidyne didanosine.
The preparation of embodiment 3. cholesteryl phosphinylidyne zidovudines
This product be phosphoryl respectively with the product of zidovudine aliphatic chain hydroxyl and cholesterol acylated hydroxy; English chemical name 1-{3-azido-5-O-[[(3b)-and cholest-5-en-3-yloxy] (hydroxy) phosphoryl]-2; 3-dideoxy-b-L-erythro-pentofuranosyl}-5-methylpyrimidine-2; 4 (1H; 3H)-dione; be abbreviated as CPZ, molecular formula C
37H
58N
5O
7P, molecular weight 715.86.Identical with embodiment 1, first synthetic cholesterol base phosphoryl chloride phosphorus oxychloride (CPC) then with the zidovudine acidylate, at last the hydrolysis of phosphoric residue acyl chlorides is obtained end-product.Concrete operations are as follows: (1.5g 3mmol) is dissolved in the 10ml dichloromethane to get CPC.Other gets zidovudine (AZT, 0.8g, 3mmol) and TEA (0.45ml 3mmol) is dissolved in the 20ml dichloromethane, be added drop-wise to gradually in the above-mentioned CPC solution, room temperature reaction 1h in the reactant liquor impouring water, collects organic facies, and with 20ml dichloromethane re-extract secondary, the organic facies anhydrous sodium sulfate drying, sucking filtration, volatilize behind the solvent cholesteryl phosphoryl chloride phosphorus oxychloride zidovudine (CPCZ).CPCZ adds 1ml water after adding 30ml oxolane (THF) dissolving, 70 ℃ of backflow 1h, most of solvent is flung in decompression, add water 20ml, divide three extractions with dichloromethane 60ml, collect the organic facies anhydrous sodium sulfate drying, sucking filtration, after volatilizing solvent, solid is used to such an extent that obtain cholesteryl phosphinylidyne zidovudine (CPZ) off-white powder behind the isopropyl alcohol recrystallization.The product thin layer chromatography shows a speckle.
1H NMR shows, chemical shift 0.82-2.45 (Cholesterol-H), 4.00,4.22 (HCH
2COPO), 7.44 (NCHCCH
3), 7.56 (POH), 11.32 (OCNHCO).Elementary analysis value C (61.78%) H (8.55%) N (9.39%) is close with theoretical value C (62.08%) H (8.17%) N (9.78%).
Combine earlier with phosphoryl with zidovudine, and then with the bonded method of cholesterol, also can obtain cholesteryl phosphinylidyne zidovudine.
The preparation of embodiment 4. cholesteryl phosphinylidyne lamivudines
This product be phosphoryl respectively with the product of lamivudine aliphatic chain hydroxyl and cholesterol acylated hydroxy; English chemical name [(2S; 5R)-5-(4-amino-2-oxopyrimidin-1 (2H)-yl)-1; 3-oxathiolan-2-yl] methyl (3b)-cholest-5-en-3-yl hydrogen phosphate; be abbreviated as CPL, molecular formula C
35H
56N
3O
6PS, molecular weight 677.87.Identical with embodiment 1, first synthetic cholesterol base phosphoryl chloride phosphorus oxychloride (CPC) then with the lamivudine acidylate, at last the hydrolysis of phosphoric residue acyl chlorides is obtained end-product.Concrete operations are as follows: (1.5g 3mmol) is dissolved in the 20ml dichloromethane to get CPC.Other gets lamivudine (3TC, 0.69g, 3mmol) and TEA (0.45ml 3mmol) is dissolved in the 10ml dimethyl formamide, be added drop-wise to gradually in the above-mentioned CPC solution, room temperature reaction 2h in the reactant liquor impouring water, collects organic facies, and with 20ml dichloromethane re-extract secondary, the organic facies anhydrous sodium sulfate drying, sucking filtration, volatilize behind the solvent cholesteryl phosphoryl chloride phosphorus oxychloride lamivudine (CPCL).CPCL adds 1ml water after adding 30ml oxolane (THF), 70 ℃ of backflow 1h, most of solvent is flung in decompression, add water 20ml, divide three extractions with dichloromethane 60ml, collect the organic facies anhydrous sodium sulfate drying, sucking filtration, after volatilizing solvent, solid is used to such an extent that obtain cholesteryl phosphinylidyne lamivudine off-white powder behind the isopropyl alcohol recrystallization.The product thin layer chromatography shows a speckle.
1H NMR shows, chemical shift 0.65-2.47 (Cholesterol-H), 3.91,4.08 (H
2COP), 5.34 (OCHS), 6.00 (H
2NCCH), 6.16 (NCHO), 7.61 (POH, NH
2), 8.02 (CHN).Elementary analysis value C (62.34%) H (8.70%) N (6.55%) is close with theoretical value C (62.01%) H (8.33%) N (6.20%).
Combine earlier with phosphoryl with lamivudine, and then with the bonded method of cholesterol, also can obtain cholesteryl phosphinylidyne lamivudine.
The preparation of embodiment 5. cholesteryl phosphinylidyne gemcitabines
This product be phosphoryl respectively with the product of gemcitabine aliphatic chain hydroxyl and cholesterol acylated hydroxy; English chemical name 5 '-O-[[(3b)-and cholest-5-en-3-yloxy] (hydroxy) phosphoryl]-2 '-deoxy-2 '; 2 '-difluorocytidine, be abbreviated as CPG, molecular formula C
36H
56F
2N
3O
7P, molecular weight 711.82.Identical with embodiment 1, first synthetic cholesterol base phosphoryl chloride phosphorus oxychloride (CPC) then with the gemcitabine acidylate, at last the hydrolysis of phosphoric residue acyl chlorides is obtained end-product.Concrete operations are as follows: (1.5g 3mmol) is dissolved in the 20ml dichloromethane to get CPC.Other get gemcitabine hydrochloride (GTB, 0.8g, 3mmol) and TEA (0.45ml, 3mmol) be dissolved in 20ml dimethyl formamide/dimethyl acetylamide (DMF/DMA, 1:1), be added drop-wise in the above-mentioned CPC solution room temperature reaction 1h gradually, in reactant liquor impouring 5% sodium-chloride water solution, collect organic facies, and with 20ml dichloromethane re-extract secondary, organic facies anhydrous sodium sulfate drying, sucking filtration, volatilize behind the solvent cholesteryl phosphoryl chloride phosphorus oxychloride gemcitabine (CPCG).CPCG adds 1ml water after adding 30ml oxolane (THF), 70 ℃ of backflow 1h, most of solvent is flung in decompression, add 1% citric acid solution 20ml, divide three extractions with dichloromethane 60ml, collect the organic facies anhydrous sodium sulfate drying, sucking filtration, after volatilizing solvent, solid is used to such an extent that obtain cholesteryl phosphinylidyne gemcitabine off-white powder behind the isopropyl alcohol recrystallization.The product thin layer chromatography shows a speckle.
1H NMR shows, chemical shift 0.65-2.47 (Cholesterol-H), 3.94 (HCOP), 4.46 (OCHCHOH), 6.06 (HCCNH
2, NCH), 6.10 (OH), 6.62 (POH), 6.73 (NH
2), 7.93 (NCH), 11.32 (OCNHCO).Elementary analysis value C (60.39%) H (8.08%) N (6.12%) is close with theoretical value C (60.74%) H (7.93%) N (5.90%).
If hydrolysis finishes, be poured in 2% hydrochloric acid solution, can obtain cholesteryl phosphinylidyne gemcitabine hydrochlorate.Elementary analysis value C (57.55%) H (7.29%) N (5.33%) is close with theoretical value C (57.78%) H (7.68%) N (5.62%).
Combine earlier with phosphoryl with gemcitabine, and then with the bonded method of cholesterol, also can obtain cholesteryl phosphinylidyne gemcitabine.
The preparation of embodiment 6. cholesteryls (propanoic acid) amido phosphinylidyne zidovudine
This product is that phosphoryl continues to obtain after the amino condensation acidylate with Beta-alanine in the cholesterol phosphinylidyne zidovudine molecule, is abbreviated as CPAZ, molecular formula C
40H
63N
6O
8P, molecular weight 786.94.Press embodiment 3 operations, first synthetic cholesterol base phosphoryl chloride phosphorus oxychloride zidovudine (CPCZ), CPCZ continues the Beta-alanine acidylate is obtained CPAZ then.
1H NMR and CPZ are approximate.Elementary analysis value C (61.28%) H (8.33%) N (10.49%) is close with theoretical value C (61.05%) H (8.07%) N (10.68%).
The preparation of embodiment 7. cholesteryl phosphinylidyne zidovudine sodium salts
Molecular formula C
37H
57N
5O
7PNa.(7.16g 0.01mol) is dissolved in the 20ml chloroform, adds the methanol solution that contains 0.01mol NaOH, and jolting is ultrasonic, and decompression volatilizes solvent, and recrystallizing methanol obtains cholesteryl phosphinylidyne zidovudine sodium salt white crystal to get cholesteryl phosphinylidyne zidovudine.Thin layer chromatography shows a speckle.Elementary analysis value C (60.55%) H (7.40%) N (9.81%) is close with theoretical value C (60.23%) H (7.79%) N (9.49%).Preparation methoies such as other alkali salt such as potassium salt, calcium salt, magnesium salt, ammonia salt, organic amine salt are close.
The preparation of embodiment 8. cholesteryl phosphinylidyne lamivudine acetate
Molecular formula C
37H
60N
3O
8PS.(6.78g 0.01mol) is dissolved in the 20ml chloroform, adds the acetone soln that contains 0.01mol acetic acid, and jolting is ultrasonic, and decompression volatilizes solvent, and the isopropyl alcohol recrystallization obtains cholesterol phosphinylidyne lamivudine acetate to get cholesterol phosphinylidyne lamivudine.Thin layer chromatography shows a speckle.Elementary analysis value C (60.51%) H (7.95%) N (5.37%) is close with theoretical value C (60.22%) H (8.20%) N (5.69%).Preparation methoies such as other acylate such as formates, oxalates, citrate are close.
The preparation of embodiment 9. cholesteryl phosphinylidyne acyclovir liposomees
Get cholesteryl phosphinylidyne acyclovir (25mg), soybean phospholipid (0.1g) in the 250ml flask, with the dissolving of 20ml dichloromethane, the decompression rotary evaporation obtains one deck alicyclic organic soluble film, the phosphate buffer 1 0ml that adds pH7.4, vibration, most of film comes off, and is ultrasonic at 50 ℃, until obtaining even suspension, microscopically is observed, and most of particle diameter is cholesteryl phosphinylidyne acyclovir liposome less than 1 micron.
The preparation of embodiment 10. cholesteryl phosphinylidyne acyclovir non-ionic surface active agent vesicles
Get cholesteryl phosphinylidyne acyclovir (30mg), sorbester p18 (0.08g) in the 250ml flask, dissolve with the 20ml dichloromethane, the decompression rotary evaporation obtains one deck alicyclic organic soluble film, adds the phosphate buffer 1 0ml of pH7.4, vibration, most of film comes off, 50 ℃ ultrasonic, until the even suspension that obtains cholesteryl phosphinylidyne acyclovir non-ionic surface active agent vesicle, the laser light scattering Particle Size Analyzer detects, and mean diameter is 285 nanometers.
The preparation of embodiment 11. cholesteryl phosphinylidyne didanosine long circulating liposomess
Get cholesteryl phosphinylidyne didanosine (50mg), soybean phospholipid (0.1g), PEGization DSPE (PEG-DSPE) (0.02g) in flask, use the 20ml chloroform: diisopropyl ether (1:1, v/v) dissolving, add an amount of distilled water, ultrasonicly make it become Emulsion, the decompression rotary evaporation, obtain the gel state material, add low amounts of water, continue the decompression rotary evaporation, the gel state material comes off and is dispersed into even suspension, and microscopically is observed, most of particle diameter is didanosine cholesterol succinate long circulating liposomes less than 1 micron.
The preparation of embodiment 12. cholesteryl phosphinylidyne zidovudine solid lipid nanoparticles
Get cholesteryl phosphinylidyne zidovudine (50mg), glyceryl monostearate (0.7g), Tween 80 (0.03g) and in beaker, be heated to 80 ℃, add the 80 ℃ of water (10ml) that contain sodium lauryl sulphate (10mg) gradually, keep temperature-resistant, be transparency liquid.Again it is injected in 0 ℃ of water of high-speed stirred with syringe, is transparency liquid.Under atomic force microscope, observe, mostly be the following particle of 100 nanometers.But this cholesteryl phosphinylidyne zidovudine solid lipid nanoparticle suspension room temperature is placed and was not seen that precipitation separated out in 10 days.This solid lipid nanoparticle suspension is lyophilized into pressed powder after adding due care agent, face with before adding entry, cholesteryl phosphinylidyne zidovudine solid lipid nanoparticle suspension.
The preparation of embodiment 13. cholesteryl phosphinylidyne zidovudine self assembly transmission systems
Get cholesteryl phosphinylidyne zidovudine and be dissolved in oxolane (5%, w/w), slowly be injected into microsyringe in the water of stirring, to obtaining even little suspension, decompression can be flung to organic solvent, and can be under heating condition further concentrated product, product is after the phosphotungstic acid negative staining, the particle transmission electron microscope is observed down, is nanoscale blister-shape structure (seeing Figure of description 1), is cholesteryl phosphinylidyne zidovudine self assembly transmission system.
The preparation of embodiment 14. cholesteryl phosphinylidyne lamivudine self assembly transmission systems
To contain cholesteryl phosphinylidyne lamivudine (5%, w/w) and Tween20 (0.5%, tetrahydrofuran solution w/w), slowly be injected into microsyringe in the water of stirring, to obtaining even little suspension, decompression can be flung to organic solvent, and can be under heating condition further concentrated product.Product is used transmission electron microscope observing after the phosphotungstic acid negative staining, be nanoscale blister-shape structure, is cholesteryl phosphinylidyne lamivudine self assembly transmission system.
The preparation of embodiment 15. cholesteryl phosphinylidyne gemcitabine self assembly transmission systems
To contain cholesteryl phosphinylidyne gemcitabine (5%, w/w) and poloxamer P188 (1%, tetrahydrofuran solution w/w), slowly be injected into microsyringe in the water of stirring, to obtaining even little suspension, decompression can be flung to organic solvent, and can be under heating condition further concentrated product.Product is used transmission electron microscope observing after the phosphotungstic acid negative staining, be nanoscale blister-shape structure, is cholesteryl phosphinylidyne gemcitabine self assembly transmission system.
Description of drawings:
Fig. 1 cholesteryl phosphinylidyne zidovudine self assembly transmission system transmission electron microscope photo
Claims (9)
1. cholesterol phosphononucleoside analogue is characterized in that its structure is:
Nu-L-Ch
Wherein Nu is the nucleoside analog group; L is a phosphoryl; Ch is the cholesterol group, and wherein nucleoside analog is selected from acyclovir, ganciclovir, famciclovir, penciclovir, valaciclovir, Abacavir, ribavirin, Sorivudine, vidarabine, zidovudine, lamivudine, didanosine, zalcitabine, stavudine, cidofovir, methotrexate, gemcitabine, capecitabine, fludarabine, doxifluridine, cytosine arabinoside, azacitidine.
2. cholesterol phosphononucleoside analogue as claimed in claim 1 connects with ester bond or amido link between Nu, L and the Ch.
3. cholesterol phosphononucleoside analogue as claimed in claim 1, wherein L except that with claim 1 in Nu become with Ch ester or the amide, remain hydroxyl and keep or continue acidylate and become ester or amide.
4. cholesterol phosphononucleoside analogue as claimed in claim 1, wherein the prototype molecule of Nu is the medicine with antiviral or antitumaous effect.
5. the transmission system of a high degree of dispersion is characterized in that it comprises the cholesterol phosphononucleoside analogue of claim 1, and is selected from liposome, non-ionic surface active agent vesicle, nanoparticle, microemulsion or self assembly transmission system.
6. the transmission system of high degree of dispersion as claimed in claim 5, wherein particle diameter is less than 1 micron.
7. the transmission system of high degree of dispersion as claimed in claim 5, the molecule molar ratio that the amount of the cholesterol phosphononucleoside analogue of claim 1 accounted for whole constituents during the particle of wherein self assembly transmission system was formed is between 50～100%, and all the other are additive.
8. the transmission system of high degree of dispersion as claimed in claim 7, additive wherein is selected from lipid molecular, surfactant.
9. the transmission system of high degree of dispersion as claimed in claim 5, the particle of wherein self assembly transmission system all is made up of the cholesterol phosphononucleoside analogue of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101122957A CN100462103C (en) | 2006-09-01 | 2006-09-01 | Cholesterol phosphononucleoside analogue |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006101122957A CN100462103C (en) | 2006-09-01 | 2006-09-01 | Cholesterol phosphononucleoside analogue |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1911449A CN1911449A (en) | 2007-02-14 |
| CN100462103C true CN100462103C (en) | 2009-02-18 |
Family
ID=37720609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006101122957A Expired - Fee Related CN100462103C (en) | 2006-09-01 | 2006-09-01 | Cholesterol phosphononucleoside analogue |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100462103C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244036B (en) * | 2008-03-28 | 2011-07-20 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | High dispersion does type containing cholesterol group phosphoryl nucleoside analogue |
| CN103864881B (en) * | 2012-03-31 | 2016-01-13 | 广西师范大学 | Oleanolic acid-uridine nucleoside conjugate and its preparation method and application |
| CN104208079B (en) * | 2014-08-01 | 2019-10-15 | 中国人民解放军军事科学院军事医学研究院 | Phospholipase A2-sensitive glycerol-skeleton antitumor prodrugs and their highly dispersed formulations |
| CN104945437B (en) * | 2015-05-19 | 2017-03-01 | 广州诺威生物技术有限公司 | A kind of miazines noval chemical compound |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013324A1 (en) * | 1992-12-16 | 1994-06-23 | Vestar, Inc. | Lipid prodrugs for oral administration |
| CN1634969A (en) * | 2004-11-11 | 2005-07-06 | 中国人民解放军军事医学科学院放射医学研究所 | Cholestrin derivative as nucleoside analog |
-
2006
- 2006-09-01 CN CNB2006101122957A patent/CN100462103C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994013324A1 (en) * | 1992-12-16 | 1994-06-23 | Vestar, Inc. | Lipid prodrugs for oral administration |
| CN1634969A (en) * | 2004-11-11 | 2005-07-06 | 中国人民解放军军事医学科学院放射医学研究所 | Cholestrin derivative as nucleoside analog |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1911449A (en) | 2007-02-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105288648B (en) | A kind of phosphatide cpd of hydrophilic medicament, its pharmaceutical composition and application | |
| CN115715190B (en) | Remdesivir and remdesivir analogs, solutions, and nanoparticle, liposome, and microparticle compositions for treating viral infections | |
| Ojewole et al. | Exploring the use of novel drug delivery systems for antiretroviral drugs | |
| CN101244036B (en) | High dispersion does type containing cholesterol group phosphoryl nucleoside analogue | |
| US10525013B2 (en) | Cationic materials and formulations for drug delivery | |
| US20220175953A1 (en) | Biomimetic anisotropic polymeric particles with naturally derived cell membranes for enhanced drug delivery | |
| JP5719594B2 (en) | Method for preparing nanoparticles based on functional amphiphilic molecules or macromolecules and use thereof | |
| KR20140026396A (en) | Targeted nanocarrier systems for delivery of actives across biological membranes | |
| JP7829485B2 (en) | Formulated and/or co-formulated liposome compositions containing Toll-like receptor ("TLR") agonist prodrugs useful in cancer treatment, and methods thereof. | |
| ES2556635T3 (en) | Multi-compartment formulations based on functional amphiphilic macromolecules or macromolecules | |
| CN104710477A (en) | Tenofovir cyclic phosphonate compound and pharmaceutically acceptable salt thereof, and preparation methods and applications thereof | |
| CN100462103C (en) | Cholesterol phosphononucleoside analogue | |
| Hillaireau et al. | Polymer-based nanoparticles for the delivery of nucleoside analogues | |
| CN104211742B (en) | Phosphoryl N-fatty acyl nucleoside analogs for viral hepatitis and liver cancer therapy | |
| CN117500494A (en) | Advantageous anti-HCV combination therapies | |
| JP2002528508A (en) | Combination therapy for the treatment of hepatitis B | |
| CN104208079B (en) | Phospholipase A2-sensitive glycerol-skeleton antitumor prodrugs and their highly dispersed formulations | |
| CN1314702C (en) | Cholestrin derivative as nucleoside analog | |
| CN101708338B (en) | Prodrug containing sterides structures and high dispersion preparation thereof | |
| CN101597312A (en) | Retinoyl cytarabine conjugate and its drug plastid, its preparation method and application | |
| CN1259331C (en) | Nucleoside analogue lipid derivative and salt thereof | |
| AU2022422071B2 (en) | Lipids for drug delivery, nanoparticles comprising same, and composition for drug delivery comprising nanoparticles | |
| Lalanne et al. | Strategies to increase the oral bioavailability of nucleoside analogs | |
| CN100525836C (en) | Double-head radical lipid prodrug | |
| US20230226031A1 (en) | Formulated and/or Co-Formulated Liposome Compositions Containing Immunogenic Cell Death (ICD) Inducing Prodrugs Useful In The Treatment of Cancer and Methods Thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090218 Termination date: 20170901 |