CN87105263A - 多羟基化且高度氟化的化合物及其制备方法和作为表面活性剂的应用 - Google Patents
多羟基化且高度氟化的化合物及其制备方法和作为表面活性剂的应用 Download PDFInfo
- Publication number
- CN87105263A CN87105263A CN198787105263A CN87105263A CN87105263A CN 87105263 A CN87105263 A CN 87105263A CN 198787105263 A CN198787105263 A CN 198787105263A CN 87105263 A CN87105263 A CN 87105263A CN 87105263 A CN87105263 A CN 87105263A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- group
- octyl group
- hexyl
- propionyl
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 239000013543 active substance Substances 0.000 title claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 37
- 239000000839 emulsion Substances 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 239000004530 micro-emulsion Substances 0.000 claims abstract 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 48
- 239000000811 xylitol Substances 0.000 claims description 35
- 229960002675 xylitol Drugs 0.000 claims description 35
- 229960001031 glucose Drugs 0.000 claims description 34
- -1 amino polyol Chemical class 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 25
- 150000002148 esters Chemical class 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 18
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 18
- 239000002994 raw material Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 13
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- HEBKCHPVOIAQTA-NGQZWQHPSA-N d-xylitol Chemical compound OC[C@H](O)C(O)[C@H](O)CO HEBKCHPVOIAQTA-NGQZWQHPSA-N 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 229960002920 sorbitol Drugs 0.000 claims description 10
- 239000004094 surface-active agent Substances 0.000 claims description 10
- 150000001263 acyl chlorides Chemical class 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 229920005862 polyol Polymers 0.000 claims description 9
- 150000003254 radicals Chemical class 0.000 claims description 9
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 150000001721 carbon Chemical group 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- ICJBPZBRDLONIF-UHFFFAOYSA-N hexane-1,1,1,2,2,3-hexol Chemical compound CCCC(O)C(O)(O)C(O)(O)O ICJBPZBRDLONIF-UHFFFAOYSA-N 0.000 claims description 8
- 239000005720 sucrose Substances 0.000 claims description 8
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000008103 glucose Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- BJHIKXHVCXFQLS-PQLUHFTBSA-N keto-D-tagatose Chemical compound OC[C@@H](O)[C@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-PQLUHFTBSA-N 0.000 claims description 5
- 239000000463 material Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 210000004556 brain Anatomy 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 210000000056 organ Anatomy 0.000 claims description 4
- 229950011087 perflunafene Drugs 0.000 claims description 4
- UWEYRJFJVCLAGH-IJWZVTFUSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)[C@@]2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C@@]21F UWEYRJFJVCLAGH-IJWZVTFUSA-N 0.000 claims description 4
- 229920001282 polysaccharide Polymers 0.000 claims description 4
- 239000005017 polysaccharide Substances 0.000 claims description 4
- 210000001519 tissue Anatomy 0.000 claims description 4
- 229960003487 xylose Drugs 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-CUHNMECISA-N D-Cellobiose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-CUHNMECISA-N 0.000 claims description 3
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 150000003999 cyclitols Chemical class 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 229930182470 glycoside Natural products 0.000 claims description 3
- 229960000367 inositol Drugs 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- SODQFLRLAOALCF-UHFFFAOYSA-N 1lambda3-bromacyclohexa-1,3,5-triene Chemical compound Br1=CC=CC=C1 SODQFLRLAOALCF-UHFFFAOYSA-N 0.000 claims description 2
- GZCGUPFRVQAUEE-UHFFFAOYSA-N 2,3,4,5,6-pentahydroxyhexanal Chemical compound OCC(O)C(O)C(O)C(O)C=O GZCGUPFRVQAUEE-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- GNWCYGORHVILIN-UHFFFAOYSA-N FC(C(C(F)=C(C1=C(C(F)=C2F)F)F)=NC1=C2F)(F)F Chemical compound FC(C(C(F)=C(C1=C(C(F)=C2F)F)F)=NC1=C2F)(F)F GNWCYGORHVILIN-UHFFFAOYSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 150000001320 aldopentoses Chemical class 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 230000001101 cardioplegic effect Effects 0.000 claims description 2
- 239000012159 carrier gas Substances 0.000 claims description 2
- 239000003218 coronary vasodilator agent Substances 0.000 claims description 2
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 2
- 210000002216 heart Anatomy 0.000 claims description 2
- 150000002581 ketopentoses Chemical class 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 229920001451 polypropylene glycol Polymers 0.000 claims description 2
- 229920001021 polysulfide Polymers 0.000 claims description 2
- 239000005077 polysulfide Substances 0.000 claims description 2
- 150000008117 polysulfides Polymers 0.000 claims description 2
- 230000010410 reperfusion Effects 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 2
- 229940098465 tincture Drugs 0.000 claims 2
- QQRLQZAYBUQDCR-UHFFFAOYSA-N 3,4-difluorohexane Chemical compound CCC(F)C(F)CC QQRLQZAYBUQDCR-UHFFFAOYSA-N 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 239000000084 colloidal system Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 208000028867 ischemia Diseases 0.000 claims 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims 1
- 150000003077 polyols Chemical class 0.000 claims 1
- 230000005855 radiation Effects 0.000 claims 1
- 210000000582 semen Anatomy 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 229960002160 maltose Drugs 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 6
- 235000010447 xylitol Nutrition 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 229920001983 poloxamer Polymers 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WQZGKKKJIJFFOK-SVZMEOIVSA-N (+)-Galactose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-SVZMEOIVSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229960002246 beta-d-glucopyranose Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 150000002243 furanoses Chemical class 0.000 description 3
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 3
- 150000004880 oxines Chemical class 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003214 pyranose derivatives Chemical class 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- DGGXBEHZGMUMOU-UHFFFAOYSA-N 8-fluorooctan-1-ol Chemical compound OCCCCCCCCF DGGXBEHZGMUMOU-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 101000983970 Conus catus Alpha-conotoxin CIB Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 2
- 239000004064 cosurfactant Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960002737 fructose Drugs 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- NDJKXXJCMXVBJW-UHFFFAOYSA-N heptadecane Chemical compound CCCCCCCCCCCCCCCCC NDJKXXJCMXVBJW-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- QZCJOXAIQXPLNS-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,4a,5,5,6,6,7,7,8,8,8a-octadecafluoronaphthalene 4-(2-aminoethyl)benzene-1,2-diol Chemical compound NCCc1ccc(O)c(O)c1.FC1(F)C(F)(F)C(F)(F)C2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C2(F)C1(F)F QZCJOXAIQXPLNS-UHFFFAOYSA-N 0.000 description 1
- MOSKUAXZYLAGNS-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydronaphthalene hydrate Chemical compound O.C1CCCC2CCCCC21 MOSKUAXZYLAGNS-UHFFFAOYSA-N 0.000 description 1
- RTPQXHZLCUUIJP-UHFFFAOYSA-N 1,2-dimethyladamantane Chemical compound C1C(C2)CC3CC1C(C)C2(C)C3 RTPQXHZLCUUIJP-UHFFFAOYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 101710134784 Agnoprotein Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 241001076960 Argon Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241000819038 Chichester Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 238000006994 Koenigs-Knorr glycosidation reaction Methods 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- RSJKGSCJYJTIGS-UHFFFAOYSA-N N-undecane Natural products CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 1
- 241001274216 Naso Species 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- MXZNUGFCDVAXLG-CHWSQXEVSA-N [(2S)-1-[(2R)-3-methyl-2-(pyridine-4-carbonylamino)butanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@@H](NC(=O)c1ccncc1)C(=O)N1CCC[C@@H]1B(O)O MXZNUGFCDVAXLG-CHWSQXEVSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001323 aldoses Chemical class 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
- WQZGKKKJIJFFOK-PQMKYFCFSA-N alpha-D-mannose Chemical compound OC[C@H]1O[C@H](O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-PQMKYFCFSA-N 0.000 description 1
- SRBFZHDQGSBBOR-LECHCGJUSA-N alpha-D-xylose Chemical compound O[C@@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-LECHCGJUSA-N 0.000 description 1
- SRBFZHDQGSBBOR-QMKXCQHVSA-N alpha-L-arabinopyranose Chemical compound O[C@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-QMKXCQHVSA-N 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 235000013876 argon Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- LKDRXBCSQODPBY-ARQDHWQXSA-N beta-D-fructopyranose Chemical compound OC[C@@]1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-ARQDHWQXSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000003633 blood substitute Substances 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229940077731 carbohydrate nutrients Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960003280 cupric chloride Drugs 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006115 defluorination reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002222 fluorine compounds Chemical class 0.000 description 1
- 229960003082 galactose Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005640 glucopyranosyl group Chemical group 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002584 ketoses Chemical class 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 150000002972 pentoses Chemical class 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0026—Blood substitute; Oxygen transporting formulations; Plasma extender
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
- C07C43/1787—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings and having unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
- C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
- C09K23/007—Organic compounds containing halogen
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
- C09K23/56—Glucosides; Mucilage; Saponins
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/004—Surface-active compounds containing F
Abstract
发明提供具有亲水基部分,高度氟化基部分和将这两部连在一起的功能连结基团的化合物以及所说化合物的制备方法。该化合物具有式X-Y-CH(OR1)-CH(OR2)CH(OR3)-Z所示的结构,式中符号的意义见说明书。该化合物具有表面活性剂和加强其它表面活性剂的作用,并具有良好的生物相容性。可用于医学中使用的各种溶液,乳液,微乳液,胶体组合物,特别是将组合物用作载氧剂。
Description
本发明涉及含有被认为是“高度氟化”成分的新型化合物,及其制备方法和作为用表面活性剂的应用,特别是在生物医药使用的组合物中作为氧载体,在可于血管内和其它方式给药的组合物中的应用。布拉恩(M.LE BLANC)和瑞斯(J.G.RIESS)已经在“有机氟化物的制备性质和工业应用”第三章中(“Preparation,Properties and Industrial Application of Organofluorine compounds”,chap 3,R.E.BANKS Ed.,Ellis Horwood Ltd.,chichester,1982)叙述过这样的组合物和它们的某些应用。在这些组合物中,能举出的有,本身就是碳氟化合物为基础且能用作血液和血浆的代用品的,治疗心脑、供血不足的配方,用于使瘤变对辐射治疗和化学药物剂治疗敏感的配方,cardiople-gic和reperfusion溶液,诊断剂,以及非血管内的载氧剂,例如用于保存离体器官和组织的配方,或者通过膨胀一下珠网膜的脑渗透制剂。
这些新化合物的应用是由于它们有表面活性作用和生物相溶性。
另外,当和其它本质上不同的表面活性剂,例如,类似于商品名“Pluronic”的环氧嵌段聚合物或卵磷酯,能产生协同作用时,它可用于组合表面活性剂。
多年以来,已经报导碳氟化合物的乳状液,其中的合成化合物起将氧传输到组织,将二氧化碳传输到肺的作用,其中的有些化合物同时还有其它功能,例如诊断对照剂的作用,营养和(或)治疗物质的载体的作用等。广义上讲,这些化合物属于碳氟化合物和全氟烷基化的衍生物这一类,由于它们不溶于血浆或水,因此必需用一种或几种表面活性剂维持它们为乳状液形式。尽管在这个领域已经有很大前进,但仍存在某些困难和问题没有解决,如瑞斯(J.G.Riess)在“人工器官(Artificial organs)”卷8(1),pp44~56(1984)中以及在期刊(“Lige Support Sustems”)卷2(4),pp273~276(1984)中所述。
事实上,现在所公知并使用的表面活性剂的性能对控制乳状液,特别是涉及到在血管内的持久性和稳定性,仍然不够理想。
另外,许多种表面活性剂有毒,显然不能用于生物药剂,甚至在本领域提倡使用的卵磷脂也不十分稳定,而且能产生有毒的分解或氧化产物。
本发明的基点在于发现了一族属于此处所论的新一类的特殊表面活性剂和组合表面活性剂,它们没有上述缺点,相反其性质适合上述应用。
本发明涉及具有多羟基化亲水部分,高度氟化部分和将上述两部连结在一起的功能连结基团的化合物,其中的亲水部分从多元醇或氨基多元醇衍生,所说的高度氟化部分由碳氟化合物基组成,其中至少有50%(特别60%)键联到碳骨架上的原子是氟,而键联到碳骨架上的其它原子可是氢,氯或溴,而且所说的高度氟化部分至少含有4(一般是5)个氟原子,本发明还涉及该化合物的内醚和缩酮。
举例来说,所说的功能连结基团可以是能通过醚,酯,酰胺或胺使亲水基和氟化部分相联的任何基团。
举例来说,亲水基团可从糖(如,戊醛糖,戊酮糖,己醛糖,己酮糖,6-脱氧己醛糖,6-脱氧己酮糖),至少含4个羟基的非糖多醇(如,戊五醇,1-脱氧己六醇,己六醇,环多醇),至少含3个羟基的氨基多醇(如,1-氨基-1-脱氧戊五醇,糖胺,2-氨基-2-脱氧戊五醇,1-氨基-1,6-二脱氧己六醇,1-氨基-1-脱氧己六醇)或者二多糖(如,麦芽糖,乳糖,蔗糖或纤维二糖)衍生。
举例来说,高度氟化的部分RF可以RF-W-基的形式引入,其中RF选自下述基团:
F(CF2)v- ≤v≤12
(CF3)2CF(CF3)w- 0≤w≤8
R1 F〔CF2CF(CF3)〕r 1≤r≤4
(R1 F是CF3,C2F5或(CF3)CF-)
(R2 F和RF3可相同,也可不同,它们选自CF3,C2F5,n-C3F7,或CF3CF2CF(CF3),或者R2 F和
R3 F共同代表-(CF2)4-或-(CF2)5-)
CF3CF2O(CF2CF2O)tCF2- 0≤t≤6
CF3(CF2)2O〔CF3(CF2)CFO〕uCF(CF3)- 0≤u≤6
而w选自下述基团:
-(CH2)n-
-(CH2)pCH=CH-(CH2)q-
-(CH2)m-CO-
-(CH2);OCH2CH(OH)CH2-
-(CH2)kOCH2CH(CH2OH)-
其中,当是最后三种情况时,RF键连到W基左端的碳原子上,
n可在1~12间改变,
m可在0~12间改变,
(p+q)可在1~12间改变,
j和k可在1~12间改变,
应当理解,W还可包含-(CH2CH2O)y-型聚氧乙烯,〔CH(CH3)CH2O〕y型聚氧丙烯,或-(CH2CH2S)y型聚硫乙烯段,或者这些链段的混合,其中1≤y≤12,而且在RF-的链中,部分氟原子可被H,Cl或Br原子取代,其比例是至少有50%键连到RF的碳原子骨架上的原子是氟,而且在RF链中至少有4个氟原子。
当RF-W-为酰基时,即W是-(CH2)m-CO-时,它或是用酯键(用亲水基的一个羟基形成)或是用酰胺键(用亲水基的氨基形成)与亲水部分相连。另外,RF-W-也可通过醚键或-N(R″)-氨的形式与亲水部分相连,其中R″可是H,C1-C18烷基,C2-C13不饱合烃基,也可是上述RF-W-基团。
优选的情况是,本发明的化合物含1或2个RF-W-基,至少60%连结到RF的碳原子骨架的原子是氟,而且RF至少含5个氟原子。
本发明还特别涉及RF是全氟化基团的上述化合物。
本发明的化合物包括用高度氟化的取代基取代式Ⅱ所示化合物所带氨基或羟基上的至少一个氢原而衍生的物质,
X-Y-CH(OH)-CH(OH)-CH(OH)-Z (Ⅱ)
其中X,Y和Z定义如下文。
因此,本发明具体涉及式Ⅰ所示的化合物,
X-Y-CH(OR1)-CH(OR2)CH(OR3)-Z (Ⅰ)
其中:X代表-CH=O,-CH2OR4,-CH2N(R5)R6或-CH(OR7)-
Y代表-CH(OR8)-,-CO-或-CH(NR5R6)-,
Z代表-H,-CH3,-CH2OR9或-CH(OR10)-,
应当理解:
当X为-CH=O时,Y代表-CH(OR8)-或-CH(NR5R6)-,
当X为-CH2N(R5)R6时,Y代表-CH(OR8)-,
当Z为-CH(OR10)-时,X代表-CH(OR7)-,而且二价基X和Z用共价键相联,
当Y为-CH(NR5R6)一时,X代表-CH=O或-CH2OR4,而且其中的R1~R10可以相同,也可不同,它们选自-H,C1-C18烷基,C2-C18不饱和烃基,脱氧-糖苷基,-(CH2CH2O)y-H,-〔CH(CH3)CH2O〕y-H,或-(CH2CH2S)-H,或所说基团的混合体,其中1≤y≤12,高度氟化基团如前文所述,
通式还有一个先决条件,即,至少R1-R10中的一个为具有高度氟化的取代基的基团,举例来说,该基团可是上述的RF-W-型基团,或者是其内醚或缩酮。
本发明还特别涉及式Ⅰ中连在多元醇或氨基多元醇的氧原子上的非氟化R基团为氢的化合物。
当然,当取代基R中的一个是脱氧-氧化物基时,基本亲水基部分为二多糖,且其每个糖部分都可带高度氟化的取代基。
在很多情况中,式Ⅰ的化合物可含有断开形的,变异或类似形的,或成环衍生结构,如在手册(“Handbook of Biochemistry and Molecular Biology,Lipids,Carbohydrates,Steroids”3rd.Ed.CRC Press,1975)中所述。因此,式Ⅰ决没有涉及到具体的立体化学的限制的意义。
举例来说,当X为CHO,Y为CHOH,式Ⅰ的化合物从醛式糖衍生而来,其结构可为变异形式的(ⅠA),(ⅠA1)和(ⅠA2):
(ⅠA)的结构为断开式,而(ⅠA1)和(ⅠA2)的结构为成环式(乙缩醛),即吡喃糖(ⅠA1)和呋喃糖(IA2)。
在第一种情况,如果在式(ⅠA)中,-Z为CH2OH,则式(ⅠA)代表各种己糖,如葡萄糖,半乳糖,甘露糖等,
Z为H,公式代表各种戊糖,如核糖,阿拉伯糖,木糖等,
Z为CH3,则公式代表各种脱氧-6-己糖,如鼠李糖,若藻糖等。
类似地,当式Ⅰ中X代表CH2OH时,也有可能的情况:
-当Y为C=O时,得到一族酮糖,其基本结构可为断开式(ⅠB),以及成(ⅠB1)和(ⅠB2)异构式,当Z为CH2OH时它是己酮糖,有结构:
其结构是异构糖,其中的果糖是典型实例,(ⅠB1)代表其吡喃糖型,(ⅠB2)代其呋喃糖型。这一族中的其它糖是从式(ⅠA)和/或(ⅠB)表示的那些结构衍生的化合物经缔合得到的,例如从乳糖,麦芽糖和纤维素二糖。
在Y为CH2OH的情况下,基本结构代表多元醇(ⅠC)
-当Z为CH2OH时,基本结构为己糖醇类,如,甘露糖醇,山梨糖醇等,
-当Z为H时,基本结构为戊糖醇类,如,木糖醇,
-当Z为XZ代表(CHOH)2时,基本结构为式(ⅠD)所示的环多醇:
其实例有环己六醇。
前述己糖醇(ⅠC)经脱水,可得单脱水物(ⅡA),然后再脱水得二脱水物(ⅡB),如下图所述:
-当X代表CH2NH2或CH2N(R5)R6,而且此Y代表CHOH时,基本结构表示氨基多元醇,其中的葡糖胺是个很好的实例,其中Z为CH2OH
不言而喻,前面的各式所表示所有异构体都在本发明的范围之内。
还应当注意到,当取代基R代表其它糖基,而且该糖基能从葡萄糖、半乳糖或果糖衍生出来并且含有呋喃糖环型的吡喃糖时,如含下述结构时:
那么,其中的取代基R1和Z1各自与式Ⅰ中的Z和相应的R具有同样的意义。在这种情况,基本的亲水结构部分是从二多糖衍生。
本发明的另一目的提供制备前述新化合物的方法。
此处所说方法的基本特征是基于下述事实,初始原料为前文所说的多元醇或氨基多醇,或者它们的衍生物,当然也包括它们的内醚或缩酮;对所说的原料,将其中的羟基或部分羟基保护起来,或者说至少将一个羟基用可离去基团取代;然后再用公知的方法使初始原料与高度氟化的衍生物反应,使多元醇或氨基多醇部分通过功能联结基团与高度氟化部分连结在一起;然后,在有保护基的情况下,按常规方法脱掉保护基。
举例来说,其中的高度氟化衍生物可是醇,胺,酐,混合酐或酰氯。
举例来说,可离去基团可是囟素(除氟以外,最好是溴)或活化的醇衍生物,如甲苯磺酸化基,甲磺酸化基或triflate基。
这样的带有可离去基团的衍生物会与高度氟化的衍生物(以醇或氨形式存在)反应形式酰胺的酯或胺键。
当高度氟化的基团是上述R-W-基型基团时,本发明的方法的基本特征是基于下述事实,如上述的亲水初始原料和下述物质反应:
(a)式RF-W-OH表示的醇,其中RF-W-不是酰基,
(b)式RF-W-NH(R″)表示的胺,其中RF-W-不是酰基,R″可为H,C1-C18烷基,C2-C18不饱和烃基或者RF-W-,而且其中的亲水初始原料中具有可离去基团,
(c)RF-W-O-CO-OALK表示的混合酐,其中ALK表示低级烷基或酰氯,RF为酰基,而且初始原料为氨基多元醇,
(d)RF-W-Cl表示的酰氯,其中RF-W-为酰基,其目的是为了:
-在(a)和(d)的情况,分别得到R-W-O-(亲水部分)型的酯或醚,
-在(b)和(c)的情况,分别得到R-W-N(R″)-(亲水部分型的胺或酰胺,
当有可离去基团存在时,再用已知脱除可离去基团的反应,去掉该基团,
对(c)的情况,当初始原料与酰氯反应时,为得到所需要的酰胺,必须将OH保护起来。
本发明特别涉及制备式Ⅰ所示的化合物,且其中有下述情况的方法:
-在初始原料类似于式Ⅰ所示的化合物,但其中没有高度氟化基团,而且有R5和R6存在且不为H,而且其中的不希望被取代的初始原料中的羟基又暂时保护起来的情况下,所说的初始原料与酰氯(当RF-W-是酰基时)或与RF-W-Z′所示的化合物(当RF-W-不是酰基时)反应(其中Z′是OH基或可去基团),以得到相应的式Ⅰ所示的酯或醚,然后再进行除保护基的反应;
-或者,当初始原料类似于式Ⅰ所示的化合物,但其中没有高度氟化基团,而且其中至少-OR1,-OR2,-OR3,-OR4,-OR7,-OR9,-OR10和-NR5R6中之一被可离去基团取代,而且-OH基被保护起来的情况下,所说的初始原料与RF-W-OH所示的醇或RF-W-NHR″所示的胺反应,其中RF-W-不是酰基且R″为H,C1-C18烷基,C2-C18不饱和烃基或RF-W-,以得到相应于式Ⅰ所示的化合物且其中的初始原料中的可离去集团分别被-O-W-RF或-N(R″)-W-RF取代,然后再进行脱除保护基的反应;
原料或是与通式Ⅰ化合物相似的化合物,它含有-NR5R6,但没有高氟化基团,其中R5和R6至少一个是H,该原料与混合的式RF-W-O-CO-OAlk(RF-W-是酰基,Alk是低级烷基)的酸酐反应,从而制得相应的含有-NR5(RFW),-NR6(RFW)或-N(RFW)2的通式Ⅰ的酰胺。
当通式Ⅰ的产物是含有RF-W-O-的醚时,W代表式为-(CH2)p-CH=CH-(CH)q-不饱和烷基,所提到的产物可按照已知方法通过还原双键转变为另一个式Ⅰ化合物。由此可获得W代表-(CH2)p+q+2-的相应化合物。
为了制备式Ⅰ化合物,其中W为-(CH2)p-CH=CH-(CH2)q-,且q=0,原料与醇HO-(CH2)p-CH=CH进行醚化。通过上述醇与囟代物RF-W-Hal(其中Hal是囟原子,但不是氟,如碘)的反应获得相应的-O-(CH2)p-CH=CH-RF类醚,如需要的话,该醚可还原成相应的-O-(CH2)p+2-RF类醚。
在常规方法中,原料中的-OH以酯的形式来保护。当原料含有离去基团时(如溴),在异头位即下一个碳原子中的羟基用成酯来保护(如Alk-CO-O-类酯,Alk是低级烷基),将醇RF-W-OH-与原料的反应按下面反应进行得到中间体为邻位酯的产物。
反应为:在无水介质和HgBr2存在下,通过重排,然后将邻位酯转变为相应的局部式为下式的-OWRF醚。
获得的含有暂时保护的羟基化合物可按照已知技术脱保护。
当原料含有离去基团,囟原子(氟除外,如溴)时,原料与醇RF-W-OH生成醚键的反应在银盐(如碳酸银)或氧化银存在下按已知的Koenigs-Knorr方法进行。在这种情况下,没醚化的羟基以醚的形式来保护。
进一步讲,当原料含有顺一邻乙二醇时,邻乙二醇中羟基可按已知方法暂时以丙酮化物保护起来。分离出保留有没保护上的羟基。然后醚化或用RFW-酯化。
当然,原料可以内部醚(酸酐)或式Ⅰ缩酮产物的形式使用。
本发明也涉及到上述定义的高氟化化合物的用途,它包括式Ⅰ化合物和其混合物作为表面活性剂或辅助表面活性剂。
上述表面活性剂尤其适用于上述介绍的生物药品制剂。
本发明也还涉及到下列形式的组合物,即非极性物和化合物(象油,烃化或没烃化)与至少含有一种亲水且氟化的上述定义化合物和任意其它表面活性剂结合在一起,并将它们溶于水或任何其它极性溶剂制成溶液,分散剂,凝胶,乳化剂和微乳化剂。
上述非极性物质,化合物或油可高氟化或全氟化。
在这些制剂中,上述分子量在400至700之间的高氟化或全氟化化合物或物质主要从下面的化合物中选择:
双(氟-烷基)-1,2-乙烷,更具体的是双(氟-丁基)-1,2-乙烷,1-氟-异丙基-2-氟-己基-乙烷和双(氟-己基)-1,2-乙烷,全氟萘烷,全氟-甲基萘烷,全氟-二甲基萘烷,全氟二甲基金刚烷,全氟三甲基二环(3,3,1)壬烷和它们的类似物,下式的醚:
(CF3)CFO(CF2CF2)OCF(CF3)2,
(CF3)2CFO(CF2CF2)3OCF(CF3)2,
(CHF3)2CFO(CF2CF2)3F,(CF3)2CFO(CF2CF2)F
F[CF(CF3)CF2O]2CHFCF3,(C6F13)O,
N(C3F7)3,N(C4F9)3,
全氟甲基喹啉定(quinolidines)和全氟异喹啉定,囟素衍生物C6F13Br,C8F17Br,C6F13CBr2CH2Br,
1-溴十七烷氟基-4-异丙基环己烷和类似物,应说明的是这些化合物可分别使用或合用。
更具体地讲,这些制剂作为气体载体(尤其是作为生命环境中的氧)用作人类和兽类的药物,尤其是作为血液代替品,对照剂,治疗大脑和心脏局部缺血,从而保护器官,组织,胚胎,精子,在心血管治疗和外科中作为可用介质,如作为心麻痹,reperfussion,或冠状血管整形术溶液,作为佐剂用于放射疗法或癌症治疗,用作药物载体。本发明的亲水且高氟化的表面活性剂化合物主要是下面的一个化合物:
2′-(氟-己基)-乙基-β-D-吡喃葡萄糖,
2′-(氟-己基)-乙基-α-D-吡喃葡萄糖苷,
2′-(氟-辛基)-乙基-β-D-吡喃葡萄糖苷,
2′-(氟-辛基)-乙基-α-D-吡喃葡萄糖苷,
2′-(氟-己基)-乙基-β-D-吡喃半乳糖苷,
2′-(氟-己基)-乙基-α-D-吡喃半乳糖苷,
3′-(氟-己基)-丙基-β-D-吡喃木糖苷,
3′-(氟-己基)-丙基-β-L-吡喃鼠李糖苷,
2′-(氟-丁基)-乙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或2′-(氟-丁基)-乙基-β-D-吡喃麦芽糖苷,
2′-(氟-己基)-乙基-4-O-(α-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或2′-(氟-己基)-乙基-β-D-吡喃麦芽糖苷,
2′-(氟-己基)-乙基-4-O-(α-D-吡喃葡萄糖基)-α-D-吡喃葡萄糖或2′-(氟-己基)-乙基-α-D-吡喃麦芽糖苷,
2′-(氟-辛基)-乙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷,或2′-(氟-辛基)-乙基-β-D-吡喃麦芽糖苷,
2′-(氟-辛基)-乙基-4-O-(α-D-吡喃葡萄糖基)-α-D-吡喃葡萄糖苷,或2′-(氟-辛基)-乙基-α-D-吡喃麦芽糖苷,
3′-(氟-丁基)-丙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或3′-(氟-丁基)-丙基-β-D-吡喃麦芽糖苷,
3′-(氟-己基)-丙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或3′-(氟-己基)-丙基-β-D-吡喃麦芽糖苷,
3′-(氟-辛基)-丙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或3′-(氟-辛基)-丙基-β-D-吡喃麦芽糖苷,
11′-(氟-丁基)-十-烷基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或11′-(F-辛基)-十一烷基-β-D-吡喃麦芽糖苷,
11′-(氟-己基)-十一烷基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或11′-(氟-己基)-十一烷基-β-D-吡喃麦芽糖苷,
11′-(氟-辛基)-十一烷基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或11′-(氟-辛基)-十一烷基-β-D-吡喃麦芽糖苷,
2′-(氟-己基)-乙基-4-O-(β-D-吡喃半乳糖基)-β-D-吡喃葡萄糖苷或2′-(氟-己基)-乙基-β-D-吡喃乳糖苷,
2′-(氟-辛基)-乙基-4-O-(β-D-吡喃半乳糖基)-β-D-吡喃葡萄糖苷或2′-(氟-辛基)-乙基-β-D-吡喃乳糖苷,
2′-(氟-辛基)-乙基-4-O-(β-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或2′-(氟-辛基)-乙基-β-D-吡喃纤维素二糖苷,
6-O-[3′-(氟-丁基)-2′-丙烯基]-D-半乳糖,
6-O-[3′-(氟-己基)-2′-丙烯基]-D-半乳糖,
6-O-[3′-(氟-辛基)-2′-丙烯基]-D-半乳糖,
3-O-[3′-(氟-丁基)-2′-丙烯基]-D-葡萄糖,
3-O-[3′-(氟-己基)-2′-丙烯基]-D-葡萄糖,
3-O-[3′-(氟-辛基)-2′-丙烯基]-D-葡萄糖,
6-O-[3′-(氟-丁基)-丙基]-D-半乳糖,
6-O-[3′-(氟-己基)-丙基]-D-半乳糖,
6-O-[3′-(氟-辛基)-丙基]-D-半乳糖,
3-O-[3′-(氟-丁基)-丙基]-D-葡萄糖,
3-O-[3′-(氟-己基)-丙基]-D-葡萄糖,
3-O-[3′-(氟-辛基)-丙基]-D-葡萄糖,
3-O-[3′-(氟-戊基)-丙酰基]-D-葡萄糖,
3-O-[3′-(氟-庚基)-丙酰基]-D-葡萄糖,
3-O-[3′-(氟-辛基)-丙酰基]-D-葡萄糖,
6-O-[3′-(氟-戊基)-丙酰基]-D-半乳糖,
6-O-[3′-(氟-庚基)-丙酰基]-D-半乳糖,
6-O-[3′-(氟-辛基)-丙酰基]-D-半乳糖,
3-O-[11′-(氟-己基)-十一烷酰基]-D-葡萄糖,
6-O-[11′-(氟-丁基)-十一烷酰基]-D-半乳糖,
6-O-[11′-(氟-己基)-十一烷酰基]-D-半乳糖,
6-O-[11′-(氟-辛基)-十一烷酰基]-D-半乳糖,
3-O-[3′-(氟-辛基)-丙酰基]-D-木糖,
6-O-[3′-(氟-辛基)-丙酰基]-D-果糖,
1-O-[3′-(氟-辛基)-丙酰基]-D-果糖,
β-D-呋喃果糖基-6-O-[3′-(氟-辛基)-丙酰基]-α-D-吡喃葡萄糖苷或6-O-[3′-(氟-辛基)-丙酰基]-蔗糖,
6-O-[3′-(氟-辛基)-丙酰基]-β-D-呋喃果糖基-6-O-[3′-(氟-辛基)-丙酰基]-α-D-吡喃葡萄糖或6-6′-[3′-(氟-辛基)-丙酰基]-蔗糖,
5-O-[3′-(氟-丁基)-2′-丙烯基]-D-木糖醇,
5-O-[3′-(氟-己基)-2′-丙烯基]-D-木糖醇,
5-O-[3′-(氟-辛基)-2′-丙烯基]-D-木糖醇,
5-O-[3′-(氟-丁基)-丙基]-木糖醇,
5-O-[3′-(氟-戊基)-丙酰基]-木糖醇,
5-O-[3′-(氟-庚基)-丙酰基]-木糖醇,
5-O-[3′-(氟-辛基)-丙酰基]-木糖醇,
5-O-[11′-(氟-己基)-十一烷酰基]-木糖醇,
3,4-二-O-[3′-(氟-辛基)-丙酰基]-D-甘露糖醇,
2-O-[3′-(氟-戊基)-丙酰基]-1,4∶3,6-双脱水-D-甘露糖
醇,
2-O-[3′-(氟-辛基)-丙酰基]-1,4∶3,6-双脱水-D-甘露糖
醇,
2-O-[3′-(氟-辛基)-丙酰基]-1,4∶3,6-双脱水-D-山梨糖醇,
5-O-[3′-(氟-辛基)-丙酰基]-1,4∶3,6-双脱水-D-山梨糖醇
6-O-[3′-(氟-辛基)-丙酰基]-1,4-D-脱水山梨糖醇,
6-O-[11′-(氟-辛基)-十一烷酰基]-1,4-D-脱水山梨糖醇,
[3′-(氟-戊基)-丙酰基]-N-甲基-D-葡糖酰胺,
[3′-(氟-庚基)-丙酰基]-N-甲基-D-葡糖酰胺,
[3′-(氟-辛基)-丙酰基]-N-甲基-D-葡糖酰胺,
2-脱氧-2-[3′-(氟-辛基)-丙酰氨基]-葡萄糖,
2-脱氧-2-[3′-(氟-辛基)-丙酰氨基]-D-glucitol,
3-O-[3′-(氟-辛基)-丙酰基]-肌醇。
下面的实施例介绍制取本发明化合物的多种多样方法,应说明的是所描述的化合物仅是获取的一部分,它们也可由除下面罗列的方法之外的其它方法制取,这些方法仅是各种制备方法的一部分。另外,在应用中,可用纯化合物或立体异构体的混和物。
实施例1:
2′(氟-己基)-乙基-D-吡喃葡萄糖,3α和3β
步骤1:邻酯的制备,1
将溶于20ml无水硝基乙烷的8.22g(20mmol)四-O-乙酰基-α-D-吡喃葡萄糖溴化物在25℃氩下用14.9g(41mmol)2-(氟-己基)-乙醇和4ml无水2,6-二甲基吡啶处理,反应后,加入2M AgNO溶液(16ml),然后再加入20ml水和50ml丙酮。用硅藻土滤出沉淀,然后用3×50ml氯仿洗涤。分离有机相,用水洗涤,然后用NaSO干燥。过滤后,减压蒸馏(0.02mmHg,70℃),先出去的是氯仿,后蒸出的是过量五氟烷基化醇。邻酯1(11g,79%)用己烷/二异丙醚混合物重结晶。
熔点=108-9℃一白色针晶|α|23 D=+21.7°(C1.2,CHCl3)
C实验值(经計算):38.32(38.05);H:3.09(3.34);F:(35.89)(35.57)。
1H(TMS):δ(异头H)=5.7ppm(J=5.3Hz);δ(CH3邻酯)=1.7ppm
13C(TMS):δ(四价C)=121ppm;δ(异头C)=97ppm;
δ(OCH2CH2)=56ppm;δ(OCH2CH2)=31ppm。
步骤2:葡萄糖2制备
溶于140ml无水硝基乙烷的9.86g(14.2mmol)邻酯1与干燥的HgBr2回流2小时。蒸除溶剂后,用氯仿提取的固体残渣通过硅胶层析提纯。产量:6.21g(63%)葡萄糖苷α和β(指2α和2β)的混合物。葡萄糖2β通过用乙烷/二异丙醚混合物重结晶分离,产量3.80g(39%)。
熔点=62-3℃|α|23 D=+73.7°(ClCHCl3)
C:38.12(38.05);H:3.30(3.34);
1H(TMS):δ(异头H)=5.0ppm(J=3.8Hz)
13C(TMS):δ(异头C)=96ppm;δ(OCH2CH2)=62ppm;δ(OCH2CH2)=31ppm。
步骤3.1:2′-(氟-己基)-乙基-β-D-吡喃葡萄糖3β的制备
3.34g(4.48mmol)2′-(氟-己基)-乙基-2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖2β与20mlMeOH/Et3N/H2O(2/1/1)混合物搅拌过夜。蒸除溶剂后,用硅胶层析,然后用ACOEt重结晶得到2.41g呈白片状的吡喃葡萄糖3β(95%)。
熔点=142℃|α|24 D=-14.4°(Cl Me OH)
C:32.07(31.95);H:2.76(2.87);F:47.52(46.93)
H(TMS):δ(异头H)=4.3ppm(J=8Hz);
δ(OCH2CH2)=63ppm;δ(OCH2CH2)=33ppm。
步骤3.2:2′-(氟-己基)-乙基-α-D-吡喃葡萄糖苷3α的制备
0.81g(1.2mmol)2′-(氟-己基)-乙基-2,3,4,6-四-O-乙酰基-α-D-吡喃葡萄糖2α与5.2mlMeOH/Et3N/H2O混合物(2/1/1)搅拌。蒸除溶剂后,用硅胶层析,得509mg(81%)3α。
|α|20 D=+65.6°(Cl Me OH)
C:32.11(31.95);H:2.75(2.87);F:46.9(46.93)
实施例2
2′-(氟-己基)-乙基-4-O-(α-D-吡喃葡萄糖基)-β(或α)-D-吡喃葡萄糖或2′(氟-己基-β-(或α)-D-麦芽糖),
在步骤2中,25g(25.5mmol)邻位酯4制成21g(84%)麦芽糖苷5α和5β。麦芽糖5β用MeOH重结晶分离。
C:41.74(41.56);H:4.00(4.00);F:24.75(25.13)
13C(TMS):δ(异头C-1)=100.5ppm;δ(异头碳C-1′)=96ppm。
重复实施例1的方法。在步骤1中,26g(37.2mmol)庚基-O-乙酰基-α-D-吡喃麦芽糖溴化物与22.7g(62.3mmol)2-(氟-己基)-乙醇反应,层析(己烷/ACOEt 1/1)后生成29g(79%)邻酯4。
熔点=101-2℃,|α|20 D=+61.7°(Cl.7CHCl3)
C:41.46(41.56);H:4.06(4.00);F:24.22(25.13)
1H(TMS):δ(异头H-1)=5.71ppm(J=4.8Hz);δ=(CH3邻位酯)=1.77ppm
13C(TMS):δ(四价C)=122ppm;δ(异头C-1)=97ppm;δ(异头C-1′)=95ppm。
在步骤3中,7.5g(7.6mmol)麦芽糖5β去乙酰化,层析后生成4.5g(86%)2′-(氟-己基)-乙基-4-O-(α吡喃葡萄糖基)-β-D-吡喃葡萄糖苷6β。
|α|26 D=+30.8°(C1.1H2O)
C:34.76(34.90);H:3.56(3.66);F:35.50(35.88)
1H(TMS):δ(异头H-1′)=5.18ppm(J=3.2Hz);δ(异头H-1)=4.35ppm(J=8Hz)
13C(TMS):δ(异头C-1)=104.6ppm;δ(异头C-1′)=103ppm。
将5α和5β吡喃麦芽糖做相似处理,通过HPLC(反相,洗脱剂MeOH/HO65/35)分离后得到6α2′-(氟-己基)-乙基-α-D-吡喃麦芽糖。
|α|D=+78.80°(C1.5H2O)
C:34.67(34.90);H:3.80(3.66);F:35.05(35.88)
13C(TMS):δ(异头C-1)=100.7ppm;δ(异头C-1′)=103.1ppm。
实施例3
9α和9β2′-(氟-辛基)-乙基-4-O-(α-D-吡喃葡萄糖基)-α-(β)-D-吡喃葡萄糖苷(或2′-(氟-辛基)-乙基-α(β)-D-吡喃麦芽糖苷)。
用实施例1同样方法,32g(45.8mmol)庚基-O-乙酰基-α-D-吡喃麦芽糖溴化物用35g(75.4mmol)2-氟-辛基-乙醇处理,用硅胶层析后(洗脱剂己烷/ACOEt 1/1)生成39g(79%)邻位酯7。
熔点=95-6℃,|α|23 D=+55.3°(C2CHCl3)
C:39.91(39.94);H:3.62(3.63);F:29.62(29.83)
1H(TMS):δ(CH邻位酯)=1.77ppm。
13C(TMS):δ(四价C)=121.7ppm;δ(异头C-1)=97ppm;δ(异头C-1′)=95.2ppm。
在步骤2中,回流36.5g(33.7mmol)邻酯7与溶于无水硝基乙烷的0.58g HgBr2混合物,重结晶粗反应产物后,得到13g(35%)8β2′-(氟-辛基)-乙基-庚基-乙酰基-β-D-吡喃麦芽糖。
熔点=154-5℃,|α|24 D=33.8°(C1.2 CHCl3)
C:39.86(39.94);H:3.59(3.63);F:29.42(29.83)
13C(TMS):δ(异头C-1)=100.5ppm;δ(异头碳C-1′)=95.7ppm。
在步骤3中,将6.07g(5.61mmol)8β2′-(氟-辛基)-乙基-庚基-O-乙酰基-β-D-吡喃麦芽糖脱乙酰化生成4.16g(94%)9β2′-(氟-辛基)-乙基-β-D-吡喃麦芽糖。
熔点=175℃|α|26 D=+30.4°(C1.1MeOH)
C:33.37(33.52);H:2.93(3.20);F:39.75(40.96)
13C(TMS):δ(异头C-1)=104.5ppm;δ(异头C-1′)=102.9ppm。
也可制备9α和9β的混合物。通过将41.3g(59mmol)庚基-O-乙酰基-α-D-吡喃麦芽糖溴化合物与59g 2-氟-辛基乙醇反应,经处理和用二异丙醚重结晶后得到56.5g(88%)邻位酯7。
在步骤2中,如上所述,化合物7被转换为脱去了乙酰基的化合物8(α+β),经过色谱层析后(CHCl/MeOH/HO 65/25/4)得到21.9克(化合物7的53%)的9α和9β的混合物。
实施例4
制备6-O-〔3′-(F-己基)-2′-丙烯基〕-D-半乳糖,11
步骤1
6-O-〔3′-(F-己基)-2′-丙烯基〕-1,2∶3,4-二-O-异亚丙基-α-D-吡喃半乳糖,10
在氩气氛下,将1.25克(4.13毫摩尔)6-O-(2′-丙烯基)-1,2∶3,4-二-O-异亚丙基-α-D-吡喃半乳糖,100毫克氯化铜,5毫升F-己基碘,1毫升乙醇胺和5毫升的叔-丁醇加热至110℃,保持24小时。冷却后,加入20毫升水,用乙醚提取反应混合物。将处理后所得粘稠液体用硅胶色谱进行层析(洗脱剂己烷/乙醚6/4),得到2.34克(91%)吡喃半乳糖苷10(顺式+反式)。
|α|21 D=-38.1°(c=1.4CHCl3)
C:41.02(40.79);H:3.75(3.75);F:40.33(39.94).
IR(薄膜):ν(C=C)=1685cm-1
1H(TMS):δ(异头H)=5.50ppm(J=5Hz);δ(CH=CH)=6.4-5.6ppm
19F(CCl3F):δ(CF2-C=C cis)=-108ppm;δ(CF2-C=C,反)=-112ppm;
顺/反比 15/85.
步骤2
制备6-O-〔3′-(F-己基)-2′-丙烯基〕-D-半乳糖,11
在室温下将1克(1.8毫摩尔)的中间体10与三氟乙酸和水的混合物(9/1 v/v)搅拌15分钟。浓缩溶液后,用硅胶色谱对其进行层析(洗脱剂ACOEt/CH3OH,4/1),得到0.82克(95%)的6-O-〔3′-(F-己基)-2′-丙烯基〕-D-半乳糖,11。
m.p.=109℃ |α|D=+13.2°(c1.4MeOH)
C:33.22(33.47);H:2.80(2.81);F:45.11(45.88).
IR(KBr):ν(OH)=3420cm-1;ν(C=C)=1685cm-1
19F(CCl3F):δ(CF2C=C cis)=-107ppm;δ(CF2C=C反)=-111ppm;
顺/反比15/85.
实施例5
制备6-O-〔3′-(F-辛基)-丙酰基〕-D-半乳糖,13
向在250毫升的含有7.21克(27.7毫摩尔)1,2∶3,4-二-O-异亚丙基-α-D-吡喃半乳糖和3毫升吡啶的无水CHCl3溶液内滴加入1.42克(27.8毫摩尔)的3′-(F-辛基)-丙酰氯。将该混合物搅拌过夜,蒸去氯仿,加入乙醚。洗涤有机相,直至中性,用Na2SO4干燥。过滤后蒸发,用己烷重结晶,得到18.6克(91%)的6-O-〔3′-(F-辛基)-丙酰基〕-1,2∶3,4-二-O-异亚丙基-α-吡喃半乳糖,12。
m.p.=90-90.5℃|α|22 D=-20.1°(c1.1 CHCl3)
C:37.88(37.62);H:3.03(3.16);F:45.19(43.98).
1H(TMS):δ(异头 H)=5.53ppm(J=5.6Hz).
在步骤2中,是在室温条件下将5.04克(6.87毫摩尔)的中间体12与25毫升CF3COOH和H2O(9/1v/v)的混合物一起搅拌30分钟。蒸发后用甲醇重结晶,得到4.44克(99%)的6-O-〔3′-(F-辛基)-丙酰基〕-D-半乳糖13。
m.p.=165-6℃|α|20 D=+36.2°(c 1.2DMSO)
C=31.56(31.21);H:2.23(2.31);F:48.28(49.36).
IR(KBr):ν(OH)=3430cm-1;ν(C=O)=1740cm-1.
实施例6
制备6-O-〔11′-(F-己基)-十一烷酰〕-D-半乳糖,15
如同实施例5步骤1,首先将11.47克(21毫摩尔)的11-(F-己基)-十一烷酰基氯与5.72克(22毫摩尔)的1,2∶3,4-二-O-异亚丙基-α-D-吡喃半乳糖反应,处理后,用硅胶色谱层析(己烷/ACOEt3/2)得到15.7克(96%)的中间体14。
m.p.=33℃|α|25 D=-18.4°(c 1.5CHCl3)
C:46.94(46.65);H:5.13(5.27);F:32.99(33.08).
1H(TMS):δ(异头 H)=5.53ppm(J=5Hz).
然后将3.45克(4.62毫摩尔)的化合物14用CF3CO2H/HO的混合物处理,用MeOH重结晶,得到2.1克(68%)的产物15。
m.p.=128℃|α|26 D=+35.0°(c 1.1DMSO)
C:41.62(44.53);H:4.69(5.52);F:37.09(30.18).
IR(KBr):ν(C=O)=1725cm-1
13C(TMS):δ(C=O)=174.1ppm.
实施例7
制备5-O-〔3′-(F-辛基)-2′-丙烯基〕-木糖醇,17
步骤1
制备5-O-〔3′-(F-辛基)-2′-丙烯基〕-1,2∶3,4-二-异亚丙基-木糖醇,16
在氯化铜和乙醇胺的存在下,将17.6克(64.7毫摩尔)的5-O-(2′-丙烯基)-1,2∶3,4-二-O-异亚丙基-木糖醇的叔-丁醇溶液与70.5毫升的F-辛基碘回流反应60小时。然后加入水,用乙醚提取混合物4次。将其洗涤至中性,用Na2SO4干燥,蒸发后得到39.5克(88%)的中间体16。
b.p.=117-8℃/0.005mm Hg
C:38.57(38.27);H:3.57(3.37);F:47.52(46.78).
IR(薄膜):ν(C=C)=1697cm-1
1H(TMS):δ(CH=CH)=5.68-6.57ppm
19F(CCl3F):δ(CF2CH=CH顺)=-108.4ppm;δ(CF2CH=CH反)=-112.3ppm;
顺/反比14/86.
步骤2
制备5-O-〔3′-(F-辛基)-2′-丙烯基〕-木糖醇,17
用CF3COOH/HO(9/1v/v)的混合物处理16.1克(23.3毫摩尔)的中间产物16 30分钟。蒸发后进行色谱层析,得到12.1克(85%)的5-O-〔3′-(F-辛基)-2′-丙烯基〕-木糖醇17。
C:31.03(31.49);H:2.47(2.48);F:51.53(52.92).
IR(KBr):ν(OH)=3364cm-1;ν(C=C)=1678cm-1
19F(CCl3F):δ(CF2CH=CH顺)=-108.4ppm;δ(CF2CH=CH反)=-112.3ppm
顺/反比6/94.
实施例8
制备5-O-〔3′-(F-辛基)-丙酰基〕-木糖醇,19
步骤1
制备5-O-〔3′-(F-辛基)-丙酰基〕-1,2∶3,4-二-O-异亚丙基-木糖醇,18
向溶解在50毫升CHCl3和1毫升吡啶的2.8克(12毫摩尔)无水1,2∶3,4-二-O-异亚丙基-木糖醇中滴加入在10毫升无水CHCl3中含有4.2克(8.2毫摩尔)3-(F-辛基)-丙酰氯的溶液。用硅胶色谱层析后(洗脱剂CHCl3/AcOEt 12/1),得到5.55克(95%)的化合物18。
C:37.39(37.40);H:3.39(3.28);F:46.07(45.72).
IR(film):ν(C=O)=1747cm-1
1H(TMS):δ(CH3)=1.42ppm;1.33ppm比率3/1;δ(C2H4)=2.55-2.70ppm
13C(TMS):δ(C=O)=171ppm
步骤2
制备5-O-〔3′-(F-辛基)-丙酰基〕-木糖醇,19
用15毫升的三氟乙酸一水混合物(9/1v/v)将21.42克(30毫摩尔)的化合物18处理30分钟。得到11.67克(62%)的5-O-〔3′-(F-辛基)-丙酰基〕木糖醇,19
m.p.=111-5℃
C:30.81(30.69);H:2.28(2.41);F:51.20(51.57).
IR(KBr):ν(OH)=3460,3300,3210cm-1;ν(C=O)=1730cm-1
1H(TMS):δ(OH)=4.74ppm;δ(CH2OCO)=4.27ppm(J=6.4Hz)
13C(TMS):δ(C=O)=173ppm.
实施例9
制备5-O-〔11′-(F-己基)十一烷酰基〕-木糖醇,21
以相似于实施例8步骤1的过程将6克(25.9毫摩尔)的1,2∶3,4-二-O-异亚丙基-木糖醇与11.6克(22.2毫摩尔)的11-(F-己基)-十一烷酰氯反应,经处理后得到13克(82%)的化合物20。
C:46.28(46.80);H:5.40(5.47);F:34.42(34.37).
IR(薄膜):ν(C=O)=1740cm-1
1H(TMS):δ(CH3)=1.37ppm;1.43ppm(12H)
13C(TMS):δ(C=O)=173.7ppm.
然后将11.8克(16.4毫摩尔)的化合物20与32毫升的三氟乙酸一水混合物(9/1)反应,得到10克(95%)-5-O-〔11′-(F-己基)-十一烷酰基)-木糖醇,21。
m.p.:89-90℃
C:41.57(41.38);H:5.05(4.89);F:38.38(38.68).
IR(KBr):ν(OH)=3450cm-1,3320cm-1;ν(C=O)=1730cm-1
13C(TMS):δ(C=O)=175.4ppm;δ(CH2CF2)=31.6ppm
实施例10
6-O-〔3′-(F-辛基)丙酰基〕-1,4-D-脱水山梨糖醇,22
将9.22克(18毫摩尔)3-(F-辛基)-丙酰氯的无水氯仿溶液滴加到5.89克(35.9毫摩尔)的1,4-脱水山梨糖醇的无水吡啶(22毫升)溶液内。在室温反应24小时后,过滤出沉淀,先用水,然后用CHCl3洗涤,用MeoH结晶得到6.85克(60%)的化合物22。
m.p.=134-6℃ |α|18 D=-2°(c 1 DMSO)
C:32.04(31.99);H:2.39(2.37);F:50.62(50.60)
IR:ν(OH)=3440cm-1;ν(C=O)=1720cm-1
13C(TMS):δ(C=O)=172ppm;δ(CH2OCO)=69.1ppm
ms(Cl:NH3):M+638(34%).
实施例11
制备〔3′-(F-辛基)-丙酰基〕-N-甲基-D-葡糖酰胺,23
在0℃,向在20毫升无水二乙醚中含有5.12克(10.4毫摩尔)3-(F-辛基)-丙酸的溶液内首先加入1毫升(13.2毫摩尔)无水吡啶,然后再加入1.36克(12.5毫摩尔)的氯甲酸乙酯。过滤后在50℃将活化了的全氟烷基化酸加入到2.03克(10.4毫摩尔)N-甲基-D-葡糖胺的无水MeOH(25毫升)溶液中。在50℃反应1小时30分钟,过夜后在0℃过夜后将混合物过滤。用MeOH重结晶沉淀物;得到3.23克(60%)的化合物23。用硅胶色谱进行层析后(洗脱剂CHCl3/MeOH 1/1)再用甲醇或二恶烷重结晶,得到2.23克(32%)的〔3′-(F-辛基)-丙酰基〕-N-甲基-D-葡糖酰胺23。
m.p.=79-81℃|α|20 D=-8.0°(c 1.2DMSO)
C:32.17(32.30);H:3.09(3.01);F:48.18(48.25).
IR(KBr):ν(OH)=3360cm-1;ν(C=O)=1630cm-1
1H(TMS):δ(NCH3)=2.95ppm
更具体地讲,本发明所包括的下述化合物已被制备出:
2′-(F-辛基)-乙基-β-D-吡喃葡糖苷;
2′-(F-辛基)-乙基-α-D-吡喃葡糖苷;
2′-(F-己基)-乙基-β-D-吡喃半乳糖苷;
2′-(F-己基)-乙基-α-D-吡喃半乳糖苷;
3′-(F-己基)-丙基-β-D-吡喃木糖苷;
3′-(F-己基)-丙基-β-L-吡喃鼠李糖苷;
2′-(F-丁基)-乙基-4-O-(α-吡喃葡糖基)-β-D-吡喃葡糖苷或2′-(F-丁基)-乙基-β-D-吡喃麦芽糖苷;
3′-(F-丁基)-丙基-4-O-(α-D-吡喃葡糖基)-β-D-吡喃葡糖苷或3′-(F-丁基)-丙基-β-D-吡喃麦芽糖苷;
3′-(F-己基)-丙基-4-O-(α-D-吡喃葡糖基)-β-D-吡喃葡糖苷或3′-(F-己基)-丙基-β-D-吡喃麦芽糖苷;
3′-(F-辛基)-丙基-4-O-(α-D-吡喃葡糖基)-β-D-吡喃葡糖苷或3′-(F-辛基)-丙基-β-D-吡喃麦芽糖苷;
11′-(F-丁基)-十一烷基-4-O-(α-D-吡喃葡糖基)-β-D-吡喃葡糖苷或11′-(F-丁基)-十一烷基-β-D-吡喃麦芽糖苷;
11′-(F-己基)-十一烷基-4-O-(α-D-吡喃葡糖基)-β-D-吡喃葡糖苷或11′-(F-己基)-十一烷基-β-D-吡喃麦芽糖苷;
11′-(F-辛基)-十一烷基-4-O-(α-D-吡喃葡糖基)-β-D-吡喃葡糖苷或11′-(F-辛基)-十一烷基-β-D-吡喃麦芽糖苷;
2′-(-F-己基)-乙基-4-O-(β-D-吡喃半乳糖基)-β-D-吡喃葡糖苷或2′-(F-己基)-乙基-β-D-吡喃乳糖苷;
2′-(-F-辛基)-乙基-4-O-(β-D-吡喃半乳糖基)-β-D-吡喃葡糖苷或2′-(F-辛基)-乙基-β-D-吡喃乳糖苷;
2′-(-F-辛基)-乙基-4-O-(β-D-吡喃葡糖基)-β-D-吡喃葡糖苷或2′-(F-辛基)-乙基-β-D-吡喃纤维素二糖苷;
6-O-〔3′-(F-丁基)-2′-丙烯基〕-D-半乳糖;
6-O-〔3′-(F-辛基)-2′-丙烯基〕-D-半乳糖;
6-O-〔3′-(F-丁基)丙基)-D-半乳糖;
6-O-〔3′-(F-己基)丙基)-D-半乳糖;
6-O-〔3′-(F-辛基)丙基)-D-半乳糖;
3-O-〔3′-(F-丁基)-2′-丙烯基〕-D-葡萄糖;
3-O-〔3′-(F-己基)-2′-丙烯基〕-D-葡萄糖;
3-O-〔3′-(F-辛基)-2′-丙烯基〕-D-葡萄糖;
3-O-〔3′-(F-丁基)丙基〕-D-葡萄糖;
3-O-〔3′-(F-己基)丙基〕-D-葡萄糖;
3-O-〔3′-(F-辛基)丙基〕-D-葡萄糖;
3-O-〔3′-(F-戊基)-丙酰基〕-D-葡萄糖;
3-O-〔3′-(F-庚基)-丙酰基〕-D-葡萄糖;
3-O-〔3′-(F-辛基)-丙酰基〕-D-葡萄糖;
3-O-〔11′-(F-己基)-十一烷酰基〕-D-葡萄糖;
6-O-〔3′-(F-戊基)-丙酰基〕-D-半乳糖;
6-O-〔11′-(F-庚基)-丙酰基〕-D-半乳糖;
6-O-〔11′-(F-丁基)-十一烷酰基〕-D-半乳糖;
6-O-〔11′-(F-辛基)-十一烷酰基〕-D-半乳糖;
3-O-〔3′-(F-辛基)-丙酰基〕-D-木糖;
6-O-〔3′-(F-辛基)-丙酰基〕-D-果糖;
1-O-〔3′-(F-辛基)-丙酰基〕-D-果糖;
β-D-呋喃果糖基-6-O-〔3′-(F-辛基)-丙酰基-α-D-吡喃葡糖苷或6-O-〔3′-(F-辛基)-丙酰基〕-蔗糖;
6-O-〔3′-(F-辛基)-丙酰基〕-β-D-吡喃果糖基-
-6-O-〔3′-(F-辛基)-丙酰基〕-α-D-吡喃葡糖苷或6,6′-二-〔3′-(F-辛基)-丙酰基〕-蔗糖;
5-O-〔3′-(F-丁基)-2′-丙烯基〕-木糖醇;
5-O-〔3′-(F-己基)-2′-丙烯基〕-木糖醇;
5-O-〔3′-(F-丁基)-2′-丙基〕-木糖醇;
5-O-〔3′-(F-戊基)-2′-丙烯基〕-木糖醇;
5-O-〔3′-(F-庚基)-2′-丙烯基〕-木糖醇;
5-O-〔11′-(F-己基)-十一烯酰基〕-木糖醇;
3,4-二-O-〔3′-(F-辛基)-丙酰基〕-D-甘露糖醇;
2-O-〔3′-(F-戊基)-丙酰基)-1,4∶3,6-二脱水-D-甘露糖醇;
2-O-〔3′-(F-辛基)-丙酰基)-1,4∶3,6-二脱水-D-甘露糖醇;
2-O-〔3′-(F-辛基)-丙酰基)-1,4∶3,6-二脱水-D-山梨糖醇;
5-O-〔3′-(F-辛基)-丙酰基)-1,4∶3,6-二脱水-D-山梨糖醇;
6-O-〔11′-(F-辛基)-十一烷酰基)-1,4-D-脱水山梨糖醇;
〔3′-(F-戊基)-丙酰基〕-N-甲基-D-葡糖酰胺;
〔3′-(F-庚基)-丙酰胺基〕-N-甲基-D-葡糖酰胺;
2-脱氧-2-〔3′-(F′-辛基)-丙酰胺基〕-D-葡萄糖;
2-脱氧-2-〔3′-(F′-辛基)-丙酰胺基〕-D-葡糖醇;
3-O-〔3′-(F-辛基)-丙酰基〕-肌醇。
本发明的化合物具有很强的表面活性,可通过将化合物加到水中,通过其降低表面张力来证明。下表给出了在20℃测定的表面张力,以毫牛顿·米(m Nm-1)表示。
化合物 水中浓度 γs(m Nm-1) γi(m Nm-1)
(±0.3) (±0.3)
2′-(F-己基)-乙基-D- 0.1% 22.5 4.7
吡喃麦芽糖苷,6
2′-(F-辛基)-乙基-D- 0.1% 22.3 2.6
吡喃麦芽糖苷,9
5-O-〔3′-(F-丁基)-2′ 0.1% 19.7 2.4
-丙烯基〕木糖醇
5-O-〔3′-(F-己基)-2′ 0.01% 17.8 1.0
-丙烯基〕木糖醇
6-O-〔3′-(F-丁基)-2′ 0.05% 20.2 1.4
-丙烯基〕-D-半乳糖
6-O-〔3′-(F-己基)-2′- 0.01% 20.9 1.4
丙烯基〕-D-半乳糖,11
更具体地讲,通过水和全氟萘烷界面张力(γi)的明显减少(56m Nm-1,无表面活性剂)测定了这些化合物在水和氟化合物界面之间的性能,上表已经示出。
本发明化合物的共表面活性剂特征是通过这些化合物使表面张力(γs)的明显降低来证明的,将其加到每升含有1克pluronic F-68(一种商业表面活性剂,用于制备生物医学用途的碳氟化合物的乳化剂,如Fluosol-DA或Oxypherol)的水溶液中,则γ值从γs=47±0.3m Nm-1变化到下表所示的数据:
化合物 lg/l pluronic γs(m Nm-1) γi(m Nm-1)
F=68 分散在 ±0.3 ±0.3
水中(%指
pluronic
F-68)
3-O[3′-(F-辛基)-丙酰 10mg/l 20.2 4.1
基]-D-葡萄糖 (1%)
5-O[3′-(F-辛基)-2-丙 10mg/l 19.5 2.8
酰基)-木糖醇,17 (1%)
5-O[3′-(F-辛基)-丙酰 200mg/l 23.7 4.3
基)-木糖醇,19 (20%)
更具体地讲,这些化合物在水和碳氟化合物之间的界面性能是通过分散这些合物在每升含有1克的pulronic-F-68的水溶液和全氟萘烷中,而界面张力明显降低来证明的。单独使用Fluronic F-68,界面张力从γi=31m Nm-1降至上表表示的数值。
与新的表面活性剂联用可获得乳化稳定效果,例如。
用2%(w/v)的pulronic-F-68和1%的(w/v)5-O[3′-(F-辛基)-2-丙酰基)-木糖醇,17,(作为表面活性剂)来制备20%(w/v)的F-萘乳化液在50℃维持30天后,其颗粒大小只增加了6倍,比单独使用3%pulronic-F-68作为表面活性剂的参比乳化液小。值得注意的是颗粒在含有氟化表面活性剂的乳化液中,在50℃维持30天其大小仍比对照乳化液在4℃维持相同的时间要小。
已证明本发明的化合物具有生物相容性。具体地讲,这是通过这些化合物的水溶液和这些化合物分散在pulronic-F-18水溶液中来证明的。例如,0.1g/l的2′-(F′-己基-乙基-D-吡喃葡糖苷3溶液,0.1g/l的[3′-(F-辛基)-丙酰基)-N-甲基-葡糖酰胺(23)溶液,0.1g/l的6-O[3′-(F-丁基)-2′-丙烯基)-D-半乳糖溶液,或1g的2′-(F′-辛基)-乙基-D-吡喃麦芽糖苷9分散在1g/l的pulronic-F-18的水溶液中,所有这些溶液和分散液均含有9%的Nacl,它们都没有干扰Namalva菌株的淋巴细胞的细胞培养基的生长和增加。
同样,本发明化合物的生物混溶性也可被如下事实所证实,例如,100g/l的2′-(F′-辛基)-乙基-D-吡喃麦芽糖苷6的水溶液,或1g/l的6-O-[3′(F-丁基)-2′-丙烯基]-D-半乳糖水溶液或1g/l的2′-(F′-辛基)-乙基-D-吡喃麦芽糖苷9分散在1g/l的Fluronic F-68水溶液中,或16g/l的6-O-[3′(F-己基)-2′-丙烯基]-D-半乳糖分散在1g/l的Fluronic F-68水溶液内,20g/l的5-O[3′-(F-辛基)-2′-丙烯基]-木糖醇17分散在10g/l的Fluronic F-68的水溶液中,都含有9%的Nacl,它们都没有引起人类红血球的溶血。
以相同的方式,本发明化合物的相容性为如下事实所证明,例如,将含有9%Nacl,10g/l的2′(F-己基)-乙基-D-吡喃麦芽糖苷6的水溶液或分散在10g/l的-pulronic F-18水溶液(含有9%Nacl)中的20g/l的5-O[3′-(F-辛基)-2-丙酰基)-木糖醇17溶液,或20g/l的6-O[3′-(F-丁基)-2′-丙酰基)-D-半乳糖或20g/l的6-O[3′-(F-己基)-2′-丙酰基)-D-半乳糖11或20g/l的5-O[3′-(F-丁基)-2-丙酰基)-木糖醇,以500μl的量注射进10只20-25g重的小鼠体内,没有引起死亡也没有出现对动物正常生长的干扰,观察期为35天。
上述化合物的生物相容性更被如下事实所证明,即分散10g/l的5-O-[3′-(F-辛基)-2-丙酰基]-木糖醇,17在20g/l的pluronic F-18溶液内以此来制备含有20%(重量)碳氟化合物的乳化剂母液,将该母液稀释得到10%(重量)的双-(F-丁基)-乙烯乳化液,将其注入大鼠体内可直至血球溶计的计量值达到15%(容积)。
组合物实施例
制备具有如下组份的乳化液:
成份 比例(w/v)
实施例7的化合物 1%
pluronic F-68 2%
双-(F-丁基)-乙烯 20%
水 q.s.p 100%
将表面活性剂加入水中。然后在搅拌条件下将双-(F-丁基)乙烯加入均质器中。所得乳化液可作为氧的载体。
在上述组合物中,可用实施例3的化合物取代实施例7的化合物,并可用双-(F-己基)-1,2-乙烯取代双-(F-丁基)-乙烯。
Claims (14)
1、具有多羟基化的亲水部分、高度氟化的部分和将上述两部分连结在一起的功能连结基团的化合物以及它的内醚和缩酮,其中的亲水部分由多元醇或氨基多元醇衍生,其中的高度氟化部分由碳氟化合物基团组成,而且在该基团中至少有50%的键连到碳原子骨架上的原子是氟原子,键连到碳原子骨架上的其它原子可是氢、氯或溴原子,所说的高度氟化部分至少含有4个氟原子。
2、根据权利要求1所述的化合物,其中的功能连结基团是通过醚、酯、酰胺或胺基将亲水基部分与氟化部相连。
3、根据权利要求1所述的化合物,其中所说的亲水基部分是从糖、(如,戊醛糖,戊酮糖,己醛糖、己酮糖,6-脱氧己醛糖,6-脱氧己酮糖)、至少含有4个羟基的非糖多元醇、(如,戊五醇,1-脱氧己六醇,己六醇,环多醇)至少含有三个羟基的氨基多元醇(如,1-氨基-1-脱氧戊五醇,糖胺,2-氨基-2-脱氧戊五醇,1-氨基-1,6-二脱氧己六醇,1-氨基-1-脱氧己六醇)或者二多糖(如,麦芽糖,乳糖,蔗糖或纤维素二糖)衍生出来的。
4、根据权利要求1所述的化合物,其中高度氟化部分是以RF-W-基团的形式出现的,而RF-选自下述基团:
F(CF2)v- 2≤v≤12
(CF3)2CF(CF2)w- 0≤w≤8
R1 F[CF2CF(CF3)]r- 1≤r≤4
其中R1 F为CF3-,C2F5-或(CF3)2CF-,
1≤s≤6
其中R2 F和R3 F可相同,也可不同,选自CF3-,C2F5-,n-C3F7或CF3CF2CF(CF3)-,或者R2 F和R3 F共同代表-(CF2)4-或-(CF2)5-,
CF3CF2O(CF2CF2O)tCF2- 0≤t≤6
CF3(CF2)2O[CF(CF3)CF2O]uCF(CF3)- 0≤u≤6
而其中w选自下述基团:
-(CH2)n-
-(CH2)pCH=CH-(CH2)q-
-(CH2)m-CO-
-(CH2)jOCH2CH(OH)CH2-
-(CH)kOCH2CH(CH2OH)-
其中,在后三种情况RF键连到W基左端的碳原子上,而且,
n可在1~12间改变,
m可在0~12间改变,
p+q可在0~12间改变,
j和k可在1~12间改变,
而且,应当理解:
基团W可还含有-(CH2CH2O)y-型聚氧乙烯段,-CH(CH3)CH2O型聚氧丙烯段或者-(CH2CH2S)y-型聚硫乙烯段,或上述各种型式链段的组合,其中1≤y≤12,
而且在RF-链中,部分氟原子可被H,Cl,或Br取代,其比例要使键连到RF的碳原子骨架上的原子中至少有50%是氟原子,该链中至少有4个氟原子。
5、根据权利要求1所述的化合物,具有通式Ⅰ所示的结构:
X-Y-CH(OR1)-CH(OR2)CH(OR3)-Z (1)
其中,X代表-CH=O,-CH2OR4,-CH2N(R5)R6或-CH(OR7)-,
Y代表-CH(OR8)-,-CO-,或CH(NR5R6)-,
Z代表-H,-CH3,-CH2OR9或者-CH(OR10)-,而且应当理解为:
-当X为-CH=O时,Y代表-CH(OR8)或-CH(NR5R6)-,
-当X为-CH2N(R5)R6时,Y代表-CH(OR8)-,
-当Z为-CH2(OR10)-时,X代表-CH(OR7)-,二价基团X和Y以共价键相连,
-当Y为-CH(NR5R6)-时,X代表-CH=O或-CH2OR4,
而且基团R1~R10即可相同,也可不同,它们选自-H C1~C18烷基,C2~C18不饱和烃基,脱氧-糖苷,-(CH2CH2O)y-H,-[CH(CH3)CH2O]y-H或(CH2CH2S)y,或者所说基团的混合,其中1≤y≤12,而高度氟化基团如前文所述,
并要满足下述先决条件:
-在R1~R10中至少有一个代表具有高度氟化的取代基的基团,或者其内醚及缩酮。
6、根据权利要求1的化合物,它选自下述具体化合物:
2′-(氟-己基)-乙基-β-D-吡喃葡萄糖苷,
2′-(氟-己基)-乙基-α-D-吡喃葡萄糖苷,
2′-(氟-辛基)-乙基-β-D-吡喃葡萄糖苷,
2′-(氟-辛基)-乙基-α-D-吡喃葡萄糖苷,
2′-(氟-己基)-乙基-β-D-吡喃半乳糖苷,
2′-(氟-己基)-乙基-α-D-吡喃半乳糖苷,
3′-(氟-己基)-丙基-β-D-吡喃木糖苷,
3′-(氟-己基)-丙基-β-L-吡喃鼠李糖苷,
2′-(氟-丁基)-乙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或2′-(氟-丁基)-乙基-β-D-吡喃麦芽糖苷,
2′-(氟-己基)-乙基-4-O-(α-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或2′-(氟-己基)-乙基-β-D-吡喃麦芽糖苷,
2′-(氟-己基)-乙基-4-O-(α-D-吡喃葡萄糖基)-α-D-吡喃葡萄糖苷或2′-(氟-己基)-乙基-α-D-吡喃麦芽糖苷,
2′-(氟-辛基)-乙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷,或2′-(氟-辛基)-乙基-β-D-吡喃麦芽糖苷,
2′-(氟-辛基)-乙基-4-O-(α-D-吡喃葡萄糖基)-α-D-吡喃葡萄糖苷,或2′-(氟-辛基)-乙基-α-D-吡喃麦芽糖苷,
3′-(氟-丁基)-丙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或3′-(氟-丁基)-丙基-β-D-吡喃麦芽糖苷,
3′-(氟-己基)-丙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或3′-(氟-己基)-丙基-β-D-吡喃麦芽糖苷,
3′-(氟-辛基)-丙基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或3′-(氟-辛基)-丙基-β-D-吡喃麦芽糖苷,
11′-(氟-丁基)-十-烷基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或11′-(F-辛基)-十一烷基-β-D-吡喃麦芽糖苷,
11′-(氟-己基)-十一烷基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或11′-(氟-己基)-十一烷基-β-D-吡喃麦芽糖苷,
11′-(氟-辛基)-十一烷基-4-O-(α-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或11′-(氟-辛基)-十一烷基-β-D-吡喃麦芽糖苷,
2′-(氟-己基)-乙基-4-O-(β-D-吡喃半乳糖基)-β-D-吡喃葡萄糖苷或2′-(氟-己基)-乙基-β-D-吡喃乳糖苷,
2′-(氟-辛基)-乙基-4-O-(β-D-吡喃半乳糖基)-β-D-吡喃葡萄糖苷或2′-(氟-辛基)-乙基-β-D-吡喃乳糖苷,
2′-(氟-辛基)-乙基-4-O-(β-D-吡喃葡萄糖基)-β-D-吡喃葡萄糖苷或2′-(氟-辛基)-乙基-β-D-吡喃纤维素二糖苷,
6-O-[3′-(氟-丁基)-2′-丙烯基]-D-半乳糖,
6-O-[3′-(氟-己基)-2′-丙烯基]-D-半乳糖,
6-O-[3′-(氟-辛基)-2′-丙烯基]-D-半乳糖,
3-O-[3′-(氟-丁基)-2′-丙烯基]-D-葡萄糖,
3-O-[3′-(氟-己基)-2′-丙烯基]-D-葡萄糖,
3-O-[3′-(氟-辛基)-2′-丙烯基]-D-葡萄糖,
6-O-[3′-(氟-丁基)-丙基]-D-半乳糖,
6-O-[3′-(氟-己基)-丙基]-D-半乳糖,
6-O-[3′-(氟-辛基)-丙基]-D-半乳糖,
3-O-[3′-(氟-丁基)-丙基]-D-葡萄糖,
3-O-[3′-(氟-己基)-丙基]-D-葡萄糖,
3-O-[3′-(氟-辛基)-丙基]-D-葡萄糖,
3-O-[3′-(氟-戊基)-丙酰基]-D-葡萄糖,
3-O-[3′-(氟-庚基)-丙酰基]-D-葡萄糖,
3-O-[3′-(氟-辛基)-丙酰基]-D-葡萄糖,
6-O-[3′-(氟-戊基)-丙酰基]-D-半乳糖,
6-O-[3′-(氟-庚基)-丙酰基]-D-半乳糖,
6-O-[3′-(氟-辛基)-丙酰基]-D-半乳糖,
3-O-[11′-(氟-己基)-十一烷酰基]-D-葡萄糖,
6-O-[11′-(氟-丁基)-十一烷酰基]-D-半乳糖,
6-O-[11′-(氟-己基)-十一烷酰基]-D-半乳糖,
6-O-[11′-(氟-辛基)-十一烷酰基]-D-半乳糖,
3-O-[3′-(氟-辛基)-丙酰基]-D-木糖,
6-O-[3′-(氟-辛基)-丙酰基]-D-果糖,
1-O-[3′-(氟-辛基)-丙酰基]-D-果糖,
β-D-呋喃果糖基-6-O-[3′-(氟-辛基)-丙酰基]-α-D-吡喃葡萄糖苷或6-O-[3′-(氟-辛基)-丙酰基]-蔗糖,
6-O-[3′-(氟-辛基)-丙酰基]-β-D-呋喃果糖基-6-O-[3′-(氟-辛基)-丙酰基]-α-D-吡喃葡萄糖苷或6-6′-[3′-(氟-辛基)-丙酰基]-蔗糖,
5-O-[3′-(氟-丁基)-丙烯基]-D-木糖醇,
5-O-[3′-(氟-己基)-2′-丙烯基]-D-木糖醇,
5-O-[3′-(氟-辛基)-2′-丙烯基]-D-木糖醇,
5-O-[3′-(氟-丁基)-丙基]-木糖醇,
5-O-[3′-(氟-戊基)-丙酰基]-木糖醇,
5-O-[3′-(氟-庚基)-丙酰基]-木糖醇,
5-O-[3′-(氟-辛基)-丙酰基]-木糖醇,
5-O-[11′-(氟-己基)-十一烷酰基]-木糖醇,
3,4-二-O-[3′-(氟-辛基)-丙酰基]-D-甘露糖醇,
2-O-[3′-(氟-戊基)-丙酰基]-1,4∶3,6-双脱水-D-甘露糖醇,
2-O-[3′-(氟-辛基)-丙酰基]-1,4∶3,6-双脱水-D-甘露糖醇,
2-O-[3′-(氟-辛基)-丙酰基]-1,4∶3,6-双脱水-D-山梨糖醇,
5-O-[3′-(氟-辛基)-丙酰基]-1,4∶3,6-双脱水-D-山梨糖醇
6-O-[3′-(氟-辛基)-丙酰基]-1,4-D-脱水山梨糖醇,
6-O-[11′-(氟-辛基)-十一烷酰基]-1,4-D-脱水山梨糖醇,
[3′-(氟-戊基)-丙酰基]-N-甲基-D-葡糖酰胺,
[3′-(氟-庚基)-丙酰基]-N-甲基-D-葡糖酰胺,
[3′-(氟-辛基)-丙酰基]-N-甲基-D-葡糖酰胺,
2-脱氧-2-[3′-(氟-辛基)-丙酰氨基]-葡萄糖,
2-脱氧-2-[3′-(氟-辛基)-丙酰氨基]-D-glucitol,
3-O-[3′-(氟-辛基)-丙酰基]-肌醇。
7、制备权利要求1~6中所述化合物的方法,其特征在于下述事实:
初始原料是所说多元醇,氨基多元醇或它们的衍生物,当然包括其内醚或缩酮,其中的羟基或部分羟基被保护起来,或者其中的至少一个羟基被可离去基团取代,
用公知的方法使上述初始原料与高度氟化的衍生物反应,使多元醇或氨基多元醇部分通过功能连结基团与高度氟化部分连结到一起,
然后,在有保护基存在时,用常规方法去掉保护基。
8、根据权利要求7所述的方法,其中所说的高度氟化部分是以RF-W-基团的形式引入的,而且其中的亲水初始原料与下述基团反应:
(a)RF-W-OH代表的醇,其中RF-W-不是酰基,
(b)RF-W-NH(R″)代表的胺,其中RF-W-不是酰基,而R″可为-H,C1-C18烷基,C2-C18不饱和羟基或者R-W-,并且亲水初始原料具有可离去基团,
(c)RF-W-O-CO-O Alk代表的混合酐,其中Alk代表低级烷基或RF-W-Cl代表的酰氯,在酰氯中RF为酰基而且其中的初始原料为氨基多元醇,
(d)RF-W-Cl表示的酰氯,其中RF-W-为酰基,目的是:
-在(a)和(d)的情况,分别得到RF-W-O-亲水基部分型的醚或酯,
-在(b)和(c)的情况,分别得到RF-W-N(R″)-亲水基团部分型的胺或酰胺,
然后,在有保护基存在时,按已知方法进行去掉保护基的反应。
9、根据权利要求7或8所述的制备通式(1)所代表的化合物的方法,其中:
-在初始原料类似于式Ⅰ所示的化合物,但其中没有高度氟化基团,而且有R5和R6存在且不为H,而且其中的不希望被取代的初始原料中的羟基又暂时保护起来的情况下,所说的初始原料与酰氯(当RF-W-是酰基时)或与RF-W-Z′所示的化合物(当RF-W-不是酰基时)反应(其中Z′是OH基或可去基团),以得到相应的式Ⅰ所示的酯或醚,然后再进行除保护基的反应;
-或者,当初始原料类似于式Ⅰ所示的化合物,但其中没有高度氟化基团,而且其中至少-OR1,-OR2,-OR3,-OR4,-OR7,-OR9,-OR10和-NR5R6中之一被可离去基团取代,而且-OH基被保护起来的情况下,所说的初始原料与RF-W-OH所示的醇或RF-W-NHR″所示的胺反应,其中RF-W-不是酰基且R″为H,C1-C18烷基,C2-C18不饱和烃基或RF-W-,以得到相应于式Ⅰ所示的化合物且其中的初始原料中的可离去集团分别被-O-W-RF或-N(R″)-W-RF取代,然后再进行脱除保护基的反应;
原料或是与通式Ⅰ化合物相似的化合物,它含有-NR5R6,但没有高氟化基团,其中R5和R6至少一个是H,该原料与混合的式RF-W-O-CO-OAlk(RF-W-是酰基,Alk是低级烷基)的酸酐反应,从而制得相应的含有-NR5(RFW),-NR6(RFW)或-N(RFW)2的通式Ⅰ的酰胺。
10、权利要求1~6所述的化合物作为表面活性剂或组合表面活性剂的应用。
11、含有带烃基或不带烃基的非极性物质或非极性化合物,以水或其它极性溶剂的溶液的分散体系,胶体,乳浊液或微乳液形式存在的组合物,其特征在于,其中至少添加了一种如权利要求1~6中所述的亲水且氟化了的化合物,或者还含其它表面活性剂。
12、根据权利要求11所述的组合物,其中的非极性化合物或物质是高度氟化的或全氟化的。
13、根据权利要求12所述的组合物,其中所说的高度氟化或全氟化的化合物或物质的分子量在400~700之间,而且至少选自下述物质的一种,
1,2-二氟烷基乙烷,更具体的是:
1,2-二氟丁基乙烷,1-氟异丙基-2-氟己基乙烷,
1,2-二氟己基乙烷,全氟萘烷,全氟-甲基萘烷,
全氟-二甲基萘烷,全氟-二甲基金刚烷,全氟三甲基二环-/3,3,1/壬烷,以及它们的类似物,公式所表示的醚,
(CF3)CFO(CF2CF2)OCF(CF3)2,
(CF3)2CFO(CF2CF2)OCF(CF3)2,
(CHF3)2CFO(CF2CF2)F,(CF)2CFO(CF2CF2)F,
F[CF(CF3)CF2O]2CHFCF3,(C6F13)2O,
以及胺
N(C3F7)3,N(C4F9)3,
全氟甲基喹啉酊(perfluoromethylquinolidine)
全氟异喹啉酊(perfluoroisoquinolidine)
囟代衍生物,C6F13Br,C8F17Br,C6F13CBr2CHBr,
1-溴十七氟-4-异丙基环己烷(1-biomoteptadecafluoro-4-isopropyl-cyclohexane)和其类似物。
14、根据权利要求12或13所述的组合物,它用作气体载体,特别是在人类和兽类的医疗生命环境中作为氧的载体,特别是作为血液的替代物,对照制剂,治疗脑和心脏缺血,用于保存对心血管治疗和外科治有用的器官,组织,精液,培养基,例如用作cardioplegic,reperfusion或冠状血管发展的溶液,用作瘤病的药剂治疗或辐射治中所使用的副助介质,或者用作药剂载体介质。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8611084A FR2602774B1 (fr) | 1986-07-29 | 1986-07-29 | Nouvelles molecules amphiphiles polyhydroxylees et perfluoroalkylees ayant des proprietes tensioactives |
FR8611084 | 1986-07-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN87105263A true CN87105263A (zh) | 1988-06-15 |
Family
ID=9337904
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN198787105263A Pending CN87105263A (zh) | 1986-07-29 | 1987-07-29 | 多羟基化且高度氟化的化合物及其制备方法和作为表面活性剂的应用 |
Country Status (17)
Country | Link |
---|---|
US (1) | US4985550A (zh) |
EP (1) | EP0255443B1 (zh) |
JP (1) | JPH0816106B2 (zh) |
CN (1) | CN87105263A (zh) |
AT (1) | ATE81507T1 (zh) |
AU (1) | AU608761B2 (zh) |
CA (1) | CA1315778C (zh) |
DD (1) | DD261363A5 (zh) |
DE (1) | DE3782210T2 (zh) |
DK (1) | DK392687A (zh) |
ES (1) | ES2052594T3 (zh) |
FR (1) | FR2602774B1 (zh) |
GR (1) | GR3006524T3 (zh) |
IE (1) | IE61102B1 (zh) |
NO (1) | NO169542C (zh) |
NZ (1) | NZ221232A (zh) |
PT (1) | PT85425B (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100396369C (zh) * | 2006-03-02 | 2008-06-25 | 翟健 | 一种杂化非离子氟表面活性剂及其合成方法 |
CN101970059B (zh) * | 2007-10-16 | 2012-11-21 | 泰科消防产品有限合伙公司 | 氟代烯基多[1,6]糖苷 |
CN105238567A (zh) * | 2015-10-10 | 2016-01-13 | 泉州市福达科技咨询有限公司 | 一种环保型含氟清洗剂及其制备方法 |
Families Citing this family (78)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1223324B (it) * | 1987-10-28 | 1990-09-19 | Ausimont Spa | Microemulsioni acquose comprendenti perfluoropolieteri funzionali |
US5055562A (en) * | 1988-02-01 | 1991-10-08 | Biomira, Inc. | Fluorocarbon chain-containing antigenic conjugates |
CA1326665C (en) * | 1988-02-27 | 1994-02-01 | Ryohei Yamaoka | Fluorine-containing glycoside and its use |
EP0375610A3 (en) * | 1988-12-19 | 1992-01-02 | Ciba-Geigy Ag | Perfluoroalkylthioglycosides |
US5776429A (en) * | 1989-12-22 | 1998-07-07 | Imarx Pharmaceutical Corp. | Method of preparing gas-filled microspheres using a lyophilized lipids |
US6001335A (en) * | 1989-12-22 | 1999-12-14 | Imarx Pharmaceutical Corp. | Contrasting agents for ultrasonic imaging and methods for preparing the same |
US5656211A (en) * | 1989-12-22 | 1997-08-12 | Imarx Pharmaceutical Corp. | Apparatus and method for making gas-filled vesicles of optimal size |
US5542935A (en) | 1989-12-22 | 1996-08-06 | Imarx Pharmaceutical Corp. | Therapeutic delivery systems related applications |
US6551576B1 (en) | 1989-12-22 | 2003-04-22 | Bristol-Myers Squibb Medical Imaging, Inc. | Container with multi-phase composition for use in diagnostic and therapeutic applications |
US6088613A (en) | 1989-12-22 | 2000-07-11 | Imarx Pharmaceutical Corp. | Method of magnetic resonance focused surgical and therapeutic ultrasound |
US5733572A (en) * | 1989-12-22 | 1998-03-31 | Imarx Pharmaceutical Corp. | Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles |
US6146657A (en) * | 1989-12-22 | 2000-11-14 | Imarx Pharmaceutical Corp. | Gas-filled lipid spheres for use in diagnostic and therapeutic applications |
US5585112A (en) * | 1989-12-22 | 1996-12-17 | Imarx Pharmaceutical Corp. | Method of preparing gas and gaseous precursor-filled microspheres |
US20020150539A1 (en) * | 1989-12-22 | 2002-10-17 | Unger Evan C. | Ultrasound imaging and treatment |
US5922304A (en) * | 1989-12-22 | 1999-07-13 | Imarx Pharmaceutical Corp. | Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents |
US5305757A (en) * | 1989-12-22 | 1994-04-26 | Unger Evan C | Gas filled liposomes and their use as ultrasonic contrast agents |
US5580575A (en) * | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
FR2665705B1 (fr) * | 1990-08-09 | 1993-07-30 | Atta | Nouveaux derives fluores amphiphiles a structure telomere, leur procede de preparation et leur utilisation dans des preparations a usage biomedical. |
US5874062A (en) * | 1991-04-05 | 1999-02-23 | Imarx Pharmaceutical Corp. | Methods of computed tomography using perfluorocarbon gaseous filled microspheres as contrast agents |
US5205290A (en) | 1991-04-05 | 1993-04-27 | Unger Evan C | Low density microspheres and their use as contrast agents for computed tomography |
FR2677360B1 (fr) * | 1991-06-05 | 1995-04-14 | Atta | Composes amphiphiles perfluoroalkyles du phosphore, leurs preparations et leurs applications notamment dans le domaine biomedical. |
FR2679150A1 (fr) * | 1991-07-17 | 1993-01-22 | Atta | Preparations comprenant un fluorocarbure ou compose hautement fluore et un compose organique lipophile-fluorophile, et leurs utilisations. |
US5409688A (en) * | 1991-09-17 | 1995-04-25 | Sonus Pharmaceuticals, Inc. | Gaseous ultrasound contrast media |
US6875420B1 (en) | 1991-09-17 | 2005-04-05 | Amersham Health As | Method of ultrasound imaging |
MX9205298A (es) | 1991-09-17 | 1993-05-01 | Steven Carl Quay | Medios gaseosos de contraste de ultrasonido y metodo para seleccionar gases para usarse como medios de contraste de ultrasonido |
US6723303B1 (en) | 1991-09-17 | 2004-04-20 | Amersham Health, As | Ultrasound contrast agents including protein stabilized microspheres of perfluoropropane, perfluorobutane or perfluoropentane |
GB9125454D0 (en) * | 1991-11-29 | 1992-01-29 | Isis Innovation | Oxygen transport agents |
US5621144A (en) * | 1991-11-29 | 1997-04-15 | Isis Innovation Limited | Fluorinated compounds as oxygen transport agents |
EP0633875B1 (en) * | 1992-04-03 | 1997-01-02 | Gist-Brocades N.V. | Selective n-acylation of amino alcohols |
US5846516A (en) * | 1992-06-03 | 1998-12-08 | Alliance Pharmaceutial Corp. | Perfluoroalkylated amphiphilic phosphorus compounds: preparation and biomedical applications |
US5350359A (en) * | 1992-07-16 | 1994-09-27 | Temple University Of The Commonwealth System Of Higher Education | Control, treatment and/or diagnosis of physiological conditions with degassed perfluorocarbon liquid |
FR2694559B1 (fr) * | 1992-08-06 | 1994-10-28 | Atta | Nouveaux dérivés amphiphiles d'aminoacides ou de peptides, leur procédé de préparation et leur utilisation dans des préparations à usage biomédical. |
IL108416A (en) | 1993-01-25 | 1998-10-30 | Sonus Pharma Inc | Colloids with phase difference as contrast ultrasound agents |
NZ262237A (en) * | 1993-01-25 | 1997-06-24 | Sonus Pharma Inc | Ultrasound contrast agents comprising phase shift colloids having a boiling point below the body temperature of the animal it is used in |
US5824781A (en) * | 1993-08-16 | 1998-10-20 | Hsia; Jen-Chang | Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules |
TW381022B (en) | 1993-08-16 | 2000-02-01 | Hsia Jen Chang | Compositions and methods utilizing nitroxides to avoid oxygen toxicity, particularly in stabilized, polymerized, conjugated, or encapsulated hemoglobin used as a red cell substitute |
US5725839A (en) * | 1993-08-16 | 1998-03-10 | Hsia; Jen-Chang | Compositions and methods utilizing nitroxides in combination with biocompatible macromolecules for ERI or MRI |
US5736121A (en) * | 1994-05-23 | 1998-04-07 | Imarx Pharmaceutical Corp. | Stabilized homogenous suspensions as computed tomography contrast agents |
FR2720943B1 (fr) * | 1994-06-09 | 1996-08-23 | Applic Transferts Technolo | Emulsions inverses stables à forte concentration en composé(s) fluoré(s) et leur utilisation pour l'administration pulmonaire de médicaments et pour la fabrication d'émulsions multiples. |
US5562893A (en) * | 1994-08-02 | 1996-10-08 | Molecular Biosystems, Inc. | Gas-filled microspheres with fluorine-containing shells |
US5730955A (en) * | 1994-08-02 | 1998-03-24 | Molecular Biosystems, Inc. | Process for making gas-filled microspheres containing a liquid hydrophobic barrier |
US5965109A (en) * | 1994-08-02 | 1999-10-12 | Molecular Biosystems, Inc. | Process for making insoluble gas-filled microspheres containing a liquid hydrophobic barrier |
US6743779B1 (en) | 1994-11-29 | 2004-06-01 | Imarx Pharmaceutical Corp. | Methods for delivering compounds into a cell |
US5830430A (en) * | 1995-02-21 | 1998-11-03 | Imarx Pharmaceutical Corp. | Cationic lipids and the use thereof |
US5997898A (en) * | 1995-06-06 | 1999-12-07 | Imarx Pharmaceutical Corp. | Stabilized compositions of fluorinated amphiphiles for methods of therapeutic delivery |
US5667809A (en) * | 1995-06-07 | 1997-09-16 | Alliance Pharmaceutical Corp. | Continuous fluorochemical microdispersions for the delivery of lipophilic pharmaceutical agents |
US6139819A (en) * | 1995-06-07 | 2000-10-31 | Imarx Pharmaceutical Corp. | Targeted contrast agents for diagnostic and therapeutic use |
US5874481A (en) * | 1995-06-07 | 1999-02-23 | Alliance Pharmaceutical Corp. | Fluorochemical solutions for the delivery of lipophilic pharmaceutical agents |
US6521211B1 (en) * | 1995-06-07 | 2003-02-18 | Bristol-Myers Squibb Medical Imaging, Inc. | Methods of imaging and treatment with targeted compositions |
US6231834B1 (en) | 1995-06-07 | 2001-05-15 | Imarx Pharmaceutical Corp. | Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same |
US5611344A (en) * | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
JP3178724B2 (ja) * | 1996-03-05 | 2001-06-25 | エイカスフィアー・インコーポレーテッド | 画像化剤として使用するためのミクロカプセル化フッ素化ガス |
AU736301B2 (en) | 1996-05-01 | 2001-07-26 | Imarx Therapeutics, Inc. | Methods for delivering compounds into a cell |
FR2750134B1 (fr) * | 1996-06-20 | 1998-08-14 | Ceca Sa | 1-c-perfluoroalkyl glycosides, procede de preparation et utilisations |
US5837221A (en) * | 1996-07-29 | 1998-11-17 | Acusphere, Inc. | Polymer-lipid microencapsulated gases for use as imaging agents |
US6414139B1 (en) | 1996-09-03 | 2002-07-02 | Imarx Therapeutics, Inc. | Silicon amphiphilic compounds and the use thereof |
WO1998010798A1 (en) * | 1996-09-11 | 1998-03-19 | Imarx Pharmaceutical Corp. | Improved methods for diagnostic imaging using a contrast agent and a vasodilator |
US5846517A (en) | 1996-09-11 | 1998-12-08 | Imarx Pharmaceutical Corp. | Methods for diagnostic imaging using a renal contrast agent and a vasodilator |
US5834519A (en) | 1996-10-11 | 1998-11-10 | Wayne State University | Stabilized gas-supersaturated emulsions and suspensions |
US5907017A (en) * | 1997-01-31 | 1999-05-25 | Cornell Research Foundation, Inc. | Semifluorinated side chain-containing polymers |
US6120751A (en) * | 1997-03-21 | 2000-09-19 | Imarx Pharmaceutical Corp. | Charged lipids and uses for the same |
US6537246B1 (en) | 1997-06-18 | 2003-03-25 | Imarx Therapeutics, Inc. | Oxygen delivery agents and uses for the same |
US6090800A (en) * | 1997-05-06 | 2000-07-18 | Imarx Pharmaceutical Corp. | Lipid soluble steroid prodrugs |
US6143276A (en) * | 1997-03-21 | 2000-11-07 | Imarx Pharmaceutical Corp. | Methods for delivering bioactive agents to regions of elevated temperatures |
US6416740B1 (en) | 1997-05-13 | 2002-07-09 | Bristol-Myers Squibb Medical Imaging, Inc. | Acoustically active drug delivery systems |
US5980936A (en) * | 1997-08-07 | 1999-11-09 | Alliance Pharmaceutical Corp. | Multiple emulsions comprising a hydrophobic continuous phase |
US6548047B1 (en) | 1997-09-15 | 2003-04-15 | Bristol-Myers Squibb Medical Imaging, Inc. | Thermal preactivation of gaseous precursor filled compositions |
US6123923A (en) * | 1997-12-18 | 2000-09-26 | Imarx Pharmaceutical Corp. | Optoacoustic contrast agents and methods for their use |
US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
DE19948651B4 (de) * | 1999-09-29 | 2006-10-05 | Schering Ag | Para- und diamagnetische perfluorhaltige Verbindungen enthaltende galenische Formulierungen, deren Herstellung und Verwendung |
GB2364702A (en) * | 2000-07-17 | 2002-02-06 | Unilever Plc | Perfluoroalkyl amphiphilic fabric treatment compounds |
US7008535B1 (en) * | 2000-08-04 | 2006-03-07 | Wayne State University | Apparatus for oxygenating wastewater |
WO2003097717A1 (fr) * | 2002-05-16 | 2003-11-27 | Daikin Industries, Ltd. | Composes actifs-surface non ionique soluble dans l'eau contenant du fluor, et utilisation et procede de preparation desdits composes |
US7025697B2 (en) * | 2003-11-26 | 2006-04-11 | New Archery Products Corp. | Blade steering apparatus |
US8012457B2 (en) * | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
US20120309853A1 (en) * | 2011-06-06 | 2012-12-06 | E I Du Pont De Nemours And Company | Aldohexose-based fluoroadditives |
DE102013102239A1 (de) * | 2013-03-06 | 2014-09-11 | Universität Zu Köln | Carbosilanhaltiger Feuerlöschschaum |
FR3072246B1 (fr) * | 2017-10-13 | 2020-06-12 | Biodesiv Efnium | Polymere antimicrobien pour semences animales |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2891052A (en) * | 1956-04-10 | 1959-06-16 | Rohm & Haas | Anhydrosorbityl amides and process of preparation |
DE1468176A1 (de) * | 1963-01-08 | 1968-12-12 | Lepetit Spa | Verfahren zur Herstellung von nichtzyklischen Xylit-Estern |
US3839318A (en) * | 1970-09-27 | 1974-10-01 | Rohm & Haas | Process for preparation of alkyl glucosides and alkyl oligosaccharides |
IT967894B (it) * | 1971-09-27 | 1974-03-11 | Fmc Corp | Composti anti macchia a base di poliuretani fluorurati e proces so per la loro applicazione a prodotti tessili |
US3952066A (en) * | 1972-07-07 | 1976-04-20 | Thiokol Corporation | Derivatives of perfluoroalkyl iodide-allyl glycidyl ether adducts |
US4089804A (en) * | 1976-12-30 | 1978-05-16 | Ciba-Geigy Corporation | Method of improving fluorinated surfactants |
JPS601175A (ja) * | 1983-06-16 | 1985-01-07 | Daikin Ind Ltd | アスコルビン酸誘導体 |
JPS604127A (ja) * | 1983-06-21 | 1985-01-10 | Daikin Ind Ltd | 抗菌剤 |
JPS6028944A (ja) * | 1983-07-25 | 1985-02-14 | Kao Corp | 新規なポリオ−ルエ−テル化合物およびその製造方法ならびにこれを含有する化粧料 |
JPS61107527A (ja) * | 1984-10-31 | 1986-05-26 | Matsushita Electric Ind Co Ltd | 磁気記録媒体 |
GB8525871D0 (en) * | 1985-10-21 | 1985-11-27 | Tate & Lyle Plc | Chemical compound |
-
1986
- 1986-07-29 FR FR8611084A patent/FR2602774B1/fr not_active Expired - Fee Related
-
1987
- 1987-07-28 DD DD87305442A patent/DD261363A5/de not_active IP Right Cessation
- 1987-07-28 NZ NZ221232A patent/NZ221232A/xx unknown
- 1987-07-28 AU AU76194/87A patent/AU608761B2/en not_active Ceased
- 1987-07-28 DK DK392687A patent/DK392687A/da not_active Application Discontinuation
- 1987-07-28 PT PT85425A patent/PT85425B/pt not_active IP Right Cessation
- 1987-07-28 IE IE204587A patent/IE61102B1/en not_active IP Right Cessation
- 1987-07-28 NO NO873168A patent/NO169542C/no unknown
- 1987-07-28 US US07/078,626 patent/US4985550A/en not_active Expired - Lifetime
- 1987-07-29 EP EP87401769A patent/EP0255443B1/en not_active Expired - Lifetime
- 1987-07-29 CA CA000543291A patent/CA1315778C/en not_active Expired - Fee Related
- 1987-07-29 ES ES87401769T patent/ES2052594T3/es not_active Expired - Lifetime
- 1987-07-29 DE DE8787401769T patent/DE3782210T2/de not_active Expired - Fee Related
- 1987-07-29 JP JP62191498A patent/JPH0816106B2/ja not_active Expired - Lifetime
- 1987-07-29 AT AT87401769T patent/ATE81507T1/de not_active IP Right Cessation
- 1987-07-29 CN CN198787105263A patent/CN87105263A/zh active Pending
-
1992
- 1992-12-14 GR GR920402898T patent/GR3006524T3/el unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100396369C (zh) * | 2006-03-02 | 2008-06-25 | 翟健 | 一种杂化非离子氟表面活性剂及其合成方法 |
CN101970059B (zh) * | 2007-10-16 | 2012-11-21 | 泰科消防产品有限合伙公司 | 氟代烯基多[1,6]糖苷 |
CN105238567A (zh) * | 2015-10-10 | 2016-01-13 | 泉州市福达科技咨询有限公司 | 一种环保型含氟清洗剂及其制备方法 |
CN105238567B (zh) * | 2015-10-10 | 2017-11-17 | 泉州市福达科技咨询有限公司 | 一种环保型含氟清洗剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
FR2602774A1 (fr) | 1988-02-19 |
US4985550A (en) | 1991-01-15 |
ES2052594T3 (es) | 1994-07-16 |
CA1315778C (en) | 1993-04-06 |
AU7619487A (en) | 1988-02-04 |
NO873168L (no) | 1988-02-01 |
GR3006524T3 (zh) | 1993-06-30 |
NO169542B (no) | 1992-03-30 |
IE61102B1 (en) | 1994-10-05 |
DE3782210T2 (de) | 1993-04-22 |
JPS6399066A (ja) | 1988-04-30 |
IE872045L (en) | 1988-01-29 |
NO169542C (no) | 1992-07-08 |
DK392687A (da) | 1988-01-30 |
EP0255443B1 (en) | 1992-10-14 |
NZ221232A (en) | 1990-08-28 |
AU608761B2 (en) | 1991-04-18 |
PT85425A (en) | 1987-08-01 |
PT85425B (pt) | 1990-06-29 |
FR2602774B1 (fr) | 1990-10-19 |
DD261363A5 (de) | 1988-10-26 |
NO873168D0 (no) | 1987-07-28 |
EP0255443A1 (en) | 1988-02-03 |
JPH0816106B2 (ja) | 1996-02-21 |
DK392687D0 (da) | 1987-07-28 |
DE3782210D1 (de) | 1992-11-19 |
ATE81507T1 (de) | 1992-10-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN87105263A (zh) | 多羟基化且高度氟化的化合物及其制备方法和作为表面活性剂的应用 | |
CN1084623C (zh) | 特定的α-半乳糖基神经酰胺、药物组合物及其用途 | |
CN1043996C (zh) | 杀寄生虫剂、其制备方法及其应用 | |
CN1145635C (zh) | 吡喃葡糖氧基吡唑衍生物、含该衍生物的药物组合物及其制备中的中间体 | |
CN1882601A (zh) | 用作豆科植物结瘤剂的合成化合物及其制备方法 | |
CN1072206C (zh) | 酰胺衍生物及外用护肤或护发制品 | |
CN1018456B (zh) | 13-卤代米尔贝霉素衍生物的制备方法 | |
CN1165550C (zh) | 合成多糖和含有它们的药物组合物以及其用途 | |
CN1053054A (zh) | 卤代链烯烃的制备方法及其作为杀虫和杀螨剂的应用 | |
CN1173964C (zh) | 新型苯并呋喃酮衍生物及其制备方法 | |
CN1200699C (zh) | 蒽酮衍生物及其在淀粉样变性中的用途 | |
CN1271363A (zh) | 具有抗菌活性的3’-n-修饰的6-o-取代的红霉素酮基内酯衍生物 | |
CN1956991A (zh) | 氮杂糖衍生物、乙酰肝素酶抑制剂、其制备方法、含有该衍生物的组合物及其应用 | |
CN1503805A (zh) | 4″-位置取代的且具有杀虫性质的除虫菌素盐 | |
CN1099038A (zh) | 3-脱氧低聚糖,其制备方法和含有它们的药物组合物 | |
CN1150589A (zh) | 新型糖醇的硫酸酯 | |
CN86105901A (zh) | 农药化合物 | |
CN1126752C (zh) | 神经氨酸化合物 | |
CN87107993A (zh) | 含n-羟乙酰神经氨(糖)酸的糖脂及其制备方法 | |
CN1681519A (zh) | 含有作为活性成分的α-糖基神经酰胺的丙型肝炎病毒抑制剂 | |
CN86103530A (zh) | 治疗和预防消化性溃疡药物的制备方法 | |
CN1058498C (zh) | 糖脂类似物 | |
CN1121223C (zh) | 含有神经鞘糖脂的冷冻干燥组合物及其制造方法 | |
CN1045590C (zh) | 肼衍生物和含有它的农业和园艺杀虫剂组合物 | |
CN1056150C (zh) | 3-或4-糖氧基苯并吡喃衍生物和含此衍生物作为活性成分的抗变应剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication |