CN112979734B - 三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 - Google Patents
三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 Download PDFInfo
- Publication number
- CN112979734B CN112979734B CN201911212746.8A CN201911212746A CN112979734B CN 112979734 B CN112979734 B CN 112979734B CN 201911212746 A CN201911212746 A CN 201911212746A CN 112979734 B CN112979734 B CN 112979734B
- Authority
- CN
- China
- Prior art keywords
- crystals
- crystal
- adenosine
- acetyl
- tri
- 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.)
- Active
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- VOGJLGJXZOVCHK-DXBBTUNJSA-N 1-[(2R,3S,4R,5R)-3,4-diacetyl-5-(6-aminopurin-9-yl)-3,4-dihydroxy-2-(hydroxymethyl)-5-(3-hydroxyphenyl)oxolan-2-yl]ethanone Chemical compound C(C)(=O)[C@]1([C@]([C@]([C@@](O1)(N1C=NC=2C(N)=NC=NC1=2)C1=CC(=CC=C1)O)(O)C(C)=O)(O)C(C)=O)CO VOGJLGJXZOVCHK-DXBBTUNJSA-N 0.000 title abstract description 4
- IUDLPZTURGVXEA-WGQQHEPDSA-N [(2r,3r,4r,5r)-3,4-diacetyloxy-5-[6-(3-hydroxyanilino)purin-9-yl]oxolan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C2=NC=NC(NC=3C=C(O)C=CC=3)=C2N=C1 IUDLPZTURGVXEA-WGQQHEPDSA-N 0.000 claims abstract description 25
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 14
- 150000002632 lipids Chemical class 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 238000002329 infrared spectrum Methods 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 11
- 239000000126 substance Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 238000010586 diagram Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 230000005855 radiation Effects 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 19
- 210000004369 blood Anatomy 0.000 abstract description 12
- 239000008280 blood Substances 0.000 abstract description 12
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 10
- 230000001105 regulatory effect Effects 0.000 abstract description 6
- 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 description 62
- 235000012000 cholesterol Nutrition 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 229940079593 drug Drugs 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000013312 flour Nutrition 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 5
- -1 plasters Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000007405 data analysis Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 229930010555 Inosine Natural products 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960003786 inosine Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical group NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 2
- 102100036009 5'-AMP-activated protein kinase catalytic subunit alpha-2 Human genes 0.000 description 2
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 2
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 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 description 2
- 235000019733 Fish meal Nutrition 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 101000783681 Homo sapiens 5'-AMP-activated protein kinase catalytic subunit alpha-2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- 244000046052 Phaseolus vulgaris Species 0.000 description 2
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 2
- POJWUDADGALRAB-UHFFFAOYSA-N allantoin Chemical compound NC(=O)NC1NC(=O)NC1=O POJWUDADGALRAB-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003833 bile salt Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940036811 bone meal Drugs 0.000 description 2
- 239000002374 bone meal Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- OFEZSBMBBKLLBJ-BAJZRUMYSA-N cordycepin Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@H]1O OFEZSBMBBKLLBJ-BAJZRUMYSA-N 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 210000002969 egg yolk Anatomy 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 239000004467 fishmeal Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012353 t test Methods 0.000 description 2
- LKOVPWSSZFDYPG-WUKNDPDISA-N trans-octadec-2-enoic acid Chemical compound CCCCCCCCCCCCCCC\C=C\C(O)=O LKOVPWSSZFDYPG-WUKNDPDISA-N 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229940018563 3-aminophenol Drugs 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
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- POJWUDADGALRAB-PVQJCKRUSA-N Allantoin Natural products NC(=O)N[C@@H]1NC(=O)NC1=O POJWUDADGALRAB-PVQJCKRUSA-N 0.000 description 1
- 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 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- KQLDDLUWUFBQHP-UHFFFAOYSA-N Cordycepin Natural products C1=NC=2C(N)=NC=NC=2N1C1OCC(CO)C1O KQLDDLUWUFBQHP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 206010048554 Endothelial dysfunction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 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 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 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 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010039020 Rhabdomyolysis Diseases 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 description 1
- 206010049418 Sudden Cardiac Death Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000035868 Vascular inflammations Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- NHOGBOFGIXMKII-BEFMGFOSSA-N [(2r,3r,4r,5r)-3,4-diacetyloxy-5-(6-amino-6-chloro-8h-purin-9-yl)oxolan-2-yl]methyl acetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C2=NC=NC(Cl)(N)C2=NC1 NHOGBOFGIXMKII-BEFMGFOSSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000003838 adenosines Chemical class 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229960000458 allantoin Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229940092738 beeswax Drugs 0.000 description 1
- 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 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 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 description 1
- 229960004853 betadex Drugs 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- SHWNNYZBHZIQQV-UHFFFAOYSA-L calcium;disodium;2-[2-[bis(carboxylatomethyl)azaniumyl]ethyl-(carboxylatomethyl)azaniumyl]acetate Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000005323 carbonate salts Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OFEZSBMBBKLLBJ-UHFFFAOYSA-N cordycepine Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)CC1O OFEZSBMBBKLLBJ-UHFFFAOYSA-N 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 201000006747 infectious mononucleosis Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229940045136 urea Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明涉及治疗高脂血症的药物三乙酰基‑3‑羟基苯基腺苷的晶型、制备方法及其用途,本发明所述晶型包括具有调血脂作用的2’,3’,5’‑三‑O‑乙酰基‑N6‑(3‑羟基苯基)腺苷的Ⅰ型结晶和Ⅱ型结晶,其中Ⅰ型结晶具有如附图1所示的X射线粉末衍射图谱,其中Ⅱ型结晶,具有如附图4所示的X射线粉末衍射图谱。
Description
技术领域
本发明涉及治疗高脂血症的药物化合物2’,3’,5’-三-O-N6-(3-羟基苯基)腺苷的晶型及其制备方法,本发明还包括上述晶型的药物组合物,以及所述晶型及其药物组合物在治疗高脂血症的药物中的用途,属医药技术领域。
背景技术
大量的基础研究资料和临床实践证明,高脂血症,包括高胆固醇血症、高甘油三酯血症及复合性高脂血症是脑卒中、冠心病、心肌梗死、心脏猝死的重要危险因素。此外,高脂血症也是促进高血压、糖耐量异常、糖尿病的一个重要危险因素。高脂血症还可导致脂肪肝、肝硬化、胰腺炎、眼底出血、失明、周围血管病变、高尿酸血症等并发症。
目前临床上应用的调血脂药物包括以他汀类为代表的胆固醇生物合成酶抑制剂,这类药物通过抑制HMG-CoA还原酶,使体内内源性胆固醇的合成减少,减少低密度脂蛋白胆固醇 (LDL-C)的来源。同时,该类药物增加或激活肝细胞表面的LDL受体表达的水平而减少血液中LDL的含量。另一类是以激活过氧化物酶增生因子活化受体(PPARs)转录因子从而降低甘油三酯水平的贝特类药物,上述两类药物是当今调血脂药物的主流,其临床药效确切,服用剂量小,生物利用度较好,但二者产生的肝损伤和横纹肌溶解症等严重不良反应均已成为当今他汀类和贝特类药物最为令人担优和关注的安全性问题。
虫草素有调节血脂的作用,以虫草素为先导化合物,通过化学结构修饰合成虫草素的衍生物,从中筛选效果好且毒副作用小的药物。中国专利CN101712709A公开了一种以次黄嘌呤核苷为原料,经过醋酐乙酰化、氯化亚砜氯化、3-羟基苯胺取代而获得的化合物2’,3’,5’- 三-O-乙酰基-N6-(3-羟基苯基)腺苷即三乙酰基-3-羟基苯基腺苷(代号为:IMM-H007), IMM-H007是一种新型调血脂化合物,化学结构为腺苷类似物。药理学研究表明,IMM-H007 (10μM)可抑制十八烯酸诱导的脂肪性变HepG2细胞内脂质的堆积。体内药效学研究发现,IMM-H007(2mg/kg)可降低高血脂症黄金地鼠升高的血清甘油三酯、总胆固醇、低密度脂蛋白和肝脏甘油三酯、总胆固醇水平。机制研究提示,IMM-H007可以上调十八烯酸诱导的脂肪病变HepG2细胞内或高血脂症黄金地鼠肝细胞内AMPK的磷酸化水平,是一种新型AMP-激活蛋白激酶(AMP-activated protein kinase,AMPK)激活剂。由此可见,IMM-H007作为一种与他汀类药物化学结构、作用靶点和代谢途径不同的新型调血脂化合物,有望成为临床预防和治疗心血管疾病的新药。目前对IMM-H007的进一步的研究包括不同治疗用途,例如抗炎症(CN104546887A)、治疗胰岛素抵抗(CN105663152A)、治疗高血脂症所伴随的单核细胞增多、动脉粥样硬化(CN107334775A)、治疗血管炎症、血管内皮功能紊乱(CN107412248A)、非酒精性脂肪肝(CN106943420A)等。
现有技术还公开了IMM-H007的以下合成路线:
所得产物为一种白色粉末状物质。
晶体通常以特定的立体几何物理形态成单个或簇状存在,在工业化生产中相对于油状或无定形在取用、称量、配制、干燥、过滤等方面均更具优势,而且晶体本身即是一种相对稳定的形态,更易保存和运输,此外,基于从溶液中结晶析出的特性,也能进一步降低最终产物中杂质的含量,获得更纯的产品。多晶型现象在药物中广泛存在,同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面都有显著的差异,从而不同程度的影响药物的稳定性、生物利用度、疗效和安全性。
本发明人在对IMM-H007化合物的研究中发现,采用现有技术制备的IMM-H007为一种白色粉末状物质,经检测为混合结晶,或无定形结晶,本发明进一步研究发现IMM-H007还具有不同的结晶形式,为此本发明对这些晶型进行了筛选,最终获得两种具有良好的稳定性,口服生物利用度高的晶型,特别有利于制备成口服的药物制剂,还可以提高降低小鼠血清总胆固醇水平的能力。
发明内容
本发明提供了具有调血脂作用的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶和Ⅱ型结晶。
其中Ⅰ型结晶当使用粉末X射线衍射分析时(CuKα辐射),衍射峰位置:2-Theta值(°) 具有如下特征::
更进一步的,本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶,其特征还在于,具有如附图1所示的X射线粉末衍射图谱。
更进一步的,本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶,其特征在于:所述晶型的差示扫描量热曲线在165-175℃范围内有吸热熔融峰,差示扫描量热分析图见附图2。
更进一步的,本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶,其特征在于:其红外光谱(IR)图具有如下特征吸收峰:1746.3,1621.9,1588.2,1470.2,1445.6, 1370.5,1229.2,1067.4,1031.7,928.8,915.2,866.2,854.8,829.2,775.6,759.5,691.1, 645.5cm-1,其红外光谱见附图3。
本发明的另一个目的是提供2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶的制备方法,其特征在于,使用乙酸乙酯、丙酮、二氯甲烷、氯仿、甲苯、石油醚、正己烷等单一或任意两种或多种经不同配比组合制成的混合溶剂进行重结晶得到。
优选的,其制备方法包括如下步骤:将2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷粉末加热溶解于乙酸乙酯、丙酮、二氯甲烷、氯仿、甲苯、石油醚、正己烷等单一或任意两种或多种经不同配比组合制成的混合溶剂中,室温或低温下析出晶体,或在室温条件下,通过缓慢挥发的方法得到Ⅰ型结晶固态物质。
同时本发明提供了具有调血脂作用的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶,当使用粉末X射线衍射分析时(CuKα辐射),衍射峰位置:2-Theta值具有如下特征:/>
更进一步的,本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶,其特征还在于,具有附图4所示的X射线粉末衍射图谱。
更进一步的,本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶,其特征在于:所述晶型的差示扫描量热曲线在145-155℃范围内有吸热熔融峰,差示扫描量热分析图见附图5。
更进一步的,本发明提供的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶,其特征在于:其红外光谱(IR)图具有如下特征吸收峰:1746.8,1626.2,1587.5,1474.0,1443.9, 1374.5,1230.2,1100.8,962.3,920.7,907.0,863.7,772.4,758.1,687.7,642.7,601.3,570.7cm-1,其红外光谱见附图6。
本发明的另一个目的是提供2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅱ型结晶的制备方法,其特征在于,使用乙醇、正丙醇、异丙醇、正丁醇、甲醇、乙腈等单一溶剂或任意两种或多种经不同配比组合制成的混合溶剂重结晶得到。
优选的,其制备方法包括如下步骤:将2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加热溶解于乙醇、正丙醇、异丙醇、正丁醇、甲醇、乙腈等单一或任意两种或多种经不同配比组合制成的混合溶剂中,室温或低温下析出晶体,或室温条件下通过缓慢挥发的方法得到晶体。
本发明还提供了药用组合物,含有治疗有效量的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基) 腺苷的I型结晶或Ⅱ型结晶和药用辅料的药用组合物。将治疗有效量的2’,3’,5’-三-O-乙酰基 -N6-(3-羟基苯基)腺苷的I型结晶或Ⅱ型结晶与一种或多种药用辅料混合或接触制成药用组合物或制剂,该药用组合物或制剂是以制药领域中熟知的方式进行制备的,在制成药物制剂时可以制成任何可药用的剂型,这些剂型选自:片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂等。
进一步的,本发明所述药物组合物还含有药学上可接受的载体。
所述药学上可接受的的载体包括但不限于:甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠,一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班 -80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物组合物在使用时根据病人的情况确定用法用量。
更进一步的,2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的晶Ⅰ型或晶Ⅱ型固态物质可用于制备用于预防和/或治疗高血脂症相关的心脑血管疾病的药物。
附图说明:
图1是晶Ⅰ型固态物质的X射线粉末衍射图谱
图2是晶Ⅰ型固态物质的的DSC图
图3是晶Ⅰ型固态物质的红外光谱图
图4是晶Ⅱ型固态物质的X射线粉末衍射图谱
图5是晶Ⅱ型固态物质的的DSC图
图6是晶Ⅱ型固态物质的红外光谱图
图7是大鼠口服不同晶型原料药后代谢产物M1血药浓度-时间曲线
具体实施方式
下面结合具体实施例对本发明作进一步的说明。
实施例1:2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷化合物的制备
1)5.36g次黄嘌呤腺苷悬浮于25ml吡啶中,冰浴至0℃,滴加醋酐16ml,滴加完毕,室温搅拌6h,TLC检测反应结束,减压蒸去绝大部分吡啶,冷却,加水,抽滤,水洗,得白色固体(3-0乙酰基次黄嘌呤腺苷)7.55g。
2)取上述产物5.5g,加入二氯甲烷50ml和1ml DMF,升温至40℃,滴加3.3g SOCl2的二氯甲烷溶液,回流,6h后TLC检测反应结束,将反应液用二氯甲烷稀释,饱和碳酸氢钠溶液洗两次,饱和氯化钠洗两次,加入无水硫酸钠干燥,减压蒸尽溶剂,得三-0-乙酰基-6- 氯腺苷5.4g。
3)取三-O-乙酰基-6-氯腺苷5.4g、3-氨基苯酚4.28g,加入无水乙醇30ml、三乙胺3.96g, 60℃条件下反应8h,减压蒸除溶剂,残余物经硅胶柱层析纯化,洗脱剂:乙酸乙酯:石油醚=2:1,收集所需组分,减压浓缩,得2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷1.51g。
实施例2. 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷I型结晶的制备
将1.0g 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加入8mL乙酸乙酯中,加热回流使澄清,过滤,得澄清溶液,缓慢搅拌下降至室温析晶2h,抽滤,得白色或类白色晶体,即晶Ⅰ型固态物质,当使用粉末X射线衍射分析时(CuKα辐射),衍射峰位置:2-Theta值具有如下特征::/> 29.64±0.2,X射线粉末衍射图谱见附图1,DSC图见附图2,红外光谱图见附图3。
实施例3. 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷I型结晶的制备
将1.0g 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加入10mL乙酸乙酯中,加热回流使澄清,滴加10mL石油醚,缓慢搅拌下降至室温析晶1h,抽滤,得白色或类白色晶体,即晶Ⅰ型固态物质。X射线粉末衍射图谱与实施例2相同,DSC图见附图2,红外光谱图见附图3。
实施例4. 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷Ⅱ型结晶的制备
将1.0g 2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷加入5mL乙醇中,加热回流使澄清,过滤,得澄清溶液,缓慢搅拌下降至室温析晶1h,抽滤,得白色或类白色晶体即Ⅱ型结晶,测得X射线粉末衍射在2θ值为: 处具有特征峰。X射线粉.末衍射图谱见附图4,DSC图见附图5,红外光谱图见附图6。
实施例5.I型结晶的稳定性研究
按专利ZL 200810223639.4描述的方法制备混晶,将混晶与I型结晶分别放置于40℃±2℃,75%±5%RH(相对湿度)条件下,加速试验6个月之后取出测试DSC、IR,结果显示I型结晶在40℃±2℃,75%±5%RH(相对湿度)条件下,加速试验6个月,晶型保持不变,I型结晶具有良好的稳定性。结果如表1所示。
表1 I型结晶的稳定性研究结果
实施例6.Ⅱ型结晶的稳定性研究
按专利ZL 200810223639.4描述的方法制备混晶,将混晶与Ⅱ型结晶分别放置于40℃±2℃,75%±5%RH(相对湿度)条件下,6个月之后取出测试DSC、IR,结果表明Ⅱ型结晶保持不变,结果如表2所示。
表2 Ⅱ型结晶的稳定性研究结果
实施例7.I型结晶的药代动力学研究
1.动物给药和血样采集
雄性SD大鼠10只,分为两组,每组5只,分别为混晶组和I型结晶组,分别按50mg/kg/10mL剂量给药。动物实验前禁食12h,自由饮水。大鼠灌胃给药后于5min,15min,30min,1h,2h,4h,6h,8h和12h各时间点从眼眶静脉丛取血。血样收集到预先冰浴化并加有100mMNaF肝素化管中,4℃离心分离血浆,立即加入两倍体积乙腈沉淀或迅速放入-20℃冰箱中保存备用。
2.样品处理
取大鼠给药后血浆样品100μL,加入20μL内标和180μL乙腈沉淀蛋白,高速离心14000rpm×5min两次,取上清液5μL进行LC/MS/MS分析。
3.LC/MS/MS测定
色谱柱:Zorbax C18(2.1×100mm,3.5μm);柱温:30℃,流动相:乙腈-水(10mM醋酸铵和0.1%甲酸)梯度洗脱,流速:0.2mL/min。检测离子对:m/z 486.200→228.100(样品);m/z 360.1→228.0(活性代谢物M1);m/z 374.1→242.0(内标)。
4.血药浓度及药动学参数
大鼠口服不同晶型药品CMC混悬液(50mg/kg)后,吸收较快,给药后5min血浆中即可检测到原型药及代谢产物M1,原型药血药浓度较低,主要为M1。I型结晶组M1的Cmax,Tmax,AUC(0-t)和MRT(0-t)分别为119.55±31.08ng/mL,0.5h,313.88±73.81ng/mL*h和2.68±0.30 h,混晶组相应参数分别为49.36±5.43ng/mL,0.5h,177.25±38.00ng/mL*h和3.63±0.41h。粉末组的Cmax和AUC(0-t)低于I型结晶组,结果如表3所示。大鼠口服不同晶型原料药后代谢产物M1血药浓度-时间曲线见附图7。
表3 大鼠口服不同晶型原料药后代谢产物M1血浆药代动力学参数(50mg/kg,n=5)
大鼠口服药物(50mg/kg)I型结晶组代谢产物M1的AUC(0-t)和峰浓度Cmax平均值均高于混晶组,说明I型结晶在大鼠体内的吸收较好,口服生物利用度高于混晶。
实施例8.不同晶型对高血脂模型小鼠总胆固醇水平的影响
1.材料和方法
实验动物:昆明种小鼠,雄性,体重20~24g,由中国人民解放军军事医学科学院实验动物中心提供,许可证编号:SCXK-(军)2012-0004。
受试品:I型结晶与混晶,使用前用0.25%的CMC配成所需浓度。
试剂盒:总胆固醇试剂盒,中生北控生物科技股份有限公司。
仪器:SeperateTM Max 190酶标仪。
饲料:基础饲料与高脂饲料,均由北京华阜康生物科技股份有限公司提供,许可证号: SCXK京2009-0008。基础饲料配方:20%面粉,10%米粉,20%玉米,20%豆粉,25%麸皮, 2%骨粉,2%鱼粉。高脂饲料配方:78.6%基础饲料,10%猪油,10%蛋黄粉,1%胆固醇,0.4%胆盐。
分组与给药:动物随机分成4组,分别为正常对照组、模型对照组、I型结晶组与混晶组,每组10只。各给药组给药剂量均为50mg/kg,每天灌胃一次,体积均为0.1ml/10g,连续给药7天,正常对照组、模型对照组每天给予等体积蒸馏水。于第7天给药半小时后动物取血,测定血清中CHO含量测定方法按照CHO试剂盒说明书进行,以酶标仪在505nm 波长下测定吸光度。按下列公式计算总胆固醇含量:CHO(mg/dl)=(待测血清OD值-空白OD 值)/(标准血清OD-空白OD值)*198。
2.数据分析:数据以平均值±标准差表示,数据分析采取t检验。
结果:统计结果显示,与正常组小鼠血清总胆固醇(CHO)水平(123.4±20.7mg/dl)比较,模型对照组小鼠CHO水平(161.7±17.4mg/dl)明显升高(P<0.01),表明造模成功。与模型组比较,混晶组CHO水平(138.3±13.5mg/dl)、晶Ⅰ型固态物质组CHO水平(139.7±15.6mg/dl) 明显降低(P<0.01)。I型结晶组与混晶组作用基本相当,未见明显差异。结果见表4
表4.不同晶型对高血脂模型小鼠总胆固醇的影响(n=10)
与模型组比较,*P<0.05,**P<0.01
与空白组比较,#P<0.05,##P<0.01
实施例9.Ⅱ型结晶与混晶对高血脂模型小鼠总胆固醇水平的影响
1.材料和方法
实验动物:昆明种小鼠,雄性,体重20~24g,由中国人民解放军军事医学科学院实验动物中心提供,许可证编号:SCXK-(军)2012-0004。
受试品:Ⅱ型结晶与混晶,使用前用0.25%的CMC配成所需浓度。
试剂盒:总胆固醇试剂盒,中生北控生物科技股份有限公司。
仪器:SeperateTM Max 190酶标仪。
饲料:基础饲料与高脂饲料,均由北京华阜康生物科技股份有限公司提供,许可证号: SCXK京2009-0008。基础饲料配方:20%面粉,10%米粉,20%玉米,20%豆粉,25%麸皮,2%骨粉,2%鱼粉。高脂饲料配方:78.6%基础饲料,10%猪油,10%蛋黄粉,1%胆固醇,0.4%胆盐。
分组与给药:动物随机分成4组,分别为正常对照组、模型对照组、Ⅱ型结晶组与混晶组,每组10只。各给药组给药剂量均为50mg/kg,每天灌胃一次,体积均为0.1ml/10g,连续给药7天,正常对照组、模型对照组每天给予等体积蒸馏水。于第7天给药半小时后动物取血,测定血清中CHO含量测定方法按照CHO试剂盒说明书进行,以酶标仪在505nm波长下测定吸光度。按下列公式计算总胆固醇含量:CHO(mg/dl)=(待测血清OD值-空白OD值)/(标准血清OD-空白OD值)*198。
2.数据分析:数据以平均值±标准差表示,数据分析采取t检验。
结果:统计结果显示,与正常组小鼠血清总胆固醇(CHO)水平(123.4±20.7mg/dl)比较,模型对照组小鼠CHO水平(161.7±17.4mg/dl)明显升高(P<0.01),表明造模成功。与模型组比较,混晶组CHO水平(138.3±13.5mg/dl)、Ⅱ型结晶组CHO水平(136.5±17.1mg/dl)明显降低 (P<0.01)。Ⅱ型结晶组与混晶组作用基本相当,未见明显差异。在50mg/kg剂量下,Ⅱ型结晶组与混晶组均明显降低小鼠血清总胆固醇水平的作用,且降血脂程度基本相当,结果见表5。
表5.不同晶型对高血脂模型小鼠总胆固醇的影响(n=10)
与模型组比较,*P<0.05,**P<0.01
与空白组比较,#P<0.05,##P<0.01。
Claims (4)
1.具有调血脂作用的2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷的Ⅰ型结晶,其特征在于,所述Ⅰ型结晶当使用粉末X射线衍射分析时,使用CuKα辐射,具有如图1所示的X射线粉末衍射图谱。
2.根据权利要求1所述的Ⅰ型结晶,其特征在于,所述晶型的差示扫描量热曲线在165-175℃范围内有吸热熔融峰,差示扫描量热分析图见图2。
3.根据权利要求1所述的Ⅰ型结晶,其特征在于,其红外光谱(IR)图具有如下特征吸收峰:1746.3,1621.9,1588.2,1470.2,1445.6,1370.5,1229.2,1067.4,1031.7,928.8,915.2,866.2,854.8,829.2,775.6,759.5,691.1,645.5cm-1,其红外光谱见图3。
4.根据权利要求1所述的Ⅰ型结晶,其特征在于,所述Ⅰ型结晶的制备方法,包括如下步骤:将2’,3’,5’-三-O-乙酰基-N6-(3-羟基苯基)腺苷粉末加热溶解于乙酸乙酯、丙酮、二氯甲烷、氯仿、甲苯、石油醚、正己烷中单一或任意两种或多种经不同配比组合制成的混合溶剂,室温或低温下析出晶体,或在室温条件下,通过缓慢挥发的方法得到Ⅰ型结晶固态物质。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911212746.8A CN112979734B (zh) | 2019-12-02 | 2019-12-02 | 三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911212746.8A CN112979734B (zh) | 2019-12-02 | 2019-12-02 | 三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112979734A CN112979734A (zh) | 2021-06-18 |
CN112979734B true CN112979734B (zh) | 2024-01-02 |
Family
ID=76331016
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911212746.8A Active CN112979734B (zh) | 2019-12-02 | 2019-12-02 | 三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112979734B (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101874036A (zh) * | 2008-10-06 | 2010-10-27 | 中国医学科学院药物研究所 | 三乙酰基-3-羟基苯基腺苷及其调血脂的用途 |
CN104546887A (zh) * | 2013-10-09 | 2015-04-29 | 中国医学科学院药物研究所 | 虫草素衍生物治疗炎症疾病的用途 |
CN105663152A (zh) * | 2014-11-19 | 2016-06-15 | 中国医学科学院药物研究所 | 三乙酰基-3-羟基苯基腺苷在制备改善胰岛素抵抗及相关疾病中的应用 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9827222B2 (en) * | 2013-07-01 | 2017-11-28 | Emory University | Treating or preventing nephrogenic diabetes insipidus |
-
2019
- 2019-12-02 CN CN201911212746.8A patent/CN112979734B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101874036A (zh) * | 2008-10-06 | 2010-10-27 | 中国医学科学院药物研究所 | 三乙酰基-3-羟基苯基腺苷及其调血脂的用途 |
CN104546887A (zh) * | 2013-10-09 | 2015-04-29 | 中国医学科学院药物研究所 | 虫草素衍生物治疗炎症疾病的用途 |
CN105663152A (zh) * | 2014-11-19 | 2016-06-15 | 中国医学科学院药物研究所 | 三乙酰基-3-羟基苯基腺苷在制备改善胰岛素抵抗及相关疾病中的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN112979734A (zh) | 2021-06-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105985396A (zh) | 氘代鹅去氧胆酸衍生物以及包含该化合物的药物组合物 | |
CN102344481A (zh) | 3-o-咖啡酰齐墩果烷型五环三萜类酯衍生物、其制备方法及应用 | |
US8435962B2 (en) | Triacetyl-3-hydroxyphenyladenosine and its use for regulating blood fat | |
CN1793132A (zh) | 环黄芪醇类衍生物以及用途 | |
CN105859814A (zh) | 一种奥贝胆酸化合物及其药物组合物 | |
JP2022549923A (ja) | Nヘテロ五員環含有カプシドタンパク質集合阻害剤の結晶形及びその使用 | |
JP2018501293A (ja) | マンギフェリン−6−o−ベルベリン塩、その製造方法および用途 | |
CN112979734B (zh) | 三乙酰基-3-羟基苯基腺苷的晶型、制备方法及其用途 | |
US11248002B2 (en) | Sesquiterpene derivative and use of the same in preparation of medicament for treating hepatitis b diseases | |
KR20040051485A (ko) | 광활성 비사이클롤, 그 제조방법과 이를 함유하는 조성물및 이용 | |
CN101307076A (zh) | 一种具有肝靶向抗乙肝病毒作用的前药 | |
CN111518157B (zh) | 一种雷公藤甲素衍生物及其制备方法和应用 | |
JP2022062193A (ja) | 不飽和脂肪族オレフィン性結合を含有するチエノピリジン誘導体、その調製方法および使用 | |
CN114644642A (zh) | 一种噻吩并吡啶化合物的晶型a、制备方法及其药物组合物 | |
CN108699060A (zh) | 结合有脂肪酸的恩替卡韦衍生化合物及其药学用途 | |
WO2013174245A1 (zh) | 一种常春藤皂苷元衍生物及其制备方法和应用 | |
CN116003469B (zh) | 嘧啶基抗病毒化合物的制备与使用方法 | |
CN114213381B (zh) | 4-色满酮衍生物及其制备方法和医药用途 | |
CN104995189B (zh) | 丙型肝炎药物的晶型及其制备方法、其药物组合物和用途 | |
AU2022100062A4 (en) | Crystal form for treating liver disease and use thereof | |
CN114933584B (zh) | 一种二氢-2h-异吲哚酯类化合物 | |
CN114736252B (zh) | 一种连翘苷衍生物及其制备方法和医用用途 | |
CN110638813A (zh) | 苯酞类化合物在降尿酸中的新用途 | |
CN115260212B (zh) | 3,5-双(亚苄基)-4-哌啶酮衍生物及其制备方法和应用 | |
CN113214206B (zh) | 橙皮素与甜菜碱共晶物b及制备方法和其组合物与用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
TA01 | Transfer of patent application right | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20210918 Address after: 1202, floor 11, building 1, No. 105, yaojiayuan Road, Chaoyang District, Beijing 100026 Applicant after: BEIJING GUSHEN LIFE HEALTH TECHNOLOGY Co.,Ltd. Address before: No.168 Chaoyang West Road, Qingpu Industrial Park, Huai'an City, Jiangsu Province Applicant before: JIANGSU TASLY DIYI PHARMACEUTICAL Co.,Ltd. |
|
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |