CN1290838C - Sulfonated derivative of andrographolide and combination of medication - Google Patents
Sulfonated derivative of andrographolide and combination of medication Download PDFInfo
- Publication number
- CN1290838C CN1290838C CNB2005100385611A CN200510038561A CN1290838C CN 1290838 C CN1290838 C CN 1290838C CN B2005100385611 A CNB2005100385611 A CN B2005100385611A CN 200510038561 A CN200510038561 A CN 200510038561A CN 1290838 C CN1290838 C CN 1290838C
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- andrographolide
- general formula
- sulfonated derivative
- mixture
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 45
- 239000003814 drug Substances 0.000 title description 3
- 229940079593 drug Drugs 0.000 title description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 239000000843 powder Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 89
- 239000000203 mixture Substances 0.000 claims description 46
- 229940125898 compound 5 Drugs 0.000 claims description 32
- 229940125904 compound 1 Drugs 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 229940125782 compound 2 Drugs 0.000 claims description 10
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 4
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 230000000202 analgesic effect Effects 0.000 claims description 3
- 230000000844 anti-bacterial effect Effects 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229940088710 antibiotic agent Drugs 0.000 claims 1
- 238000002347 injection Methods 0.000 abstract description 22
- 239000007924 injection Substances 0.000 abstract description 22
- 239000000126 substance Substances 0.000 abstract description 16
- 238000005057 refrigeration Methods 0.000 abstract description 7
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 abstract description 4
- 206010035664 Pneumonia Diseases 0.000 abstract description 2
- 206010006451 bronchitis Diseases 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 208000004429 Bacillary Dysentery Diseases 0.000 abstract 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 abstract 1
- 239000003708 ampul Substances 0.000 abstract 1
- 230000003260 anti-sepsis Effects 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 201000005113 shigellosis Diseases 0.000 abstract 1
- 206010044008 tonsillitis Diseases 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 115
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 22
- 229940090044 injection Drugs 0.000 description 21
- 229960004756 ethanol Drugs 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 150000002148 esters Chemical class 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000004869 Labdanum Substances 0.000 description 11
- 230000003595 spectral effect Effects 0.000 description 11
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 238000010253 intravenous injection Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 8
- 239000002504 physiological saline solution Substances 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000006277 sulfonation reaction Methods 0.000 description 7
- 210000003462 vein Anatomy 0.000 description 7
- 239000004593 Epoxy Substances 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- KYEPHZAHIRDQSR-SXASYTFBSA-L potassium;sodium;4-[[(1r,2r,4ar,5r,8as)-2-(3-carboxylatopropanoyloxy)-1,4a-dimethyl-6-methylidene-5-[(e)-2-(5-oxo-2h-furan-4-yl)ethenyl]-3,4,5,7,8,8a-hexahydro-2h-naphthalen-1-yl]methoxy]-4-oxobutanoate Chemical compound [Na+].[K+].C(/[C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@H]([C@]2(COC(=O)CCC([O-])=O)C)OC(=O)CCC([O-])=O)=C\C1=CCOC1=O KYEPHZAHIRDQSR-SXASYTFBSA-L 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 241000746375 Andrographis Species 0.000 description 5
- YQYBUJYBXOVWQW-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3,4-dihydro-1H-isoquinolin-2-yl)methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1CC2=CC=CC=C2CC1 YQYBUJYBXOVWQW-UHFFFAOYSA-N 0.000 description 5
- 230000036760 body temperature Effects 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 230000003115 biocidal effect Effects 0.000 description 4
- 229940125773 compound 10 Drugs 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- 229920000647 polyepoxide Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000008354 sodium chloride injection Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 239000003053 toxin Substances 0.000 description 4
- 231100000765 toxin Toxicity 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 230000003068 static effect Effects 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- -1 iginates Species 0.000 description 2
- 239000000644 isotonic solution Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000012982 microporous membrane Substances 0.000 description 2
- 239000006916 nutrient agar Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000002689 soil Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- VYWYYJYRVSBHJQ-UHFFFAOYSA-N 3,5-dinitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 VYWYYJYRVSBHJQ-UHFFFAOYSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 241000207965 Acanthaceae Species 0.000 description 1
- 244000118350 Andrographis paniculata Species 0.000 description 1
- 208000031636 Body Temperature Changes Diseases 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 241000581650 Ivesia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 241001529246 Platymiscium Species 0.000 description 1
- 235000014258 Polygonum bistorta Nutrition 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 240000003186 Stachytarpheta cayennensis Species 0.000 description 1
- 235000009233 Stachytarpheta cayennensis Nutrition 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 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
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 241001123263 Zostera Species 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 210000000544 articulatio talocruralis Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000011549 displacement method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 230000037308 hair color Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses 11 types of sulfonationderivant of andrographolide and the medical combination containing the sulfonationderivant of andrographolide, which has functions for antisepsis, antiinflammation and refrigeration. The present invention has the advantages of obvious treating effects, stable chemical properties and good water solubility. Quality standards are specific and controllable, and the present invention can be used for preparing frozen dry powder ampules, or injection, or oral preparations. The present invention can be used for treating diseases, such as pneumonia, bronchitis, tonsillitis, bacillary dysentery, etc.
Description
Technical field
The present invention relates to have the sulfonated derivative of andrographolide of antibiotic, anti-inflammatory, refrigeration function and contain their pharmaceutical composition.
Background technology
Herba Andrographis (Andrographis paniculata (Burm.f.) Nees) is Acanthaceae Herba Andrographis platymiscium, calls Herba Andrographitis, cuts snakeweed, eel grass, olive lotus, originates in India, and areas such as Fujian, China Guangdong are extensively cultivation also.Chemistry and pharmacological evaluation show the activeconstituents of Herba Andrographis for being the diterpene-kind compound and the glucoside derivative of representative with the rographolide, and the rographolide structure is:
Molecular formula: C
20H
30O
5, be colourless square or rectangle crystallization, m.p.230-232 ℃, [α]
D 20-126 ° of (c0.2, H
2O).Flavor is extremely bitter, dissolves in methyl alcohol, ethanol, propyl alcohol, the pyridine, is slightly soluble in chloroform, ether, is insoluble in water and sherwood oil.Water insoluble because of rographolide, brought difficulty for the preparation injection liquid.At present, existing several different methods is used to transform rographolide and becomes various derivatives, to improve the water-soluble of rographolide.The present application people once applied for " sulfonation process of water soluble andrographolide " (patent No. ZL01131382.x.), wherein the structure identification to sulfonated derivative of andrographolide is wrong, in fact the total sulfonated bodies that generates after the rographolide sulfonation is a mixture, thereby be difficult to formulate quality standard, and have influence on the quality control of product.
Summary of the invention
The technical problem to be solved in the present invention is in the mixture (being total sulfonated bodies) how to obtain from " sulfonation process of water soluble andrographolide " (patent No. ZL01131382.x.), isolate the various derivatives that generate after the rographolide sulfonation, be the various sulfonated derivatives of rographolide, identify its chemical structure, study and filter out and have excellent antibacterial, anti-inflammatory, the sulfonated derivative of andrographolide that the structure of refrigeration function is clear and definite, comprise the mixture of forming by the clear and definite sulfonated derivative of andrographolide of structure, and contain they and the pharmaceutical composition of available support pharmaceutically.
For addressing the above problem, the invention provides following technical scheme:
Sulfonated derivative of andrographolide or its mixture of following general formula (I), (II) expression:
General formula (I)
R in the general formula (I)
1, R
2Be selected from independently of one another-H ,-SO
3H; R
3During for hydroxyl, R
4For-ONa, perhaps R
3=R
4=-O-;
General formula (II)
R in the general formula (II)
1, R
2Be selected from independently of one another-H ,-SO
3H; R
3Be the H of R body or the H of S body; R
4Methyl for the S body.
The mixture of described general formula (I), (II) sulfonated derivative of andrographolide is meant the sulfonated derivative of andrographolide assembly arbitrarily of general formula (I), (II) expression, promptly be selected from the sulfonated derivative of andrographolide of general formula (I), (II) expression two or more, can reach 11 kinds.
Aforementioned formula (I), (II) sulfonated derivative of andrographolide or its mixture, wherein
General formula (I)
R 1 | R 2 | R 3 | R 4 | |
Compound 1 compound 2 compounds 3 compounds 4 compounds 5 | H SO 3H SO 3H H SO 3H | SO 3H H SO 3H SO 3H H | OH OH | ONa ONa R 3=R 4 O O O |
General formula (II)
Above-mentioned general formula (I), (II) sulfonated derivative of andrographolide or its mixture, wherein mixture is meant two or more mixture in the sulfonated derivative of andrographolide that is selected from general formula (I), (II) expression.Wherein mixture is meant two or more mixture that is selected from compound 1, compound 4, compound 5, the compound 8 preferably.
The pharmaceutical composition of general formula of the present invention (I), (II) sulfonated derivative of andrographolide or its mixture mainly is made up of general formula (I), (II) sulfonated derivative of andrographolide or its mixture and pharmaceutically acceptable carrier.
The pharmaceutical composition of general formula of the present invention (I), (II) sulfonated derivative of andrographolide or its mixture mainly is made up of general formula (I), (II) sulfonated derivative of andrographolide or its mixture and water for injection.
The pharmaceutical composition of general formula of the present invention (I), (II) sulfonated derivative of andrographolide or its mixture mainly is made up of general formula (I), (II) sulfonated derivative of andrographolide or its mixture and N.F,USP MANNITOL freeze-dried powder auxiliary material.
The pharmaceutical composition of general formula of the present invention (I), (II) sulfonated derivative of andrographolide or its mixture mainly is made up of general formula (I), (II) sulfonated derivative of andrographolide or its mixture and oral preparations auxiliary material.
The invention provides new sulfonated derivative of andrographolide, provide the pharmaceutical composition that contains them antibiotic simultaneously in preparation, anti-inflammatory, analgesic, the application in the antiviral.
The present invention is raw material with the rographolide, take process for sulfonation, prepared a series of new sulfonated derivative of andrographolide, these sulfonated bodies derivant structures are clear and definite, have good antibiotic, anti-inflammatory, analgesic, antiviral activity is made clear and definite, quality controllable, the preparation stabilization of Chemical Composition behind all kinds of preparations, to pneumonia, upper respiratory tract infection such as bronchitis have good therapeutic action.Compare with rographolide and the total sulfonated bodies of rographolide, these sulfonated derivative of andrographolide water solubility of monomer are good, purity is high, and quality controllable.
The present invention includes from the total sulfonated bodies of rographolide to separate and obtain above-mentioned 11 kinds of sulfonated derivative of andrographolide, be the new constituent that obtains first, have good water-solubility, stability, can be made into various preparations, be particularly useful for preparing intravenous injection.11 kinds of sulfonated derivative of andrographolide all have good antibiotic, anti-inflammatory, refrigeration function.
The preparation method of the total sulfonated bodies of rographolide is referring to the separation of patent of invention ZL01131382.x. sulfonated derivative of andrographolide, purification process: get the total sulfonated bodies 50g of rographolide, add water 50mL and make dissolving fully, filter, the D101 type macroporous resin column of anticipating on the sample liquid, water successively, 10%, 20%, 30%, 40%, 50%, 80%, 90% ethanol carries out gradient elution, tentatively be divided into six sections [F1 (10%), F2 (20%), F3 (30%), F4 (40%-50%), F5 (80%), F6 (90%)] silica gel H on the back, ODS (reversed-phase column) and Sephadex LH-20 (gel) post etc. carry out separation and purification, finally obtain 11 compounds.The F1 section is by the ODS post, and 20%~25% methyl alcohol carries out wash-out, gets compound 1 (rographolide 19-sulfuric ester, 16-carboxylic acid sodium salt) and compound 2 (rographolide 3-sulfuric ester, 16-carboxylic acid sodium salt); The F2 section is by the ODS post, and the methyl alcohol with 30%~40% carries out getting compound 3 (3,19-di-sulfate rographolide) and compound 5 (3-sulfuric ester rographolide) behind the wash-out; The F3 section goes up the silica gel H post for three times repeatedly with chloroform-methanol (6: 1) separates, and carries out purifying through Sephadex LH-20, gets compound 4 (19-sulfuric ester rographolide); F5 and F6 section are carried out silica gel column chromatography three times repeatedly with chloroform-methanol (9: 1), get compound 6 (8 (12)-epoxy rographolide (8S, 12S)) and compound 9 (8 (12)-epoxy rographolide (8S, mixture 12R)), the compound 6 that is prepared through HPLC and the pure product of compound 9 again; After concentrating, the F4 section separates three times with the silica gel H post repeatedly, carry out wash-out with chloroform-methanol (6: 1~4: 1), carry out purifying through Sephadex LH-20, and prepare the type post in conjunction with HPLC and be prepared, final compound 7 (8 (12)-epoxies, the 19-sulfuric ester, rographolide (8S, 12S)), compound 8 (8 (12)-epoxies, the 3-sulfuric ester, rographolide (8S, 12S)), compound 10 (8 (12)-epoxies, the 19-sulfuric ester, rographolide (8S, 12R)) and compound 11 (8 (12)-epoxies, 3-sulfuric ester, rographolide (8S, 12R)).
Embodiment
Embodiment 1
Prepare the total sulfonated bodies of rographolide (referring to ZL01131382.x.) with the rographolide process for sulfonation:.
The extraction of rographolide:
Get Herba Andrographis 1000g, add the ethanol 5000ml of 90% above concentration, cold soaking, 72 hours for the first time, 24 hours for the second time, cooling bath is evacuated in the return tank, press the Folium Andrographis charging capacity and calculate, add the 15-18% gac, refluxed 2 hours; Liquid filtering behind the reflux decolour, filtrate is concentrated into when 10% left and right sides ethanol is still arranged and emits, crystallization in static 24 hours, with coarse crystallization ethanol successive soaking twice, each time was not less than 6 hours, filtered, crystallization is added 8 times of amount ethanol, after the heating for dissolving, filtered in static 24 hours white crystals, crystallization vacuum-drying is got rographolide.
The sulfonation of rographolide:
Get dehydrated alcohol 1000ml, put in the reaction flask, slowly drip sulfuric acid 600ml, after stirring evenly, add the 1000g rographolide, stir, room temperature was placed 72 hours.Put adding ethanol 1000ml in the water-bath, stir evenly, transfer pH to 7.0, add ethanol, reach 80% to containing the alcohol amount, static 24 hours, the adding small amount of activated was filtered, and filtrate recycling ethanol is condensed into thick paste, and vacuum-drying promptly gets total sulfonated bodies of rographolide.
Embodiment 2
The separation of compound 1, compound 2, purifying
(high-efficient silica gel plate and silica gel H are that Haiyang Chemical Plant, Qingdao produces; C18 (ODS post) is Merck ﹠ Co., Inc.'s product; All reagent are analytical pure.Down together.)
Get the total sulfonated bodies 50g of rographolide and add water 50ml dissolving, filter the D101 macroporous resin column of anticipating on the back, water, 10%, 20%, 30%, 40%, 50%, 80%, 90% ethanol carry out gradient elution successively.
Get 10% ethanol eluate of D101 macroporous resin column, concentrate the back and go up the ODS post, use 20% methanol-eluted fractions earlier, use 25% methanol-eluted fractions again.
20% meoh eluate concentrates the back recrystallizing methanol, filters, and crystallization vacuum-drying (60 ℃) gets compound 1.25% meoh eluate concentrates the back recrystallizing methanol, filters, and crystallization vacuum-drying (60 ℃) gets compound 2.
The physico-chemical property of compound 1 and spectral data
The chemistry Chinese: 3,14,19-trihydroxy--8 (9), 12 (13)-labdanum diene-16-carboxylic acid sodium, 19-sulfuric ester.
Colourless needle (methyl alcohol) is soluble in methyl alcohol, water, is slightly soluble in acetone, is insoluble to chloroform, ether and sherwood oil.
Molecular formula: C
20H
31O
8SNa, molecular weight: 493.11; Mp:230-232 ℃; [α]
D 24:-62.0 (c 0.1, MeOH).
ESI-MS:493[M+Na]
+
1H-NMR(CD
3OD)δ:6.45(1H,dd,J=4.8Hz,7.8Hz,H-12),4.58(1H,dd,J=4.8Hz,7.5Hz,H-14),3.67(1H,dd,J=11.1,7.7Hz,H-15),3.50(1H,dd,J=11.1,4.9Hz,H-15),4.18(2H,q,J=10.2Hz,H-19),3.25(1H,dd,J=11.1,5.1Hz,H-3),3.0(1H,dd,J=17.3,7.9Hz,H-11),2.73(1H,dd,J=17.3,4.9Hz,H-11),1.54(3H,s,H-17),1.19(3H,s,H-18),1.05(3H,s,H-20)
13C-NMR(CD
3OD)δ:19.7(C-17),20.5(C-20),21.2(C-6),23.4(C-18),27.4(C-11),28.6(C-2),35.7(C-7),36.7(C-1),40.0(C-10),43.5(C-4),53.7(C-5),67.3(C-15),70.9(C-19),72.0(C-14),80.0(C-3),129.2(C-8),134.8(C-13),139.6(C-9),141.5(C-12),175.9(C-16).
The physico-chemical property of compound 2 and spectral data
The chemistry Chinese: 3,14,19-trihydroxy--8 (9), 12 (13)-labdanum diene-16-carboxylic acid sodium, 3-sulfuric ester
Colourless needle (methyl alcohol) is soluble in methyl alcohol, water, is slightly soluble in acetone, is insoluble to chloroform, ether and sherwood oil.
Molecular formula: C
20H
31O
8SNa, molecular weight: 493.11; Mp:242-244 ℃; [α]
D 24:-53.0 (c 0.1, MeOH).
ESI-MS:493[M+Na]
+
1H-NMR(CD
3OD)δ:6.46(1H,dd,J=4.8Hz,7.8Hz,H-12),4.60(1H,dd,J=2.8Hz,9.0Hz,H-14),4.16(2H,q,J=6Hz,H-19),3.67(1H,dd,J=11.1,7.7Hz,H-15),3.50(1H,dd,J=11.1,4.9Hz,H-15),3.26(1H,dd,J=11.1,4.6Hz,H-3),3.0(1H,dd,J=10.4,4.8Hz,H-11),2.73(1H,dd,J=10.4,2.8Hz,H-11),1.54(3H,s,H-17),1.20(3H,s,H-18),1.05(3H,s,H-20);
13C-NMR(CD
3OD)δ:19.7(C-17),20.6(C-20),21.2(C-6),23.3(C-18),27.4(C-11),28.6(C-2),35.7(C-7),36.7(C-1),39.9(C-10),43.4(C-4),54.0(C-5),67.1(C-15),70.8(C-19),72.0(C-14),88.1(C-3),129.3(C-8),134.6(C-13),139.5(C-9),141.5(C-12),175.9(C-16).
Embodiment 3
The separation of compound 3, compound 5, purifying
Get the ethanol eluate of D101 macroporous resin column 20% among the embodiment 2, concentrate the back and go up the ODS post, use 30% methanol-eluted fractions earlier, use the 35-40% methanol-eluted fractions again.30% meoh eluate concentrates the back recrystallizing methanol, filters, and crystallization vacuum-drying (60 ℃) gets compound 3.
The 35-40% meoh eluate concentrates the back recrystallizing methanol, filters, and crystallization vacuum-drying (60 ℃) gets compound 5.
The physico-chemical property of compound 3 and spectral data
The chemistry Chinese: 3,14,19-trihydroxy--8 (9), 12 (13)-labdanum diene-15,16-lactone-19-sulfuric ester.
Colourless needle (methyl alcohol) is soluble in methyl alcohol, water, is slightly soluble in acetone, is insoluble to chloroform, ether and sherwood oil.
Molecular formula: C
20H
30O
11S
2, molecular weight: 510; Mp:251-253 ℃; [α]
D 24:-27.0 (c 0.1, MeOH).
IR
max KBrcm
-1:3437(OH),1759,1669(C=C-C=O),1630,1637(C=C),1293,1254,1204,1068,995,972,436,418;
ESI-MS:511[M+H]
+,350[M-SO
3H]
+,430[M-SO
3H-SO
3H]
+;
1H-NMR(CD
3OD)δ:6.74(1H,m,H-12),5.07(1H,dd,J=1.4Hz,4.5Hz,H-14),4.49(1H,dd,J=10.2,6.2Hz,H-15),4.15(1H,dd,J=10.2,2.3Hz,H-15),4.36(1H,d,J=10.1Hz,H-19),4.05(1H,d,J=10.1Hz,H-19),4.0(1H,dd,J=12.2,4.4Hz,H-3),3.27(1H,dd,J=17.7Hz,4.9Hz,H-11),3.12(1H,dd,J=17.7,5.0Hz,H-11),1.62(3H,s,H-17),1.27(3H,s,H-18),1.17(3H,s,H-20).
13C-NMR(CD
3OD)δ:19.8(C-17),20.2(C-20),21.8(C-6),23.6(C-18),25.8(C-2),29.2(C-11),35.8(C-7),36.6(C-1),40.0(C-10),43.0(C-4),54.0(C-5),66.8(C-14),71.0(C-19),76.0(C-15),86.8(C-3),129.1(C-13),130.5(C-8),138.0(C-9),149.5(C-12),172.7(C-16)
The physico-chemical property of compound 5 and spectral data
The chemistry Chinese: 3,14,19-trihydroxy--8 (9), 12 (13)-labdanum diene-15,16-lactone-3-sulfuric ester.
Colourless needle (methyl alcohol) is soluble in methyl alcohol, water, is slightly soluble in acetone, is insoluble to chloroform, ether and sherwood oil.
Molecular formula: C
20H
30O
8S, molecular weight: 430; Mp:159-161 ℃; [α]
D 24:-36.0 (c 0.1, MeOH).
IR
max KBrcm
-1:3414(OH),1749,1670(C=C-C=O),1470,1427(C=C),1254,1230,1218,1197,1060,1033,966,981,,922,832,582;
ESI-MS:429[M-H]
+,349[M-SO
3H]
+,412[M-H
2O]
+;
1H-NMR(CD
3OD)8:6.72(1H,m,H-12),5.06(1H,dd,J=1.4Hz,4.5Hz,H-14),4.49(1H,dd,J=10.2,6.2Hz,H-15),4.15(1H,dd,J=10.2,2.3Hz,H-15),4.36(1H,d,J=10.1Hz,H-19),4.05(1H,d,J=10.1Hz,H-19),4.04(1H,dd,J=11.8,4.4Hz,H-3),3.26(1H,dd,J=17.6Hz,5.2Hz,H-11),3.10(1H,dd,J=17.6,5.0Hz,H-11),1.61(3H,s,H-17),1.22(3H,s,H-18),1.03(3H,s,H-20).
13C-NMR(CD
3OD)δ:19.8(C-17),20.6(C-20),20.7(C-6),23.1(C-18),25.7(C-2),29.0(C-11),35.4(C-7),36.3(C-1),39.8(C-10),44.3(C-4),53.9(C-5),64.1(C-14),66.9(C-19),76.0(C-15),87.9(C-3),129.2(C-13),130.4(C-8),137.9(C-9),149.3(C-12),172.6(C-16).
Embodiment 4
The separation of compound 4, purifying
Get the ethanol eluate of D101 macroporous resin column 30% among the embodiment 2, go up the silica gel H post after concentrating repeatedly for three times and separate, eluting solvent is chloroform-methanol (6: 1), carries out purifying through Sephadex LH-20 again, and recrystallizing methanol gets compound 4.
The physico-chemical property of compound 4 and spectral data
The chemistry Chinese: 3,14,19-trihydroxy--8 (9), 12 (13)-labdanum diene-15,16-lactone-19-sulfuric ester.
Off-white color or pale yellow powder are soluble in methyl alcohol, water, are slightly soluble in acetone, are insoluble to chloroform, ether and sherwood oil.
Molecular formula: C
20H
30O
8S, molecular weight: 430; Mp:166-168 ℃; [α]
D 24:-48.0 (c 0.1, MeOH).
UVλ
max MeOH nm:227;
IR
max KBrcm
-1:3431(OH),1734,1636(C=C-C=O),1541,1457(C=C),1214,1070,983,436,418;
ESI-MS:429[M-H]
+,349[M-SO
3H]
+,412[M-H
2O]
+;
1H-NMR(CD
3OD)δ:6.74(1H,m,H-12),5.06(1H,d,J=4.8Hz,H-14),4.48(1H,dd,J=10.2,6.2Hz,H-15),4.15(1H,dd,J=10.2,2.3Hz,H-15),3.20(1H,dd,J=17.6,5.0Hz,H-11),3.08(1H,dd,J=17.6,5.2Hz,H-11),1.60(3H,s,H-17),1.14(3H,s,H-18),1.10(3H,s,H-20).
13C-NMR(CD
3OD)δ:19.9(C-17),20.5(C-20),21.2(C-6),23.4(C-18),28.6(C-2),29.1(C-11),35.7(C-7),36.8(C-1),40.0(C-10),43.5(C-4),53.6(C-5),66.9(C-14),71.0(C-19),76.1(C-15),79.8(C-3),129.2(C-13),130.5(C-8),138.1(C-9),149.6(C-12),172.7(C-16).
Embodiment 5
The separation of compound 6, compound 9, purifying
Get the ethanol eluate of D101 macroporous resin column 80%~90% among the embodiment 2, concentrate the back and make eluting solvent with chloroform-methanol (9: 1), carry out silica gel column chromatography three times repeatedly, elutriant is prepared through HPLC again, and chromatographic condition is: chromatographic column: phe-nomenex C18-ODS (250mm * 10.0mm 5 μ m); Moving phase is: methyl alcohol: water (30: 70), flow velocity: during 2ml/min, be prepared into compound 6; Moving phase is: methyl alcohol: water (45: 55), flow velocity: during 2ml/min, be prepared into compound 9.
The physico-chemical property of compound 6 and spectral data
The chemistry Chinese: 3,19-dihydroxyl-8 (12) epoxies-13 (14)-labdanum alkene-15,16-lactone.
Colourless needle is soluble in methyl alcohol, acetone, is slightly soluble in chloroform, is insoluble to ether and sherwood oil.
Molecular formula: C
20H
30O
5, molecular weight: 350.1; Mp:210-212 ℃; [α]
D 24:-16.4 (c 0.1, MeOH).
IR
max KBrcm
-1:3489,3425cm
-1(OH),1758,1650cm
-1,(C=C-C=O),1450,1380(C=C),1223,1196,1083,1031,1019,988,963,846;
ESI-MS:349[M-H]
+,301[M-CH
2OH-H
2O]
+,257[M-H
2O-CH
2OH-CO
2]
+;
1H-NMR(CD
3OD)δ:7.43(1H,t,J=1.5Hz,H-14),4.85(2H,m,H-15),4.80(1H,t,J=6.7Hz,H-12),4.03(1H,d,J=11.1Hz,H-19),3.46(1H,d,J=11.1Hz,H-19),3.21(1H,dd,J=4.7,11.9Hz,H-3),2.18(1H,dd,J=11.3,12.2Hz,H-11),1.64(1H,t,J=10.2Hz,H-11),1.20(3H,s,H-18),
1.19(3H,s,H-17),0.90(3H,s,H-20).
13C-NMR(CD
3OD)δ:39.1(C-1),28.3(C-2),81.2(C-3),43.7(C-4),57.7(C-5),22.0(C-6),41.1(C-7),83.3(C-8),59.4(C-9),37.0(C-10),29.7(C-11),72.0(C-12),137.1(C-13),148.4(C-14),72.4(C-15),174.8(C-16),21.8(C-17),23.5(C-18),65.0(C-19),15.9(C-20).
The physico-chemical property of compound 9 and spectral data
The chemistry Chinese: 3,19-dihydroxyl-8 (12) epoxies-13 (14)-labdanum alkene-15, the 16-lactone is a white powder, soluble in water, methyl alcohol is slightly soluble in acetone, is insoluble to ether and sherwood oil.
Molecular formula: C
20H
30O
8S, molecular weight: 430;
1H-NMR(CD
3OD)δ:7.46(1H,m,H-14),4.86(2H,m,H-15),4.60(1H,m,H-12),3.80(1H,d,J=11.2Hz,H-19),3.60(1H,d,J=11.2Hz,H-19),4.03(1H,m,H-3),1.22(3H,s,H-18),1.13(3H,s,H-17),1.0(3H,s,H-20).
13C-NMR(CD
3OD)δ:40.3(C-1),25.1(C-2),87.9(C-3),44.3(C-4),54.3(C-5),37.2(C-6),19.8(C-7),84.3(C-8),58.0(C-9),36.8(C-10),33.8(C-11),72.3(C-12),138.4(C-13),147.0(C-14),74.2(C-15),175.0(C-16),31.9(C-17),23.4(C-18),64.0(C-19),16.6(C-20).
Embodiment 6
The separation of compound 7, compound 8, purifying
Get 40%~50% ethanol eluate of D101 macroporous resin column among the embodiment 2, go up the silica gel H post three times repeatedly after concentrating, all use chloroform-methanol (6: 1~4: 1) to carry out gradient elution at every turn, carry out purifying through Sephadex LH-20, get the mixture of compound 7,8, be prepared through HPLC again, chromatographic condition: chromatographic column: Waters Novapak C18 (40mm * 150mm.6 μ m), moving phase is methyl alcohol: water: during phosphoric acid (30: 70: 0.2), get compound 7; Moving phase is methyl alcohol: water: during phosphoric acid (40: 60: 0.2), get compound 8.
The physico-chemical property of compound 7 and spectral data
The chemistry Chinese: 3,19-dihydroxyl-8 (12) epoxies-13 (14)-labdanum alkene-15,16-lactone-19 sulfuric ester.
Colourless needle, soluble in water, methyl alcohol is slightly soluble in acetone, is insoluble to ether and sherwood oil
Molecular formula: C
20H
30O
8S, molecular weight: 430; Mp:255-257 ℃; [α]
D 24:-18.4 (c 0.1, MeOH).
ESI-MS:429[M-H]
+,301[M-CH
2OH-H
2O-SO
3H]
+;
1H-NMR(CD
3OD)δ:7.43(1H,t,J=1.5Hz,H-14),4.85(2H,m,H-15),4.83(1H,m,H-12),4.20(1H,d,J=10.2Hz,H-19),4.15(1H,d,J=10.2Hz,H-19),3.21(1H,dd,J=4.7,11.9Hz,H-3),1.22(3H,s,H-18),1.18(3H,s,H-17),1.0(3H,s,H-20).
13C-NMR(CD
3OD)δ:39.5(C-1),27.9(C-2),80.0(C-3),43.5(C-4),57.9(C-5),23.0(C-6),41.4(C-7),83.5(C-8),59.5(C-9),37.1(C-10),29.7(C-11),71.9(C-12),137.2(C-13),148.5(C-14),72.4(C-15),174.9(C-16),21.6(C-17),23.3(C-18),71.0(C-19),15.5(C-20).
The physico-chemical property of compound 8 and spectral data
The chemistry Chinese: 3,19-dihydroxyl-8 (12) epoxies-13 (14)-labdanum alkene-15,16-lactone-3 sulfuric ester.
Be white powder, soluble in water, methyl alcohol is slightly soluble in acetone, is insoluble to ether and sherwood oil.
Molecular formula: C
20H
30O
8S, molecular weight: 430;
1H-NMR(CD
3OD)δ:7.43(1H,m,H-14),4.86(2H,m,H-15),4.56(1H,m,H-12),4.03(1H,m,H-19),3.60(1H,d,J=11.1Hz,H-19),4.56(1H,m,H-3),1.20(3H,s,H-18),1.19(3H,s,H-17),0.93(3H,s,H-20)
13C-NMR(CD
3OD)δ:39.1(C-1),25.1(C-2),88.2(C-3),44.3(C-4),58.1(C-5),23.2(C-6),41.1(C-7),83.2(C-8),59.1(C-9),36.8(C-10),29.7(C-11),71.9(C-12),137.2(C-13),148.4(C-14),72.4(C-15),174.8(C-16),21.6(C-17),23.4(C-18),64.0(C-19),15.3(C-20).
Embodiment 7
The separation of compound 10, compound 11, purifying
Get 40%~50% ethanol eluate of D101 macroporous resin column among the embodiment, go up the silica gel H post three times repeatedly after concentrating, carry out gradient elution with chloroform-methanol (6: 1~4: 1), elutriant prepares the type post through HPLC and carries out purifying, chromatographic condition: chromatographic column Waters Novapak C18 (40mm * 150mm.6 μ m) is a water with moving phase earlier: acetonitrile: 0.05M phosphoric acid (58: 12: 30); It is water with moving phase again: acetonitrile: 0.05M phosphoric acid (30: 40: 30).
Moving phase is water: acetonitrile: during 0.05M phosphoric acid (58: 12: 30), get compound 10; Moving phase is water: acetonitrile: during 0.05M phosphoric acid (30: 40: 30), get compound 11.
The physico-chemical property of compound 10 and spectral data
The chemistry Chinese: 3,19-dihydroxyl-8 (12) epoxies-13 (14)-labdanum alkene-15,16-lactone.
Colourless needle is soluble in methyl alcohol, acetone, is slightly soluble in chloroform, is insoluble to ether and sherwood oil.
Molecular formula: C
20H
30O
5, molecular weight: 350.1; Mp:210-212 ℃; [α]
D 24:-21.4 (c 0.1, MeOH).
IR
max KBrcm
-1:3489,3425cm
-1(OH),1758,1650cm
-1,(C=C-C=O),1450,1380(C=C),1223,1196,1083,1031,1019,988,963,846;
ESI-MS:349[M-H]
+,305[M-CO
2-H]
+;
1H-NMR(CD
3OD)δ:7.46(1H,m,H-14),4.85(2H,m,H-15),4.66(1H,m,H-12),4.05(1H,d,J=11.1Hz,H-19),3.46(1H,d,J=11.1Hz,H-19),3.35(1H,dd,J=4.9,11.6Hz,H-3),2.37(1H,dd,J=13.2,6.8Hz,H-11),2.07(1H,td,J=10.2Hz,H-11),1.22(3H,s,H-18),1.13(3H,s,H-17),1.0(3H,s,H-20).
13C-NMR(CD
3OD)δ:40.4(C-1),28.4(C-2),81.5(C-3),43.5(C-4),53.7(C-5),37.2(C-6),19.5(C-7),84.4(C-8),59.6(C-9),36.9(C-10),33.9(C-11),74.3(C-12),138.5(C-13),146.5(C-14),72.4(C-15),175.0(C-16),32.0(C-17),23.5(C-18),65.2(C-19),17.0(C-20)..
The physico-chemical property of compound 11 and spectral data
The chemistry Chinese: 3,19-dihydroxyl-8 (12) epoxies-13 (14)-labdanum alkene-15,16-lactone.
Colourless needle, soluble in water, methyl alcohol is slightly soluble in acetone, is insoluble to ether and sherwood oil
Molecular formula: C
20H
30O
8S, molecular weight: 430; Mp:255-257 ℃; [α]
D 24:-18.4 (c 0.1, MeOH).
IR
max KBrcm
-1:3489,3425cm
-1(OH),1758,1650cm
-1,(C=C-C=O);
ESI-MS:429[M-H]
+,301[M-CH
2OH-H
2O-SO
3H]
+,;
1H-NMR(CD
3OD)δ:7.41(1H,m,H-14),4.84(2H,m,H-15),4.64(1H,m,H-12),4.28(1H,d,J=11.2Hz,H-19),3.14(1H,d,J=11.2Hz,H-19),3.24(1H,dd,J=4.7,11.6Hz,H-3),2.39(1H,dd,J=13.2,6.8Hz,H-11),2.07(1H,td,J=10.2Hz,H-11),1.20(3H,s,H-18),1.13(3H,s,H-17),1.0(3H,s,H-20);
13C-NMR(CD
3OD)δ:40.4(C-1),28.4(C-2),81.5(C-3),43.5(C-4),53.7(C-5),37.2(C-6),19.5(C-7),84.4(C-8),59.6(C-9),36.9(C-10),33.9(C-11),74.3(C-12),138.5(C-13),146.5(C-14),72.4(C-15),175.0(C-16),32.0(C-17),23.5(C-18),65.2(C-19),17.0(C-20)..
Embodiment 8
One, animal acute toxicity test
1. test objective: measure acute reaction and the death condition of the composition of compound 1,2,3,4,5,7,8, compound 4 and compound 5 through vein single administration mouse.
2. test materials:
2.1 trial drug
The composition of compound 1, compound 2, compound 3, compound 4, compound 5, compound 7, compound 8, compound 4 and compound 5, concentration is 0.1g/ml, is provided by Jiangxi QingFeng Pharmacy Co., Ltd.Lot number: 20030806.
2.2 animal subject
The ICR mouse, body weight 18-20g, male and female half and half are supplied with by Jiangxi QingFeng Pharmacy Co., Ltd's Experimental Animal Center.Laboratory animal occupancy permit number: SKYX (Jiangxi) 2003-0001
3. test conditions:
Before and after the administration, the experiment mice male and female are divided cage, and full-valence pellet feed is fed, and freely drinks water 20 ± 2 ℃ of room temperatures, humidity: 45%-65%.
4. test method and result:
4.1 method: get 180 of ICR mouse, body weight 18-20g, male and female half and half.Be divided into 9 groups at random, 20 every group.Control group: 0.9% sodium chloride injection.The composition of the compound 1 of sample sets: 100mg/ml, compound 2, compound 3, compound 4, compound 5, compound 7, compound 8, compound 4 and compound 5.Sample sets is once given mouse tail vein injection 25ml/kg respectively, and control group gives 0.9% sodium chloride injection of equivalent.Observed for two weeks continuously, record is tried situations such as mouse behavior, activity, food ration, body weight, ight soil, death, and not dead mouse is put to death after two weeks and performs an autopsy on sb.
4.2 test-results:
Group | Administration volume (ml/kg) | Number of animals (only) | Dead animal number (only) | Maximum dosage-feeding (mg/kg) | Be equivalent to the clinical application multiple |
Control group | 25.0 | 20 | 0 | / | / |
Sample sets | |||||
Compound 1 | 25.0 | 20 | 0 | 2500 | 600 |
Compound 2 | 25.0 | 20 | 0 | 2500 | 600 |
Compound 3 | 25.0 | 20 | 0 | 2500 | 600 |
Compound 4 | 25.0 | 20 | 0 | 2500 | 600 |
Compound 5 | 25.0 | 20 | 0 | 2500 | 600 |
Compound 7 | 25.0 | 20 | 0 | 2500 | 600 |
Compound 8 | 25.0 | 20 | 0 | 2500 | 600 |
Compound 4 and compound 5 compositions | 25.0 | 20 | 0 | 2500 | 600 |
100mg/ml×25ml/kg (2500mg/kg+250mg/60kg) |
(20 mouse of dosage vein single administration of 100mg/ml * 25ml/kg) saw that the mouse hair color was smooth, movable the same day, ingested, ight soil color and luster and quality be normal, with control group no significant difference relatively to press 2500mg/kg; And do not have dead in two weeks and other unusual phenomenon takes place, two groups perform an autopsy on sb after putting to death simultaneously, and each main organs (heart, liver, spleen, lung, kidney) changes through the visual inspection no abnormality seen, with control group no significant difference relatively.
4.3 conclusion (of pressure testing):
Maximum dosage-feeding test-results through the vein single administration shows: all do not have tangible toxic reaction after 160 mouse administrations, also do not have dead in two weeks.Therefore, compound 1, compound 2, compound 3, compound 4, compound 5, compound 7, compound 8, compound 4 and compound 5 compositions, once the mouse maximum dosage-feeding through intravenously administrable is 2500mg/kg, calculate by clinical adult's consumption every day 250mg/60kg, then be equivalent to 600 times of clinical adult's consumption.
Two, pharmacodynamic study
1. material
1.1 medicine: the composition of compound 1, compound 4, compound 5, compound 8, compound 4 and compound 5 is provided lot number: 20030816 by Jiangxi QingFeng Pharmacy Co., Ltd, high dosage: 300mg/kg, middle dosage: 150mg/kg, low dosage: 75mg/kg, all fresh at every turn preparation.
Injection potassium sodium dehydroandroan drographolide succinate (14-deshydroxy-11.12-two dehydrogenations rographolide-3.9-disuccinic acid half ester k-na salt), Chongqing Yaoyou Pharmaceutical Co., Ltd., lot number: 20030509.
1.2 animal: mouse, body weight 22-25g; The Wistar rat, body weight 150-200g; Rabbit 2.5-3.0kg, all the male and female dual-purpose is provided by Jiangxi QingFeng Pharmacy Co., Ltd's Experimental Animal Center.Animal occupancy permit: SKYX (Jiangxi) 2003-0001.
1.3 reagent: intracellular toxin 10EU/ props up, Nat'l Pharmaceutical ﹠ Biological Products Control Institute; 2.4-dinitrophenol(DNP), Shanghai chemical reagent factory, lot number: 20030312; Nutrient agar medium, Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
1.4 bacterial strain; Streptococcus aureus, intestinal bacteria, streptococcus pneumoniae provide by Jiangxi Medical College.
1.5 testing circumstance: temperature: 25 ± 3 ℃, humidity: 45-65%.
2. experimental technique and conclusion
2.1 refrigeration function
2.1.1 intracellular toxin is caused the influence of fever in rabbits
Test preceding 2 day every day and survey rabbit body temperature 1 time, select body temperature at 38.0-39.5 ℃, and self body temperature changes less than 85 of 0.3 ℃ rabbit, 2.5-3.0kg, male and female half and half, be divided into 17 groups at random, every group 5, one group in rabbit left side ear tissue edge intravenous injection physiological saline, and two groups in rabbit left side auricular vein injection potassium sodium dehydroandroan drographolide succinate 150mg/kg, and three to 17 groups respectively at rabbit left side ear vein injection compound 1, compound 4, compound 5, the composition of compound 8 and compound 4 and compound 5, high dosage: 300mg/kg, middle dosage: 150mg/kg, low dosage: 75mg/kg, each is organized volumetric injection and is 5ml/kg.Basal body temperature when before administration, measuring a body temperature and doing zero, after the administration immediately in rabbit right auricular vein injection intracellular toxin 200EU/kg, the body temperature when measuring 1h, 2h after the administration, 3h, 4h, 6h.(seeing the following form)
Fervescence (℃) |
Dosage | 1h | 2h | 3h | 4h | 6h | |
The physiological saline control group | / | 1.58±0.18 | 1.72±0.22 | 1.68±0.16 | 1.28±0.15 | 0.88±0.16 |
The injection potassium sodium dehydroandroan drographolide succinate | 150 | 0.72±0.16 | 1.10±0.22 | 1.52±0.24 | 1.25±0.28 | 1.23±0.23 |
Compound 1 | 300 | 0.18±0.12 | 0.22±0.15 | 0.20±0.14 | 0.16±0.11 | 0.15±0.12 |
150 | 0.58±0.21 | 0.62±0.18 | 0.52±0.23 | 0.48±0.13 | 0.42±0.11 | |
75 | 1.23±0.25 | 1.25±0.26 | 0.95±0.19 | 0.82±0.20 | 0.52±0.15 | |
Compound 4 | 300 | 0.23±0.15 | 0.31±0.13 | 0.46±0.17 | 0.69±0.16 | 0.51±0.13 |
150 | 0.62±0.22 | 0.68±0.19 | 0.46±0.12 | 0.36±0.13 | 0.32±0.11 | |
75 | 1.18±0.23 | 1.25±0.26 | 0.86±0.22 | 0.68±0.20 | 0.43±0.12 | |
Compound 5 | 300 | 0.32±0.18 | 0.45±0.22 | 0.58±0.25 | 0.39±0.20 | 0.30±0.16 |
150 | 0.68±0.23 | 0.79±0.22 | 0.86±0.17 | 0.48±0.19 | 0.36±0.18 | |
75 | 1.16±0.23 | 1.28±0.27 | 0.88±0.22 | 0.62±0.19 | 0.48±0.13 | |
Compound 8 | 300 | 0.26±0.16 | 0.48±0.21 | 0.62±0.22 | 0.72±0.19 | 0.38±0.12 |
150 | 0.57±0.22 | 0.66±0.18 | 0.71±0.22 | 0.49±0.14 | 0.45±0.12 | |
75 | 1.12±0.25 | 1.15±0.26 | 0.78±0.24 | 0.46±0.16 | 0.38±0.15 | |
The composition of compound 4 and compound 5 | 300 | 0.25±0.17 | 0.46±0.21 | 0.64±0.22 | 0.49±0.18 | 0.36±0.16 |
150 | 0.63±0.23 | 0.76±0.19 | 0.78±0.21 | 0.52±0.17 | 0.49±0.16 | |
75 | 1.21±0.26 | 1.32±0.28 | 0.88±0.24 | 0.76±0.16 | 0.58±0.17 |
2.1.2 the result shows: the composition 300mg/kg and the 150mg/kg of thing 5, compound 8, compound 4 and compound 5 in compound 1, compound 4, the change, fever in rabbits due to the intracellular toxin is all had good refrigeration function, and 75mg/kg is not obvious to refrigeration function.
2.2 anti-inflammatory action
2.2.1 egg white is caused the swollen influence of rat foot
85 of rats, 180-210g, male and female half and half, be divided into 17 groups at random, every group 5, one group of intravenous injection physiological saline, two groups of intravenous injection potassium sodium dehydroandroan drographolide succinate 200mg/kg, three, four, five groups of difference intravenous injection compounds 1,400mg/kg, 200mg/kg, 100mg/kg, six, seven, eight groups of difference intravenous injection compounds 4,400mg/kg, 200mg/kg, 100mg/kg, nine, ten, 11 groups of difference intravenous injection compounds 5,400mg/kg, 200mg/kg, 100mg/kg, 12,13,14 difference intravenous injection compounds 8,400mg/kg, 200mg/kg, 100mg/kg, 15,16,17 groups of compositions of distinguishing intravenous injection compound 4 and compound 5,400mg/kg, 200mg/kg, 100mg/kg, each is organized volumetric injection and is 0.1ml/10g.Before the administration with the right ankle joint flooding boundary of marking pen mark rat, the Volume of Displacement method measure cause for 1 time scorching before the right sufficient Volume of Displacement of rat, after the administration immediately only in the right back sole SC of rat fresh albumen 0.1ml/.Rat foot Volume of Displacement when measuring 1h, 2h after the administration, 3h, 5h.(seeing the following form)
Group | Dosage (mg/kg) | Volume of Displacement | |||
1h | 2h | 3h | 5h | ||
The physiological saline control group | / | 0.75±0.20 | 0.78±0.15 | 0.58±0.09 | 0.36±0.08 |
The injection potassium sodium dehydroandroan drographolide succinate | 200 | 0.56±0.11 | 0.59±0.08 | 0.42±0.07 | 0.33±0.05 |
Compound 1 | 400 | 0.25±0.08 | 0.27±0.06 | 0.23±0.07 | 0.15±0.05 |
200 | 0.55±0.07 | 0.55±0.07 | 0.43±0.04 | 0.30±0.07 | |
100 | 0.76±0.13 | 0.72±0.13 | 0.56±0.08 | 0.36±0.05 | |
Compound 4 | 400 | 0.28±0.07 | 0.29±0.06 | 0.23±0.07 | 0.16±0.05 |
200 | 0.53±0.07 | 0.54±0.07 | 0.46±0.04 | 0.32±0.07 | |
100 | 0.78±0.14 | 0.75±0.13 | 0.58±0.08 | 0.39±0.05 | |
Compound 5 | 400 | 0.26±0.08 | 0.28±0.07 | 0.23±0.07 | 0.16±0.05 |
200 | 0.60±0.06 | 0.65±0.08 | 0.53±0.06 | 0.48±0.05 | |
100 | 0.86±0.12 | 0.82±0.13 | 0.63±0.07 | 0.43±0.04 | |
Compound 8 | 400 | 0.23±0.07 | 0.25±0.08 | 0.22±0.07 | 0.18±0.06 |
200 | 0.57±0.07 | 0.54±0.07 | 0.41±0.06 | 0.36±0.05 | |
100 | 0.72±0.12 | 0.73±0.12 | 0.63±0.07 | 0.42±0.04 | |
The composition of compound 4 and compound 5 | 400 | 0.24±0.07 | 0.26±0.08 | 0.23±0.07 | 0.19±0.06 |
200 | 0.55±0.07 | 0.53±0.07 | 0.48±0.06 | 0.42±0.04 | |
100 | 0.73±0.12 | 0.75±0.12 | 0.64±0.07 | 0.48±0.05 |
2.2.2 conclusion: compound 1, compound 4, compound 5, compound 8 and compound 4 have good anti-inflammatory action with the composition of compound 5.
2.3 antibacterial tests:
2.3.1 extracorporeal bacteria inhibitor test:
With physiological saline the composition of compound 1, compound 4, compound 5, compound 8, compound 4 and compound 5 is made into 2% injection liquid, make starting point concentration after the filtering with microporous membrane degerming, reducing by half with injection physiological saline is diluted to 1/2,1/4,1/8,1/6,1/32 concentration again.With injection physiological saline the injection potassium sodium dehydroandroan drographolide succinate is mixed with 2% injection liquid, make starting point concentration after the filtration sterilization, reduce by half with physiological saline again and be diluted to 1/2,1/4,1/8,1/16,1/32 concentration, draw 1ml respectively in sterile test tube, add the 9ml nutrient agar medium, shake up, in 37 ℃ of constant incubators, cultivate 24h behind the inoculated bacteria and observe.
1/4 | + | + | + | |
1/8 | + | + | + | |
1/16 | + | + | + | |
1/32 | + | + | + | |
Compound 4 and compound 5 compositions | 1/1 | - | - | - |
1/2 | - | - | - | |
1/4 | + | + | + | |
1/8 | + | + | + | |
1/16 | + | + | + | |
1/32 | + | + | + |
2.3.2 result: compound 1, compound 4, compound 5, compound 8, compound 4 all have stronger anti-microbial effect with the composition of compound 5.
Embodiment 9
The stability test of compound 1-11
1, instrument and reagent
Instrument TV-1800SPC ultraviolet-visible pectrophotometer (Beijing Puxi General Instrument Co., Ltd).
Reagent is analytical pure; Sample is provided by Jiangxi QingFeng Pharmacy Co., Ltd.
2, constant temperature accelerated test: compound 1-11 sample is placed in the 37-40 ℃ of constant temperature accelerated tests case,, measures content as follows in sampling 0 month, 1 month, 2 months, 3 months, 6 months pitch times.
3, measuring method
3.1 the preparation of reference substance (compound 1-11, purity is all more than 99%) solution: precision takes by weighing the reference substance that is dried to constant weight at 105 ℃, adds ethanol and makes the solution that every 1ml contains 1mg.
3.2 the preparation of sample (compound 1-11) solution: precision takes by weighing sample 50mg, puts in the 50ml volumetric flask, is diluted to scale, shakes up with Diluted Alcohol.
3.3 assay method: precision is measured reference substance solution and each 2ml of need testing solution, place the 10ml measuring bottle respectively, put in 20 ℃ of water-baths, accurate adding 2%3,5-dinitrobenzoic acid ethanolic soln 2ml shakes up, accurately again add potassium hydroxide solution (2ml of 1.22g → 100ml), shakes up to scale with 60% alcohol dilution, placed 5 minutes, with the reagent corresponding is blank, measures optical density according to spectrophotometry (appendix VB of Chinese Pharmacopoeia version in 2000) respectively at the wavelength place of 540nm, calculates.
Constant temperature accelerated test result
Conclusion: the constant temperature accelerated test through 6 months proves: compound 1-11 chemical property is stable.
Embodiment 10
Take by weighing compound 4.25g, with the about 800ml dissolving of water for injection, add 0.1% gac and stirred 10 minutes, filter, add the injection water to 1000ml, filter, regulate the pH value to 4.5-6.5 with 10% sodium hydroxide solution, embedding (small-volume injection, specification is that 2ml/ props up, 5ml/ props up, 10ml/ props up), 100 ℃, sterilization in 30 minutes, clarity test, packing, promptly.
Usage and dosage: intramuscularly: the 50-100mg that is grown up a time, 2-3 time on the one, children's is cut down according to the circumstance or is followed the doctor's advice.Intravenous drip: 250-500mg on the one adds among 5% glucose injection or the sodium chloride injection 250-500ml and instils; Children's is cut down according to the circumstance or is followed the doctor's advice.
Embodiment 11
Take by weighing compound 4, compound 5, each 1g with the about 800ml dissolving of glucose isotonic solution, adds 0.1% gac and stirred 10 minutes, filter, add the glucose isotonic solution to 1000ml, filter, regulate the pH value to 4.5-6.5 with 10% dissolution of sodium hydroxide, embedding (high-capacity injection, specification is 50ml/ bottle, 100ml/ bottle, 250ml/ bottle, 500ml/ bottle) 100 ℃, sterilization in 30 minutes, clarity test, packing, promptly.
Usage and dosage: intravenous drip: 250-500mg on the one.Children's is cut down according to the circumstance or is followed the doctor's advice.
Embodiment 12
Take by weighing compound 4.25g, add injection water 600ml, stirring and dissolving, add 25g N.F,USP MANNITOL, after the stirring and dissolving, add the injection water to 1000ml, mixing, with 0.22 μ m filtering with microporous membrane, gained solution is sub-packed in the 7ml cillin bottle, every bottle of 2ml, capping plug, put into Freeze Drying Equipment, carry out lyophilize, get compound 4 freeze-dried powders (every 50mg) according to the freeze-drying curve that designs.
Usage and dosage: intramuscularly: the 50-100mg that is grown up a time, 2-3 time on the one, children's is cut down according to the circumstance or is followed the doctor's advice, intravenous drip: 250-500mg on the one, add among 5% glucose injection or the sodium chloride injection 250-500ml and instil, children's is cut down according to the circumstance or is followed the doctor's advice.
Embodiment 13
Take by weighing compound 4.25g,, add 0.1% gac and stirred 10 minutes with the about 800ml dissolving of water for injection, filter, add the injection water to 1000ml, filter, after the adding sucrose 200g stirring and dissolving, regulate the pH value to 4.5-6.5 with 10% sodium hydroxide solution, filter, the filtrate can in 10ml glass bottle, 100 ℃, sterilization in 30 minutes, clarity test, packing, promptly.
Usage and dosage: oral: one time 1, three times on the one.
Claims (8)
1, following general formula (I) or (II) sulfonated derivative of andrographolide of expression,
Each group definition is as follows in the general formula (I):
R
1 R
2 R
3 R
4
Compound 1 compound 2 compounds 3 compounds 4 compounds 5 H SO
3H SO
3H H SO
3H
SO
3H H SO
3H SO
3H H
OH OH ONa ONa R
3=R
4 O O O
Each group definition is as follows in the general formula (II):
。
2, the general formula of claim 1 (I) or (II) mixture of sulfonated derivative of andrographolide of expression, described mixture are selected from two or more in the sulfonated derivative of andrographolide of general formula (I), (II) expression.
3, the general formula of claim 2 (I) or (II) mixture of the sulfonated derivative of andrographolide of expression, described mixture is selected from two or more in compound 1, compound 4, compound 5, the compound 8.
4, a kind of pharmaceutical composition, the mixture and the pharmaceutically acceptable carrier of the sulfonated derivative of andrographolide of expression are formed by the general formula (I) of the general formula (I) of claim 1 or sulfonated derivative of andrographolide of (II) representing or claim 2 or (II).
5, the pharmaceutical composition of claim 4, the mixture and the water for injection of the sulfonated derivative of andrographolide of expression are formed by the general formula (I) of the general formula (I) of claim 1 or sulfonated derivative of andrographolide of (II) representing or claim 2 or (II).
6, the pharmaceutical composition of claim 4, the mixture and the N.F,USP MANNITOL freeze-dried powder auxiliary material of the sulfonated derivative of andrographolide of expression are formed by the general formula (I) of the general formula (I) of claim 1 or sulfonated derivative of andrographolide of (II) representing or claim 2 or (II).
7, the pharmaceutical composition of claim 4, the mixture and the oral preparations auxiliary material of the sulfonated derivative of andrographolide of expression are formed by the general formula (I) of the general formula (I) of claim 1 or sulfonated derivative of andrographolide of (II) representing or claim 2 or (II).
8, the general formula of claim 1 (I) or (II) sulfonated derivative of andrographolide of expression or the general formula (I) of claim 2 or (II) application in the mixture of the sulfonated derivative of andrographolide of expression, anti-inflammatory analgesic or the antibacterials in preparation.
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