CN102516301A - Therapeutic wogonin derivate - Google Patents
Therapeutic wogonin derivate Download PDFInfo
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- CN102516301A CN102516301A CN2011103859371A CN201110385937A CN102516301A CN 102516301 A CN102516301 A CN 102516301A CN 2011103859371 A CN2011103859371 A CN 2011103859371A CN 201110385937 A CN201110385937 A CN 201110385937A CN 102516301 A CN102516301 A CN 102516301A
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- wogonin
- derivate
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- XLTFNNCXVBYBSX-UHFFFAOYSA-N wogonin Chemical compound COC1=C(O)C=C(O)C(C(C=2)=O)=C1OC=2C1=CC=CC=C1 XLTFNNCXVBYBSX-UHFFFAOYSA-N 0.000 title abstract description 24
- HIMJIPRMECETLJ-UHFFFAOYSA-N Wogonin Natural products COc1cc(O)c(O)c2C(=O)C=C(Oc12)c3ccccc3 HIMJIPRMECETLJ-UHFFFAOYSA-N 0.000 title abstract description 22
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 4
- 208000019838 Blood disease Diseases 0.000 claims description 2
- 239000002131 composite material Substances 0.000 claims description 2
- 208000014951 hematologic disease Diseases 0.000 claims description 2
- 208000018706 hematopoietic system disease Diseases 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- 208000032839 leukemia Diseases 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 0 C*COc(cc1OC*C)c(C(C=C(C2C=CC=CC2)O2)=O)c2c1OC Chemical compound C*COc(cc1OC*C)c(C(C=C(C2C=CC=CC2)O2)=O)c2c1OC 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000011579 SCID mouse model Methods 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- -1 benzyloxycarbonyl (CBz) Chemical class 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical group O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 229960001627 lamivudine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005374 membrane filtration Methods 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 description 1
- 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
- XQYAIMXBMWASIN-UHFFFAOYSA-N COc(c(OC(c1ccccc1)=C1)c(c(OP(O)(O)=O)c2)C1=O)c2OP(O)(O)=O Chemical compound COc(c(OC(c1ccccc1)=C1)c(c(OP(O)(O)=O)c2)C1=O)c2OP(O)(O)=O XQYAIMXBMWASIN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000207929 Scutellaria Species 0.000 description 1
- 240000004534 Scutellaria baicalensis Species 0.000 description 1
- 101000874347 Streptococcus agalactiae IgA FC receptor Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229940098312 lamivudine 100 mg Drugs 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a wogonin derivate, and a preparation method and an application thereof. The structural hydroxyl groups are chemically modified, thereby obtaining the wogonin derivate. The wogonin derivate can be applied to the medicinal composition and can be used for producing the medicines for treating hepatitis B and leukemia.
Description
Technical field:
The present invention relates to the wogonin verivate that is used to treat.
Technical background:
Wogonin (wogonin) is a kind of flavones ingredient that extracts among the labiate root of large-flowered skullcap Scutellaria baicalensisGeorgi. for the root of large-flowered skullcap.Antibacterial, diuresis, spasmolysis are not only arranged, but also have stronger antivirus action.Research in recent years shows that wogonin can reduce the amount of transgenic mice serum hepatitis B surface antigen and alleviate DHB model liver inflammation.Can prolong the leukemia mouse survival time of NB4 cell induction.In the further research to wogonin, we find that he has stronger antitumor action, apoptosis that can inducing tumor cell, and further mechanism of action is just under study for action.Therapeutic action about wogonin.
Therefore wogonin is as a kind of novel hepatitis B medicine, and to alleviating numerous cancer patientss' misery, the quality of life that improves the patient has important effect, and vast market and heavy demand are at home and abroad arranged.
But because its very low oral administration biaavailability it has been generally acknowledged that wogonin is not suitable for other administering mode except administered parenterally at the commercial preparation that gets, and generally must intravenous injection or input.When wogonin when vein gives under clinical setting, suggestion can be used for certain indication through other non-oral route.
We are again through finding in the research to the wogonin verivate; Through deriving; Can obtain multiple verivate with curative effect; These verivates have difference to a certain degree with wogonin on chemical property, exist to make it have better stability and preparations shaping property, are to have the compound that further exploitation is worth.
Summary of the invention:
The object of the present invention is to provide a kind of verivate of new wogonin.
Its structure is:
N represents 0,1,2
Another object of the present invention is to provide the preparation method of wogonin verivate.
R1, R2 can be the residue of amino acid, phosphoric acid, carboxylic acid or have the composite structure of above two kinds of residues simultaneously.Can carry out the A preparation by following flow process:
Flow process A
The group Pg1 and the Pg2 of Serine protection can remove under given conditions among the flow process A; Nonrestrictive example for the useful protection base of nitrogen-atoms comprises butoxy carbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenyl methoxy carbonyl (Fmoc) part, and the protection base that is used for carboxyl comprises the tertiary butyl, benzyl and 9-fluorenyl methyl ester.
In the preparation, also can after in advance the verivate residue partly being modified, further react with wogonin again, prepare like flow process B.
Flow process B
1 step is used ethylene bromohyrin among the flow process B, N, N-Dimethylamino pyridine, NSC 57182, temperature of reaction 0-25 ℃, reaction times 6-48 hour; 2 steps are used chloroiodomethane, sodium hydrogencarbonate, temperature of reaction 0-50 ℃, reaction times 1-18 hour; 3 steps 1,3-propylene dichloride, N, N-Dimethylamino pyridine, NSC 57182, temperature of reaction 0-25 ℃, reaction times 18-60 hour.
Comprise in the used amino acid of the present invention and to have chiral amino acid, the present invention comprises these chiral amino acids.
Compound of the present invention can be prepared into corresponding pharmacy acceptable salt as required.For example, with the amino part salify of compound such as mineral acid sulfuric acid, hydrochloric acid, phosphoric acid or organic acid such as Hydrocerol A, toxilic acid etc.; With the salt of compound carboxy moiety formation such as the salt of sodium salt, sylvite, magnesium salts or organic bases formation.
Typical compound of the present invention is:
In the effective dosage scope 80mg of The compounds of this invention～5000mg scope, can be used for treatment and prevention hepatitis B, also can be used for leukemia treating.
Below in conjunction with embodiment the present invention is done further explain, but should understand the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1: the preparation of compd A
With wogonin 1.78g, be dissolved in the 20ml acetonitrile, slowly drip POCl3 solution 3ml under the room temperature; Drip and finish, stirring at room reaction 5 hours slowly adds frozen water and stirred hydrolysis reaction 2 hours; Add ethyl acetate extraction 10ml * 3 time, the water layer evaporate to dryness, compd A 0.63g.
Embodiment 2: the preparation of compd B
With wogonin 2g, be dissolved in the 20ml THF, 30 ℃ add 20ml chloroiodomethane, stirring reaction 16 hours down; 60 ℃ of evaporated under reduced pressure add 20ml acetonitrile dissolution residual substance as midbody, and other gets triethylamine 9ml and is dissolved in the 10ml acetonitrile; Drip 3.6ml phosphoric acid, after dropping finishes, stir and slowly splash into midbody down; Continued 60 ℃ of stirring reactions 12 hours, steaming desolventizes, and residue adds water 20ml dissolving; Add ETHYLE ACETATE 10ml * 3 washing water layers, water layer filters clarification, and freeze-drying promptly gets compd B 0.31g.
Embodiment 3: the preparation of Compound C
Serine 3 grams, ethylene bromohyrin 2.5g, N with the BOC protection; N-Dimethylamino pyridine 3g and NSC 57182 3g are dissolved in the THF; Stirring at room 10 hours, vacuum concentration is with the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 30%); Merging filtrate, evaporate to dryness gets intermediate A; Wogonin 2g and intermediate A 2.5g are dissolved with THF 30ml, add triphenyl phosphorus 2g, slowly drip diethyl azodiformate solution 2ml, room temperature reaction 5 hours; Reaction is finished, and evaporated under reduced pressure adds ETHYLE ACETATE 50ml dissolving, filters insolubles; With the thick product of chromatography purification (with the ETHYLE ACETATE/normal hexane wash-out of normal hexane to 10%), merging filtrate, evaporate to dryness dissolves with methylene dichloride 20ml then; Feed hydrogen chloride gas to saturated, stirring reaction 5 hours filters; Get the hydrochloride of Compound D, transferring pH behind the use dissolved in distilled water is about 8, and the water layer lyophilize gets Compound C 0.27g.
Embodiment 4: the preparation of Compound D
Preparing different according to the method for implementing 2 is to replace phosphoric acid with propanedioic acid.
Embodiment 5: the preparation of compd E
Get compd B 1.3g, be dissolved in the 30ml acetonitrile, add 5gBoc-Ser-OBZL in batches, 50 ℃ of stirring reactions, HPLC monitoring react to compd B less than 5%; Add 0.1M hydrochloric acid soln 10ml, 60 ℃ of heating hydrolysis 5 hours are regulated pH to 7, evaporated under reduced pressure, and residue adds the 20ml water dissolution; Add ETHYLE ACETATE 10ml * 3 time washing, the water layer evaporate to dryness adds anhydrous alcohol solution, removes by filter insolubles in batches; Evaporated under reduced pressure adds the 5ml water dissolution, and filtering, lyophilize get compd E 0.18g
Embodiment 6: the preparation of compd A injection liquid
Prescription
Get recipe quantity auxiliary material and raw material, be added to 90000ml water for injection, adding 10g gac, 80 ℃ are stirred decolouring 30 minutes, and the membrane filtration of 0.22 μ m is removed gac, measures midbody content, adds water for injection, and can, sterilization had both got the compd A injection liquid.
Embodiment 7: the preparation of injection compd B
Prescription:
Get raw material and each auxiliary material of recipe quantity, add 100ml water for injection, stir, add the 0.2g gac; 60 ℃ were stirred 30 minutes, and the membrane filtration clarification of 0.22 μ m detects midbody content; Specification branch by every bottle of 35mg is filled in the control cillin bottle ,-50 ℃ freezing 4 hours, vacuumize; The intensification freeze-drying, control moisture is not more than 5%, has both got the injection compd B.
Embodiment 8: compd B metabolism research in animal body
40 of HBV transgenic mouses just are divided into 5 groups according to serum HbsAg concentration, respectively the administration compd B; High dose group 50mg/kg, middle dose groups 25mg/kg, low dose group 12.5mg/kg; Positive controls (lamivudine 100mg/kg), blank assay group (saline water).Every group of 8 mouse, administration 10 days, high, medium and low dose groups was whenever passed through the tail vein injection administration at a distance from 2 days; Lamivudine group gastric infusion every day.Before serum sample picks up from administration respectively, administration 5 days, administration 10 days and drug withdrawal 5 days.Respectively put to death 3 mouse at random for every group behind the 24h of last administration, get liver, kidney and other organs sample; All the other mouse administration are the last time put to death after getting blood, get liver, kidney and other organs sample.
Hepatitis B antigen surface quantification kit is used in the serum HBsAg inspection, and operation reference reagent box specification sheets carries out.The mark curve uses recombination hepatitis B surface antigen to make up.Serum sample detects after diluting 20 times with saline water.
Treated the 10th day, high dose group mice serum HBsAg content obviously descends, and descends approximately 27.1% with comparing before the treatment, and compares before saline water control group and the administration that there were significant differences; Middle dose groups mice serum HBsAg content descends about 41.7%.After the drug withdrawal 5 days, it is stable that high dose group and middle dose groups mice serum HBsAg content keep, and rebound phenomenon does not take place, and on the contrary, lamivudine group mice serum HBsAg content raise than administration in 10 days to some extent.
Conclusion: treated the hepatitis B transgenic mouse 10 days, and can obviously reduce the amount of serum hepatitis B surface antigen, compare significance with control group and treatment group.
Embodiment 9: compd B is to induction of differentiation in the white blood disease cell paste.
Get the SCID mouse and be divided into four groups at random, 8 every group, the blank group gives saline water (NS) 20ml/kg.
Compd B high dose group concentration is 50mg/kg, and middle dose groups concentration is 25mg/kg, and low dose group concentration is 12.5mg/kg, and positive controls gives vitamin A acid 15mg/kg.Respectively with NB4 cell (10
6) 100 μ l abdominal injections are inoculated in the SCID mouse, beginning administration in second day, each group is two weeks respectively, observes mouse survival fate,
Test-results shows, compares with the blank group, and high, middle dosage can the significant prolongation SCID mouse survival time.
Claims (3)
1. the compound of general formula (I) or its hydrate and their pharmaceutical salts:
N represents 0,1,2
R1, R2 can be the residue of amino acid, phosphoric acid, carboxylic acid and comprise the composite structure that has above two kinds of residues simultaneously.
2. a medicinal compsns is characterized in that, contain the treatment effective dose according to claim 1 compound as activeconstituents and pharmaceutically acceptable carrier.
3. according to the purposes of the said pharmaceutical composition of claim 3, be used for treatment, prevention hepatitis B and treatment white blood disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110385937.1A CN102516301B (en) | 2011-11-28 | 2011-11-28 | Wogonin derivant for treatment |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110385937.1A CN102516301B (en) | 2011-11-28 | 2011-11-28 | Wogonin derivant for treatment |
Publications (2)
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103230398A (en) * | 2013-04-10 | 2013-08-07 | 中国药科大学 | Applications of a Wogonin derivative in the preparation of antineoplastic drugs |
| WO2021032844A1 (en) * | 2019-08-22 | 2021-02-25 | Mühlbauer Technology Gmbh | Flavonoid derivative for treating dental caries |
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| WO2010040254A1 (en) * | 2008-10-06 | 2010-04-15 | 大百汇生物科技（深圳）有限公司 | The use of flavones from radix scutellariae in manufacture of medicaments for treating enterovirus infection |
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| US3549662A (en) * | 1967-10-12 | 1970-12-22 | Takeda Chemical Industries Ltd | Derivatives of baicalein |
| WO2004037193A2 (en) * | 2002-10-22 | 2004-05-06 | Jenken Biosciences, Inc. | Chromones and chromone derivatives and uses thereof |
| CN1705473A (en) * | 2002-10-22 | 2005-12-07 | 詹肯生物科学公司 | Chromones and chromone derivatives and uses thereof |
| AU2003269928A1 (en) * | 2003-03-06 | 2004-09-30 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising prenyl flavonoids |
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| CN1556101A (en) * | 2003-12-31 | 2004-12-22 | 中国药科大学 | Extraction technology of Hanbaicalein, medicinal composition and preparation technology of medicine |
| WO2010040254A1 (en) * | 2008-10-06 | 2010-04-15 | 大百汇生物科技（深圳）有限公司 | The use of flavones from radix scutellariae in manufacture of medicaments for treating enterovirus infection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103230398A (en) * | 2013-04-10 | 2013-08-07 | 中国药科大学 | Applications of a Wogonin derivative in the preparation of antineoplastic drugs |
| CN103230398B (en) * | 2013-04-10 | 2015-05-13 | 中国药科大学 | Applications of a Wogonin derivative in the preparation of antineoplastic drugs |
| WO2021032844A1 (en) * | 2019-08-22 | 2021-02-25 | Mühlbauer Technology Gmbh | Flavonoid derivative for treating dental caries |
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| CN102516301B (en) | 2016-08-03 |
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