CN102516301B - Wogonin derivant for treatment - Google Patents
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- CN102516301B CN102516301B CN201110385937.1A CN201110385937A CN102516301B CN 102516301 B CN102516301 B CN 102516301B CN 201110385937 A CN201110385937 A CN 201110385937A CN 102516301 B CN102516301 B CN 102516301B
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- 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
- 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 22
- 241001597008 Nomeidae Species 0.000 title abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 24
- 235000001014 amino acid Nutrition 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 5
- 125000000539 amino acid group Chemical group 0.000 claims 3
- 239000003937 drug carrier Substances 0.000 claims 1
- 208000002672 hepatitis B Diseases 0.000 abstract description 8
- 208000032839 leukemia Diseases 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- -1 benzyloxycarbonyl (CBz) Chemical class 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229940126062 Compound A Drugs 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 238000011579 SCID mouse model Methods 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 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
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 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
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical class ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 2
- 238000011097 chromatography purification Methods 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004108 freeze drying 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
- 210000004185 liver Anatomy 0.000 description 2
- 238000005374 membrane filtration Methods 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
- 239000002994 raw material Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 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
- HXWDNCGKKYUTTH-UHFFFAOYSA-N CN(N1CC=CC=2C=CC=NC12)C Chemical compound CN(N1CC=CC=2C=CC=NC12)C HXWDNCGKKYUTTH-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- LWLSVNFEVKJDBZ-UHFFFAOYSA-N N-[4-(trifluoromethoxy)phenyl]-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide Chemical compound FC(OC1=CC=C(C=C1)NC(=O)N1CCC(CC1)CC1=CC(=CC=C1)OC1=NC=C(C=C1)C(F)(F)F)(F)F LWLSVNFEVKJDBZ-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 235000017089 Scutellaria baicalensis Nutrition 0.000 description 1
- 240000004534 Scutellaria baicalensis Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 101000874347 Streptococcus agalactiae IgA FC receptor Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 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
- 239000002131 composite material Substances 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 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
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 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
- 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
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process 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
- 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
- 239000011976 maleic acid Substances 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
- 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
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 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 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 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
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960001727 tretinoin Drugs 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
Abstract
Present invention derivant that wogonin is provided and its production and use, the derivant of wogonin is by the oh group of its structure is chemically modified gained, the derivant of involved wogonin can use in pharmaceutical composition, for producing treatment hepatitis B and the medicine of leukemia treating.
Description
Technical field:
The present invention relates to the wogonin derivant and its production and use for treatment.
Technical background:
Wogonin (wogonin) be Radix Scutellariae be in labiate Radix Scutellariae ScutellariabaicalensisGeorgi. extract a kind of flavones ingredient.The most antibacterial, diuresis, spasmolysis, but also there is stronger antivirus action.Research in recent years shows, wogonin can reduce the amount of serum of transgenic mice hepatitis B surface antigen and alleviate DHB model inflammation.The leukemia mouse time-to-live of NB4 cell induction can be extended.In the research further to wogonin, it has been found that he has stronger antitumor action, can be with the apoptosis of inducing tumor cell, and further mechanism of action is the most under study for action.Therapeutical effect about wogonin.
Therefore wogonin is as a kind of novel hepatitis B medicine, and to alleviating the misery of numerous cancer patients, the quality of life improving patient has very important effect, at home and abroad has wide market and wilderness demand.
But due to the oral administration biaavailability that it is the lowest, it is generally recognized that the commercially available preparation of wogonin is not suitable for other administering mode except parenteral, and typically must intravenous injection or input.When vein gives wogonin in a clinical setting, it is proposed that can be come for certain indication by other non-oral routes.
We are again by finding in the research to wogonin derivant, by derivative, the medicable derivant of multiple tool can be obtained, these derivants have a certain degree of difference in the chemically with wogonin, existing makes it have more preferable stability and preparations shaping, is the compound with further Development volue.
Summary of the invention:
It is an object of the invention to provide the derivant of a kind 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 derivant.
R1, R2 can be aminoacid, phosphoric acid, the residue of carboxylic acid or the composite construction with both the above residue.A can be carried out by below scheme to prepare:
Flow process A
In flow process A, group Pg1 and Pg2 of serine protection can remove under given conditions; nonrestrictive example for the useful protection group of nitrogen-atoms includes butoxy carbonyl (Boc), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl groups (Fmoc) part, and the protection group for carboxyl includes the tert-butyl group, benzyl and 9-fluorenylmethvl ester.
In the preparation, it is possible to by reacting further with wogonin again, as prepared by flow process B after in advance derivant residue moiety being modified.
Flow process B
1 step ethylene bromohyrin in flow process B, N, N-dimethylamino naphthyridine, dicyclohexylcarbodiimide, reaction temperature 0-25 DEG C, 6-48 hour response time；2 step chloroiodomethanes, sodium bicarbonate, reaction temperature 0-50 DEG C, 1-18 hour response time；3 steps 1,3-dichloropropane, N, N-dimethylamino naphthyridine, dicyclohexylcarbodiimide, reaction temperature 0-25 DEG C, 18-60 hour response time.
Comprising in aminoacid used by the present invention and there is chiral amino acid, the present invention comprises these chiral amino acids.
Compound of the present invention can be prepared as corresponding pharmaceutically acceptable salt as required.Such as, salt such as mineral acid sulphuric acid, hydrochloric acid, phosphoric acid or organic acid such as citric acid, maleic acid etc. is become with compound amino part；Salt such as sodium salt, potassium salt, magnesium salt or the salt of organic base formation formed with compound carboxy moiety.
Typical compound of the present invention is:
In the range of the compounds of this invention effective dosage scope 80mg～5000mg, can be used for treating and preventing hepatitis B it can also be used to leukemia treating.
Below in conjunction with embodiment, the present invention is described in further detail, it should be understood that the non-scope being only limitted to these embodiments of the scope of the present invention.
Embodiment 1: the preparation of compound A
By wogonin 1.78g, it is dissolved in 20ml acetonitrile, under room temperature, slowly drips phosphorus oxychloride solution 3ml, drip and finish, reaction 5 hour is stirred at room temperature, be slowly added into frozen water stirring hydrolysis 2 hours, adding ethyl acetate and extract 10ml × 3 time, water layer is evaporated, and obtains compound A-40 .63g.
Embodiment 2: the preparation of compound B
By wogonin 2g, it is dissolved in 20ml oxolane, 20ml chloroiodomethane is added at 30 DEG C, stirring reaction 16 hours, 60 DEG C of evaporated under reduced pressure, addition 20ml acetonitrile dissolution residual substance, as intermediate, separately takes triethylamine 9ml and is dissolved in 10ml acetonitrile, drips 3.6ml phosphoric acid, after completion of dropwise addition, slowly instill intermediate under stirring, continue 60 DEG C of stirring reactions 12 hours, solvent is evaporated off, residue add water 20ml dissolve, adding ethyl acetate 10ml × 3 time washing water layer, water layer filters clarification, and lyophilizing i.e. obtains compound B0.31g.
Embodiment 3: the preparation of compound C
By serine 3 grams, ethylene bromohyrin 2.5g, N of BOC protection; N-dimethylamino naphthyridine 3g and dicyclohexylcarbodiimide 3g is dissolved in oxolane; it is stirred at room temperature 10 hours; it is concentrated in vacuo; with the thick product of chromatography purification (with the ethyl acetate of normal hexane to 30%/normal hexane eluting); merging filtrate, is evaporated to obtain intermediate A；Wogonin 2g and intermediate A 2.5g oxolane 30ml is dissolved, add triphenyl phosphorus 2g, slowly dropping diethyl azodiformate solution 2ml, room temperature reaction 5 hours, reaction is finished, evaporated under reduced pressure, add ethyl acetate 50ml to dissolve, filter insoluble matter, with the thick product of chromatography purification (with the ethyl acetate of normal hexane to 10%/normal hexane eluting), merging filtrate, it is evaporated, then dissolve with dichloromethane 20ml, it is passed through hydrogen chloride gas to saturated, stirring reaction 5 hours, filter, obtain the hydrochlorate of compound D, adjusting pH with distilled water after dissolving is about 8, water layer lyophilization obtains compound C0.27g.
Embodiment 4: the preparation of compound D
Phosphoric acid is replaced with malonic acid unlike the method preparation of enforcement 2.
Embodiment 5: the preparation of compound E
Take compound B-11 .3g, be dissolved in 30ml acetonitrile, be dividedly in some parts 5gBoc-Ser-OBZL, 50 DEG C of stirring reactions, HPLC monitoring reaction less than 5%, adds 0.1M hydrochloric acid solution 10ml to compound B, 60 DEG C add pyrohydrolysis 5 hours, regulate pH to 7, evaporated under reduced pressure, residue adds 20ml water dissolution, is dividedly in some parts ethyl acetate 10ml × 3 time washing, and water layer is evaporated, add anhydrous alcohol solution, be filtered to remove insoluble matter, evaporated under reduced pressure, adding 5ml water dissolution, filtering, lyophilization obtains compound E0.18g
Embodiment 6: prepared by compound A injection
Prescription
Taking recipe quantity adjuvant and raw material, add to 90000ml water for injection, addition 10g activated carbon, 80 DEG C are stirred decolouring 30 minutes, and the membrane filtration of 0.22 μm removes activated carbon, measure intermediates content, add water for injection, fill, and sterilizing had both obtained compound A injection.
Embodiment 7: prepared by injection compound B
Prescription:
Take the raw material of recipe quantity and each adjuvant, add 100ml water for injection, stirring, add 0.2g activated carbon, 60 DEG C are stirred 30 minutes, the membrane filtration clarification of 0.22 μm, detect intermediates content, by in the specification subpackage of every bottle of 35mg to control cillin bottle,-50 DEG C of freezings 4 hours, evacuation, intensification lyophilizing, control moisture and be not more than 5%, both obtain injection compound B.
Embodiment 8: compound B metabolism in animal body is studied
HBV transgenic mouse 40, is divided into 5 groups according to serum HbsAg concentration level, gives drug compound B respectively, high dose group 50mg/kg, middle dosage group 25mg/kg, low dose group 12.5mg/kg, positive controls (lamivudine 100mg/kg), blank experiment group (normal saline).Often 8 Mus of group, are administered 10 days, and high, medium and low dosage group was administered by tail vein injection every 2 days；Lamivudine group gastric infusion every day.Before serum sample picks up from administration respectively, it is administered 5 days, is administered 10 days and drug withdrawal 5 days.Often organize 3 Mus of each random execution after the last 24h being administered, take liver, kidney and other organs specimen；Remaining Mus is administered the last time after taking blood and puts to death, and takes liver, kidney and other organs specimen.
Serum HBsAg inspection uses hepatitis B antigen surface basis weight test kit, operation reference reagent box description to carry out.Mark curve uses recombination hepatitis B surface antigen to build.Detect after serum sample normal saline dilution 20 times.
Treating the 10th day, high dose group mice serum HBsAg content is decreased obviously, and declines about 27.1% compared with before treatment, and there were significant differences compared with before saline control group and administration；Middle dosage group mice serum HBsAg content declines about 41.7%.After drug withdrawal 5 days, high dose group and middle dosage group mice serum HBsAg content keep stable, and rebound phenomenon does not occur, and on the contrary, lamivudine group mice serum HBsAg content is relatively administered 10 days and has raised.
Conclusion: treatment hepatitis B transgenic mouse 10 days, it is possible to substantially reduce the amount of serum hepatitis B surface antigen, significance compared with matched group and treatment group.
Embodiment 9: compound B is to induction of differentiation in leukemia cyton.
Taking SCID mice and be randomly divided into four groups, often group 8, blank group gives normal saline (NS) 20ml/kg.
Compound B high dose group concentration is 50mg/kg, and middle dosage group concentration is 25mg/kg, and low dose group concentration is 12.5mg/kg, and positive controls gives retinoic acid 15mg/kg.Respectively by NB4 cell (106) 100 μ l lumbar injections are inoculated in SCID mice, within second day, start to be administered, each group two weeks respectively, observe mouse survival natural law,
Result of the test shows, compared with blank group, dosage high, middle can significantly extend the SCID mice time-to-live.
Claims (6)
1. lead to the compound of formula I and their pharmaceutical salts:
N represents 1,2
R1For aminoacid or phosphate moiety, R2For aminoacid or phosphate moiety.
2. the compound of claim 1, it is characterised in that R1For amino acid residue, R2For phosphate moiety.
3. the compound of claim 1, it is characterised in that R1For phosphate moiety, R2For amino acid residue.
4. the compound of claim 1, it is characterised in that R1、R2For amino acid residue.
5. the compound of claim 1, it is characterised in that R1、R2For phosphate moiety.
6. a Pharmaceutical composition, it is characterised in that containing treatment effective dose as described in claim 1-5 compound as active component and pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| 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 |
| DE102019122569A1 (en) * | 2019-08-22 | 2021-02-25 | Mühlbauer Technology Gmbh | Flavonoid derivative |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| 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 |
| CN1705473A (en) * | 2002-10-22 | 2005-12-07 | 詹肯生物科学公司 | Chromones and chromone derivatives and uses thereof |
| 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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| US20040242907A1 (en) * | 2003-05-30 | 2004-12-02 | Unitech Pharmaceuticals, Inc. | Methods of synthesizing flavonoids and chalcones |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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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