CN1289505C - New compound,its preparation method, medicine preparation using said compound as active component, its action and application - Google Patents
New compound,its preparation method, medicine preparation using said compound as active component, its action and application Download PDFInfo
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- CN1289505C CN1289505C CN 03109398 CN03109398A CN1289505C CN 1289505 C CN1289505 C CN 1289505C CN 03109398 CN03109398 CN 03109398 CN 03109398 A CN03109398 A CN 03109398A CN 1289505 C CN1289505 C CN 1289505C
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- Medicinal Preparation (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention discloses a novel compound, a preparation method thereof, medicinal preparation with the compound as an active component, and the functions and the applications of the medicinal preparation. The compound is 2-butenoic acid, 4-[9-(3, 7-dimethyl-2, 6-octadienyl)-3, 4, 5, 7-tetrahydro-8, 10-dihydroxy-3, 3-dimethyl-11 (3-methyl-2-butenyl)-7, 13-bicarbonyl-1, 5-methylene-1H, 3H-furan-[3, 4-d] xanthene-1-acyl]-2-methyl-[1R-1 alpha, 1 (Z), 3 alpha beta, 5 alpha, 9 (E), 12 alpha S<[star]>]-. The compound has an anticancer function and an anti-AIDS function.
Description
Invention field
The present invention relates to a kind of new compound and preparation method thereof and be the pharmaceutical preparation of active ingredient and effect thereof, purposes, belong to the field of Chinese medicines with this compound.
Background technology
Present tumour is in China, and even the world, has been listed in one of major disease, and sickness rate, mortality ratio remain high, and the healthy of the mankind in serious threat.In numerous tumours, liver cancer, lung cancer, cancer of the stomach, uterus carcinoma and leukemia sickness rate height not only especially, and become human common disease, frequently-occurring disease.Because neoplastic disease is because of unclear fully as yet, so tumor treatment does not still have specific medicament and method.Although the medicine of treatment tumour is more both at home and abroad at present, real effectively medicine is very few, and specific medicament just still less.For this reason, seek and study new effective cancer therapy drug and include country " 85,95,15 " medical research brainstorm project already in, become medical research worker's the task of top priority, wish to capture early the pharmacological agent high point of cancer.
Summary of the invention
One object of the present invention is to disclose a kind of new compound; Another object of the present invention is the method for a kind of new compound of open preparation; The 3rd purpose of the present invention is that open is pharmaceutical preparation and anticancer, the anti-AIDS toxic action and the purposes of active ingredient with this compound.
The structural formula of The compounds of this invention is:
The preparation method of The compounds of this invention (TH-2):
Get the Gamboge acetone extract, reclaim solvent and get extract, water one vinyl acetic monomer distributes, and divides and gets ethyl acetate extraction liquid, adds anhydrous sodium sulfate drying, filters, and filtrate decompression reclaims solvent and gets residue; Get the residue that is equivalent to the 9g crude drug, last silica gel column chromatography, use 14-16: 0.5-2: 0.5-2 chloroform-methanol-diethylamine wash-out, collect 100ml for every bottle, instruct with silica gel tlc, developping agent: 14-16: 0.5-2: 0.5-2 chloroform-methanol-diethylamine, the glassy yellow part that merges Rf value 0.4 promptly merges 8-13 bottle elutriant, neutralize with 2N hydrochloric acid, be washed to PH=7, add anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent and gets residue, and (95: 100: 75: 4) the mixed solvent complex crystallization got yellow needle with methyl alcohol-Virahol-water-formic acid.
The preparation method of this compound also can be: get the Gamboge acetone extract, reclaim solvent and get extract, water one vinyl acetic monomer distributes, and divides and gets ethyl acetate extraction liquid, adds anhydrous sodium sulfate drying, filters, and filtrate decompression reclaims solvent and gets residue; Get the residue that is equivalent to the 9g crude drug, or directly get the Gamboge acetone extract that is equivalent to the 9g crude drug, last silica gel column chromatography, use 14-16: 0.5-2: 0.5-2 chloroform-methanol-diethylamine wash-out, collect 100ml for every bottle, instruct with silica gel tlc, developping agent: 14-16: 0.5-2: 0.5-2 chloroform-methanol-diethylamine, the glassy yellow part that merges Rf value 0.4 promptly merges 8-13 bottle elutriant, neutralize with 2N hydrochloric acid, be washed to PH=7, add anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent and gets residue, use 94-96: 95-105: 70-80: 3-5 methyl alcohol-Virahol-water-formic acid mixed solvent complex crystallization gets yellow needle, i.e. the The compounds of this invention TH-2.
TH-2 of the present invention can be extracted from gamboge (Garcinia hanburyi) excretory dry resin and obtains, and also can synthesize, or obtain with additive method.
Structure is identified
Yellow needle, mpl18-120 ℃, FABMS (m/z): 629.3111600 (M-1)
-, C
38H
45O
8, [M-1]
-Calculated value 629.3119684; UV λ max (EtoH) nm (log ε): 360 (4.03);
1H-NMR δ (CDCl
3) 1.28 (3H, s, CH
3), 1.38 (1H, dd, J=9.3,13.71Hz), 1.59 (3H, s, CH
3), 1.67 (6H, s, 2 * CH
3), 1.69 (3H, s, CH
3), 1.71 (3H, s, CH
3), 1.75 (3H, s, CH
3), 1.79 (3H, s, CH
3), 2.04 (2H, d, J=6.0Hz), 2.08 (2H, t, J=6.7Hz), 2.32 (1H, dd, J=9.0,13.5Hz), 2.51 (1H, d, J=9.0Hz), 2.88 (1H, dd, J=5.6,15.9Hz), 3.14 (1H, dd, J=9.0,15.8Hz), 3.25 (1H, dd, J=7.2,15.9Hz), 3.29-3.35 (3H, m), 3.49 (1H, dd, J=4.8,6.5Hz), 5.05 (1H, t, J=6.5Hz), 5.09 (1H, t, J=6.5Hz), 5.20 (1H, t, J=6,6Hz), 5.85 (1H, t, J=7.2Hz), 6.46 (1H, S, OH, D
2O exchanges disappearance), 7.54 (1H, J=6.9Hz), 12.83 (1H, S, OH, D
2O exchanges disappearance).
13C-NMR: δ (CDCl
3) 16.34,17.86,18.15,20.85,21.29,22.23,25.45,25.85,26.58,29.12,29.72,29.89,30.03,39.89,47.11,49.17,83.96,84.16,90.68,100.84,106.84,107.60,121.59,122.18,124.09,128.39,132.00,133.86,133.93,135.29,137.88,139.13,156.15,160.22,163.59,171.36,179.35,203.66.
Comprehensive above data, identify that the TH-2 chemical structure is:
[chemical name] 2-Butenoic acid, and 4-[9-(3,7-dimethyl-2,6-octadienyl)-3 α, 4,5,7-tetrahydro-8,10-dihydroxy-3,3-dimethyl-11-(3-methyl-2-butenyl)-7,13-dioxo-1,5-methano-1H, 3H-furo-[3,4-d] xathen-1-y1]-2-methyl-[1R-[1 α, 1 (Z), 3 α β, 5 α, 9 (E), 12 α S
★]]-
The acid of [chemical name] 2-butylene, and 4-[9-(3,7-dimethyl-2; the 6-octadienyl)-3,4,5; 7-tetrahydrochysene-8,10-dihydroxyl-3,3-dimethyl-11-(3-methyl-2-butene base)-7; 13-dicarbapentaborane-1,5-methylene radical-1H, 3H-furans-[3; 4-d] xanthenes-1-acyl group]-2-methyl-[1R-1 α, 1 (Z), 3 α β; 5 α, 9 (E), 12 α S
★]]-
This compound is fat-soluble, for solubleness and the bioavailability that improves this compound, need make water soluble preparation.Can adopt and add solubility promoter such as tween-80, employing can with miscible propylene glycol of water or polyoxyethylene glycol-400 dissolving, adopt and nitrogenous organic base, or mineral alkali forms salt and methods such as employing and basic aminoacids (preferred arginine or Methionin) formation mixture are made water soluble preparation.
The preparation method of water soluble preparation of the present invention is: TH-2 and nitrogenous organic base, basic aminoacids (preferred arginine or Methionin), all with 1: the ratio of 0.8-20 (mol ratio), in water and/or alcoholic solvent, react.
Pharmaceutical preparation of the present invention contains the TH-2 of 0.5%-99.5% and the vehicle of 99.5%-0.5% (medicine that comprises other adapted), preferably contains the TH-2 of 1%-60% and the pharmaceutical excipient of 99%-40% (comprising the medicine that other compatibility is used).
Press practice of pharmacy, TH-2 of the present invention can be prepared into the various clinical pharmaceutical dosage form as antitumor, anti-AIDS drug, comprise the formulation of oral preparations or parenterai administration.Said oral preparations is selected from any in tablet, capsule, pill, granule, suspensoid, dripping pill, the oral liquid; Said non-enteron aisle is selected from a kind of in the middle of injection, aerosol, suppository or the subcutaneous administration formulation to formulation.
Auxiliary material in antitumor, the anti-AIDS drug of the present invention is meant conventional vehicle, as solvent, disintegrating agent, correctives, sanitas, tinting material, tackiness agent etc.The medicine that the present invention is antitumor, other compatibility in the anti-AIDS drug is used, the TH-2 that refers to effective dose is certain medicine material, other has allowed the Chinese medicine or the pharmaceutical chemicals that share compatibility.
It is the pharmaceutical composition of active ingredient that The compounds of this invention reaches with this compound, has anticancer, anti-AIDS effect.
The compounds of this invention and be that the pharmaceutical composition of active ingredient is effectively nontoxic to cancer cells with this compound.
Following experimental example is used to further specify the present invention, but does not limit the present invention in any way.
Experimental example
1. the antitumor action of TH-2 (TH-2)
The anticancer experiment of table 1 TH-2
| Sample number into spectrum | Compound number | Test purpose | Test model | Proof load | Test effect (%) |
| 020546 | TH-2 | Antitumor | Mtt assay (HL-60 human leukemia) | 1ug/ml 10ug/ml 100ug/ml | 31.98 96.74 96.13 |
| Srb assay (BGC-823 people's cancer of the stomach) | 1ug/ml 10ug/ml 100ug/ml | -9.47 76.33 94.42 | |||
| Srb assay (Bel-7402 people's liver cancer) | 1ug/ml 10ug/ml 100ug/ml | -13.21 81.03 94.20 | |||
| Srb assay (Hela human cervical carcinoma) | 1ug/ml 10ug/ml 100ug/ml | -5.47 83.44 95.80 |
Annotate: the result shows that TH-2 all has restraining effect to above 4 kinds of cancer cells, and dose-dependently is arranged.
Has tangible antitumous effect in the body, as leukemia, lung cancer, liver cancer, cancer of the stomach, uterus carcinoma etc.
2. the anti AIDS virus (HIV) of TH-2 (TH-2) effect
Table 2 TH-2 is to the restraining effect of HIV-1 reversed transcriptive enzyme
| Medicine | Concentration (ug/ml) | CPM | Average inhibiting rate (%) | IC50 (ug/ml) | |
| 1 | 2 | ||||
| PFA (contrast medicine) | 1.6 0.32 0.064 0.0128 | 1024 1840 3563 4688 | 94.3 78.9 46.3 25.0 | 0.073 …… | |
| TH-2 | 200 40 8 1.6 | 1448 5737 7343 7049 | 1131 4745 5546 7862 | 89.3 14.5 4.3 0 | 82.6 …… |
| The enzyme contrast is blank | 6246 874 | 5768 574 | |||
Table 1 is the result show, TH-2 has stronger restraining effect to the HIV-1 reversed transcriptive enzyme, and heavy dose of (200ug/ml) inhibiting rate is up to 89.3%, and dose-dependence is arranged.A kind of antiviral active drug of positive control drug phosphorus carboxyl sodium formiate (PFA), this test-results as seen, PFA has shown higher inhibition effect to the HIV-1 reversed transcriptive enzyme, and tangible dose-effect relationship is arranged, and illustrates that this test is successful, its reliable results.
Embodiment 1: the preparation of TH-2
Get the Gamboge acetone extract, reclaim solvent and get extract, water one vinyl acetic monomer distributes, and divides and gets ethyl acetate extraction liquid, adds anhydrous sodium sulfate drying, filters, and filtrate decompression reclaims solvent and gets residue; Get the residue that is equivalent to the 9g crude drug, last silica gel column chromatography (150g silica gel), with 15: 1: 1 chloroform-methanol-diethylamine wash-outs, collect 100ml for every bottle, instruct with silica gel tlc, developping agent: 15: 1: 1 chloroform-methanol-diethylamine, the glassy yellow part that merges Rf value 0.4 promptly merges 8-13 bottle elutriant, with the neutralization of 2N hydrochloric acid, be washed to PH7, add anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent and gets residue, and with 95: 100: 75: 4 methyl alcohol-Virahol-water-formic acid mixed solvent complex crystallization got yellow needle, i.e. the The compounds of this invention TH-2.
Embodiment 2:
The preparation of capsule (1)
TH-2 raw material 100g, medical starch 100g
TH-2 and medical starch are crossed 100 mesh sieves respectively, and mix, use an amount of alcohol granulation, dry in 60 degree, whole grain incapsulates.
The preparation of capsule (2)
TH-2 raw material 20g, L-arginine 5g, starch 60g, Microcrystalline Cellulose 20g, 10% starch slurry is an amount of, Magnesium Stearate 1g, microcrystalline silicon 1g.
Get TH-2 raw material 20g, put in the appropriate vessel, add dissolve with ethanol, get, 5g is soluble in water for the L-arginine, adds in the TH-2 solution, stir evenly, decompression take out desolvate light yellow solid 30g.Mixture is crossed 160 mesh sieves, Microcrystalline Cellulose 20g, starch 60g crosses 100 mesh sieves respectively, mixture and above-mentioned auxiliary material are mixed, and are that tamanori is made softwood with 10% starch slurry, cross 20 mesh sieve system particles, wet grain is put 60 degree baking oven forced air dryings, dry granulation is crossed the whole grain of 20 mesh sieves, and with Magnesium Stearate 1g and microcrystalline silicon 1g mixing, can is in capsule.
Embodiment 3:
The preparation of tablet (1)
TH-2 raw material 100g, medical starch 100g.
TH-2 and medical starch are crossed 100 mesh sieves respectively, and mix, use an amount of alcohol granulation, dry in 60 degree, through the whole grain of pelletizing machine, compressing tablet.
The preparation of tablet (2)
TH-2 raw material 20g, L-arginine 5g, starch 60g, Microcrystalline Cellulose 20g, 10% starch slurry is an amount of, Magnesium Stearate 1g,
Get TH-2 raw material 20g, put in the appropriate vessel, add dissolve with ethanol, get, 5g is soluble in water for the L-arginine, adds in the TH-2 solution, stir evenly, decompression take out desolvate light yellow solid 30g.Mixture is crossed 160 mesh sieves, Microcrystalline Cellulose 20g, starch 60g crosses 100 mesh sieves respectively, mixture and above-mentioned auxiliary material are mixed, and are that tamanori is made softwood with 10% starch slurry, cross 20 mesh sieve system particles, wet grain is put 60 degree baking oven forced air dryings, dry granulation is crossed the whole grain of 20 mesh sieves, with Magnesium Stearate 1g mixing, compressing tablet.
Embodiment 4: the preparation of granule
TH-2 raw material 10g, starch 100g, Icing Sugar 40g.
TH-2, medical starch and Icing Sugar are crossed 100 mesh sieves respectively, and mix, use an amount of alcohol granulation, dry in 60 degree, through the whole grain of pelletizing machine, packing promptly.
Embodiment 5: the preparation of injection
TH-2 raw material 10g, propylene glycol 20ml, polyoxyethylene glycol-400 50ml, water for injection 300ml mixes heating in water bath 30 minutes, add phenylcarbinol 50ml, add to 1000ml with water for injection again, in ultrasonic wave, handled 10 minutes, heated 30 minutes in the water-bath again, transfer pH value 5.5-6.5, filter clear and bright, embedding, the sterilization promptly.
Embodiment 6: the preparation of TH-2 powder injection
TH-2 raw material 10g, L-arginase 12 .5g, N.F,USP MANNITOL 45g.
Get TH-2 raw material 20g, put in the appropriate vessel, add dissolve with ethanol, get, L-arginase 12 .5g is dissolved in water for injection and adds in the TH-2 solution, stir evenly, decompression take out desolvate light yellow solid 15g, add water for injection 2700ml.With the filtering with microporous membrane of 0.22nm, under the aseptic condition, can in the 10ml cillin bottle, every bottle of 10ml; part is the fourth rubber plug beyond the Great Wall, and sabot is sent into and frozen in the loft drier, inserts eutectic point and temp probe; close chamber door, open Freeze Drying Equipment, utilize thermal oil that flaggy is freezed, the product temperature is descended; when the product temperature reaches eutectic point (-22 degree approximately), open vacuum system, begin to sublime up into drying, the final drying temperature is 35 degree; shut down close plug, venting; outlet, Zha Gai gets final product.
Claims (10)
1, a kind of new compound, its structural formula is:
2, compound as claimed in claim 1, the preparation method who it is characterized in that this compound is: get the Gamboge acetone extract, reclaim solvent and get extract, water-vinyl acetic monomer distributes, divide and get ethyl acetate extraction liquid, add anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent and gets residue; Get the residue that is equivalent to the 9g crude drug, or directly get the Gamboge acetone extract that is equivalent to the 9g crude drug, last silica gel column chromatography, use 14-16: 0.5-2: 0.5-2 chloroform-methanol-diethylamine wash-out, collect 100ml for every bottle, instruct with silica gel tlc, developping agent: 14-16: 0.5-2: 0.5-2 chloroform-methanol-diethylamine, the glassy yellow part that merges Rf value 0.4 promptly merges 8-13 bottle elutriant, neutralize with 2N hydrochloric acid, be washed to PH=7, add anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent and gets residue, use 94-96: 95-105: 70-80: 3-5 methyl alcohol-Virahol-water-formic acid mixed solvent complex crystallization gets yellow needle, i.e. the The compounds of this invention TH-2.
3, as the preparation method of compound as described in the claim 2, it is characterized in that this method is: get the Gamboge acetone extract, reclaim solvent and get extract, water-vinyl acetic monomer distributes, and divides and gets ethyl acetate extraction liquid, adds anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent and gets residue; Get the residue that is equivalent to the 9g crude drug, or directly get the Gamboge acetone extract that is equivalent to the 9g crude drug, last silica gel column chromatography, silica gel 150g, with 15: 1: 1 chloroform-methanol-diethylamine wash-outs, collect 100ml for every bottle, instruct developping agent: 15: 1: 1 chloroform-methanol-diethylamine with silica gel tlc, the glassy yellow part that merges Rf value 0.4 promptly merges 8-13 bottle elutriant, with the neutralization of 2N hydrochloric acid, be washed to PH7, add anhydrous sodium sulfate drying, filter, filtrate decompression reclaims solvent and gets residue, and with 95: 100: 75: 4 methyl alcohol-Virahol-water-formic acid mixed solvent complex crystallization got yellow needle, i.e. the The compounds of this invention TH-2.
4, the preparation method of the water soluble preparation made of the mixture of compound according to claim 1 is characterized in that this method is:
TH-2 and nitrogenous organic base or basic aminoacids, with 1: the mol ratio of 0.8-20, in water and/or alcoholic solvent, react.
5, a kind of pharmaceutical preparation of compound as claimed in claim 1 or 2 that contains is characterized in that this pharmaceutical preparation contains the The compounds of this invention of 0.5%-99.5% and the drug excipient of 99.5%-0.5%.
6, pharmaceutical preparation as claimed in claim 5 is characterized in that this pharmaceutical preparation contains the The compounds of this invention of 1%-60% and the drug excipient of 99%-40%.
7,, it is characterized in that said pharmaceutical preparation is oral preparations or parenterai administration formulation as claim 5 or 6 described pharmaceutical preparations.
8, pharmaceutical preparation as claimed in claim 7 is characterized in that said oral preparations is selected from any in the middle of the tablet, pill, capsule, granule, suspensoid, dripping pill, oral liquid.
9, pharmaceutical preparation as claimed in claim 7 is characterized in that said parenterai administration formulation is selected from any in the middle of injection, aerosol, suppository or the subcutaneous administration formulation.
10, the application of The compounds of this invention TH-2 in preparing antitumor and anti-AIDS drug as claimed in claim 1 or 2.
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| CN 03109398 CN1289505C (en) | 2003-04-08 | 2003-04-08 | New compound,its preparation method, medicine preparation using said compound as active component, its action and application |
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| CN 03109398 CN1289505C (en) | 2003-04-08 | 2003-04-08 | New compound,its preparation method, medicine preparation using said compound as active component, its action and application |
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| CN1289505C true CN1289505C (en) | 2006-12-13 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276621A (en) * | 2010-06-11 | 2011-12-14 | 台湾森本生物科技开发股份有限公司 | Compound separated from gamboge resin and derivative thereof and pharmaceutical composition comprising compound and derivative |
| CN103421021A (en) * | 2010-06-11 | 2013-12-04 | 台湾森本生物科技开发股份有限公司 | Compound divorced from gamboge resin, derivative of compound, and pharmaceutical composition containing compound and derivative |
| US9498463B2 (en) | 2010-06-11 | 2016-11-22 | Taiwan Sunpan Biotechnology Development Co., Ltd. | Compound obtained from gamboge resin, and medical uses of the same |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927861B (en) * | 2006-07-06 | 2011-01-26 | 中国药科大学 | Garcinia acid derivatives, preparation method and application thereof in pharmacy |
-
2003
- 2003-04-08 CN CN 03109398 patent/CN1289505C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276621A (en) * | 2010-06-11 | 2011-12-14 | 台湾森本生物科技开发股份有限公司 | Compound separated from gamboge resin and derivative thereof and pharmaceutical composition comprising compound and derivative |
| CN103421021A (en) * | 2010-06-11 | 2013-12-04 | 台湾森本生物科技开发股份有限公司 | Compound divorced from gamboge resin, derivative of compound, and pharmaceutical composition containing compound and derivative |
| CN103421021B (en) * | 2010-06-11 | 2016-08-10 | 台湾森本生物科技开发股份有限公司 | Separated compound and its derivative from Gamboge, and the pharmaceutical composition that includes these compounds and derivative |
| US9498463B2 (en) | 2010-06-11 | 2016-11-22 | Taiwan Sunpan Biotechnology Development Co., Ltd. | Compound obtained from gamboge resin, and medical uses of the same |
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| Publication number | Publication date |
|---|---|
| CN1535972A (en) | 2004-10-13 |
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