CN102898362A - Preparation method and applications of derivatives containing nicotinic acids and acetylsalicylic acid curcumin - Google Patents
Preparation method and applications of derivatives containing nicotinic acids and acetylsalicylic acid curcumin Download PDFInfo
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- CN102898362A CN102898362A CN2012103653922A CN201210365392A CN102898362A CN 102898362 A CN102898362 A CN 102898362A CN 2012103653922 A CN2012103653922 A CN 2012103653922A CN 201210365392 A CN201210365392 A CN 201210365392A CN 102898362 A CN102898362 A CN 102898362A
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Abstract
The invention relates to a preparation method and applications of derivatives containing nicotinic acids and acetylsalicylic acid curcumin. The compounds are prepared by reacting curcumin and derivatives of the curcumin with acetylsalicylic acids, nicotinic acids and derivatives of the acetylsalicylic acids and the nicotinic acids in a solvent and extracting, purifying and drying the mixture. The kind of the compounds has effects of regulating blood lipids, reducing blood sugar and pressure, being cancer, inflammatory, thrombus and virus resistance, protecting nervous systems and curing senile dementia.
Description
Technical field
The present invention relates to contain the preparation method and its usage of nicotinic acid, acetylsalicylic acid curcumin ester derivative; this compounds forms by extraction, purifying, drying with acetylsalicylic acid and derivative thereof and nicotinic acid and derivatives reaction thereof in solvent with curcumine and derivative thereof, and this compounds has that the blood fat of adjusting, hypoglycemic, step-down, anticancer, anti-inflammatory, antithrombotic form, antiviral, neural system protection and the effect for the treatment of senile dementia.
Background technology
Acetylsalicylic acid has antipyretic-antalgic, the anti-inflammatory rheumatism, anticancer, the multiple physiologically active such as antithrombotic and pharmacological action, use for many years clinically, but, acetylsalicylic acid has obvious gastrointestinal reaction, aspirin asthma, a series of untoward reactions such as salicylism reaction, at present acetylsalicylic acid is carried out structural modification and mainly concentrate on CN94111849.5 and CN01160875.X, nicotinic acid can lower the utilization of coenzyme A, by suppressing the synthetic delivery that affects blood cholesterol of vldl, heavy dose can reduce serum cholesterol and triglyceride concentration, but nicotinic acid can cause skin rubefaction, diarrhoea, dizzy, weak, xerosis cutis, itch, xerophthalmia scheorma, feel sick, vomiting, a series of untoward reactions such as stomachache are carried out structural modification to nicotinic acid at present and are mainly concentrated on ZL200910042665.8.
Curcumine is a kind of important activity composition that nearly all zingiberaceous plant all contains, curcumine has anti-inflammatory, antibiotic, antitumor, hypotensive, prevent and treat trachitis, multiple physiologically active and the pharmacological actions such as anti-oxidant and neuroprotective, curcumine has entered the I phase clinical experiment stage in the U.S., but, further in vivo active on the low side of curcumine found in research, absorb few in the body, tachytrophism and bioavailability are low, greatly limited its application, at present to curcumine, curcumin ester carries out structural modification and mainly concentrates on the following aspects: CN 200710066787.1; CN 1646473A; WO 2003/088927; CN200910042665.8; Cancer Lett., 2000 (159): 135-140.
The technology of above-mentioned patent, bibliographical information fails effectively to solve curcumine, nicotinic acid, acetysalicylic problem.
Summary of the invention
One of technical issues that need to address of the present invention provide a kind of new nicotinic acid, acetylsalicylic acid curcumin ester derivative of containing, to satisfy the needs of field of medicaments.
Two of the technical issues that need to address of the present invention provide the above-mentioned preparation method who contains nicotinic acid, acetylsalicylic acid curcumin ester derivative.
Another technical issues that need to address of the present invention provide described contain nicotinic acid, the application of acetylsalicylic acid curcumin ester derivative in the medicine of the diseases such as preparation treatment hyperlipidemia, hyperglycemia, hypertension, thrombosis, inflammation, malignant tumour, virus infection, alzheimer's disease (Alzheimer's disease).
Technical conceive of the present invention is such: in order to strengthen the activity of curcumin chemical compounds, reduce nicotinic acid, acetysalicylic untoward reaction, the contriver introduces nicotinic acid, acetylsalicylic acid group in the curcumin chemical compounds, with obtain a class novel contain nicotinic acid, acetylsalicylic acid curcumin ester derivative, to satisfy the needs of clinical application.
Of the present invention contain nicotinic acid, acetylsalicylic acid curcumin ester derivative for have general structure (
1) a compounds:
Wherein: general formula (
1) middle R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18Can be identical or different: can be hydrogen, halogen, hydroxyl, sulfydryl or the alkyl that contains 1-8 carbon atom, alkoxyl group, acyl alkoxyl group or contain alkynyl, the thiazolinyl of 2-6 carbon atom or contain the cycloalkyl of 3-9 carbon atom or aralkyl, phenyl, cyano group alkyl, 4-nitro alkyl, carboxyl, alkylhalide group, list or polyhydroxy alkyl, alkyl-thio-alkyl, alkyl sulfonyl alkyl, acyloxy alkyl, acyl group alkyl, sulfonic group, but R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10In at least one is R and R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10In at least one is R
'
The present invention also comprises pharmaceutically acceptable pharmaceutical preparation of this compounds; and their purposes pharmaceutically; correlative study of the present invention shows; the purposes of this compounds comprises (but being not limited to), as lipid regulating agent, hypoglycemic agents, hypotensor, anti-malignant-tumor agent, antiphlogiston, antiviral drug and neural system protection medicine.
The preferred compound of the present invention comprises compound
1, compound
2, compound
3, compound
4, compound
5, compound
6, its structure (formula 1) is as follows:
Formula 1
Also comprise compound
1, compound
2, compound
3, compound
4, compound
5, compound
6(is suc as formula 2-7) 
Formula 2 formulas 3
Formula 4 formulas 5
Formula 6 formulas 7
Reach pharmaceutically acceptable any preparation of other sections.
The preparation method of compound of the present invention is as follows:
With curcumine and derivative thereof in sulfur oxychloride or Acetyl Chloride 98Min. solvent in 55 ~ 80 ℃ of lower and acetylsalicylic acid and derivatives reaction thereof after 2 ~ 20 hours, with ethyl acetate extraction 2-4 time, anhydrous sodium sulfate drying, then use ethyl acetate: sherwood oil=1:3 column chromatography, obtain monomeric compound, then namely obtain this compounds with nicotinic acid and derivatives reaction thereof.
It is as follows that compound of the present invention has carried out following pharmacological evaluation.
Transfer lipid aspects:Adopt ApoE knock-out mice Atherosclerosis Model, with the full-automatic biochemical analyzing equipment enzyme process of HITACHI7060 (Zhang C, et al. J Lipid Res. 2006; 47 (9): 2055-63) measured and have general formula (
1) compound of structure
1, compound
3, compound
6Accent blood fat and study of anti-atherogenic effect, oral 20mg/Kg/ days (sneaking in the feed), 8 weeks of successive administration, can significantly reduce blood plasma LDL-C, TC level, TG also there is certain reducing effect, simultaneously, the effect of the HDL-C that raises in addition, its usefulness and lovastatin are suitable, and obviously suppress atherosclerosis plaque forming.
Hypoglycemic aspect: oral 0.1-35mg/Kg compound
1, compound
3, compound
6, detect blood sugar concentration after 7 days and find compound
1, compound
3, compound
6Has remarkable hypoglycemic activity.
Hypotensive aspect: oral 0.8-20mg/Kg compound
1, compound
3, compound
6, detect blood pressure after 14 days and find compound
1, compound
3, compound
6Has remarkable hypotensive activity.
Anticancer aspect: the anticancer experiment in inside and outside shows compound
1, compound
3, compound
6Has significant antitumous effect.
Neural system protection aspect: compound
1, compound
3, compound
6Has significant neural system provide protection.
Antithrombotic formation aspect: compound
1, compound
3, compound
6Significantly anticoagulant and thrombosis effect.
The anti-inflammatory aspect:Show compound at body and isolated experiment
1, compound
3, compound
6Has significant anti-inflammatory action.
Acute toxicity test: with 1 heavy dose to the mice lavage compound
1, compound
3, compound
6, observe index and the toxic reaction degree such as small white mouse behavioral activity, and when experiment finishes, put to death small white mouse and analyse, to obtain compound
1, compound
3, compound
6Toxicity data, Continuous Observation 14 days, small white mouse is unusual without evident act, also occur dead, the maximum dose level 2000mg/kg that experiment is set and following dosage thereof to small white mouse all without overt toxicity.
Prove by pharmacological evaluation; compound of the present invention has in various degree accent blood fat, hypoglycemic, step-down, antitumor, antithrombotic formation, anti-inflammatory, antiviral and neural system provide protection; and toxicity is lower; therefore, compound of the present invention can be used for preparing and transfers that blood fat, hypoglycemic, step-down, anticancer, anti-inflammatory, antithrombotic form, the medicine of antiviral and neural system protection.
Compound of the present invention can composition form be applied to the patient who needs treatment, said composition comprises the compound of the present invention for the treatment of significant quantity and pharmaceutically acceptable carrier, said carrier comprises thinner (such as water), weighting agent (such as starch), wetting agent (such as glycerine), tackiness agent (such as derivatived cellulose) etc., and be prepared into tablet, capsule, pill, granule, syrup, emulsion, suspension liquid and solution with method well known in the art, routinely administration, preferential oral administration, dosage is 0.001 ~ 25mg/kg body weight.
By above-mentioned disclosed technical scheme as seen; compound of the present invention has good accent blood fat, hypoglycemic, step-down, anticancer, anti-inflammatory, antiviral, antithrombotic forms and neuroprotective; and toxicity is less; the preparation method is easy; be convenient to suitability for industrialized production; can satisfy the needs of field of medicaments, compound of the present invention has curative effect height, low toxin.
Embodiment:
1 preparation of embodiment 1(compound):
The 0.01mol curcumine lower was reacted 6-12 hour with the 0.03mol acetylsalicylic acid in 60 ~ 75 ℃ in the 10ml sulfur oxychloride, pour in the ice-water bath, with ethyl acetate extraction 3 times, anhydrous sodium sulfate drying, then use ethyl acetate: sherwood oil=1:3 column chromatography obtains monomeric compound, further namely obtains the target product compound with the nicotinic acid reaction
1, related data is as follows:
Compound
1: MS (EI, 70ev) m/z:635; Anal. Calcd. for C
36H
29NO
10: C, 68.03, H, 4.60, N 2.20; Found C, 68.02, H, 4.59, N 2.08.
Embodiment 2(compound 2, compound 3, compound 4, compound 5, compound 6 preparations):Carry out with reference to embodiment 1, related data is as follows:
Compound
2: MS (EI, 70ev) m/z:726; Anal. Calcd. for C
41H
30N
2O
11: C, 67.77, H, 4.16, N 3.85; Found C, 67.65, H, 4.37, N 3.66.
Compound
3: MS (EI, 70ev) m/z:621; Anal. Calcd. for C
35H
27NO
10: C, 67.63, H, 4.38, N 2.25; Found C, 67.39, H, 4.29, N 2.28.
Compound
4: MS (EI, 70ev) m/z:621; Anal. Calcd. for C
35H
27NO
10: C, 67.63, H, 4.38, N 2.25; Found C, 67.58, H, 4.45, N 2.19.
Compound
5: MS (EI, 70ev) m/z:783; Anal. Calcd. for C
44H
33NO
13: C, 67.43, H, 4.24, N 1.79; Found C, 67.51, H, 4.50, N 1.67.
Compound
6: MS (EI, 70ev) m/z:783; Anal. Calcd. for C
44H
33NO
13: C, 67.43, H, 4.24, N 1.79; Found C, 67.62, H, 4.35, N 1.72.
Embodiment 3:
Adopt ELISA method detection compound
1, compound
3, compound
6Anti-inflammatory action.As an example, some that obtain the results are shown in following table 1:
Table 1: compound
1, compound
3, compound
6Impact (n=10) on high fat rat blood serum inflammatory factor secretion
* the high fat group of p＜0.05 vs
Embodiment 4:
Adopt the full-automatic biochemical analyzing equipment enzyme process of HITACHI7060 (Zhang C, et al. J Lipid Res. 2006; 47 (9): 2055-63) measured the reducing blood lipid of part of compounds of the present invention.As an example, some that obtain the results are shown in Table 2:
Table 2Compound
1, compound
3, compound
6Impact on atherosclerosis mouse (ApoE-/-) blood fat
The TC=total cholesterol; The TG=triacylglycerol; The LDL-C=low density lipoprotein cholesterol;
DL-C=low hdl cholesterol; *, p＜0.05; *, p＜0.01 vs model group
Embodiment 5:
With reference to the method (Mosman, T. J. Immunol Methods. 1983,65,55) of Mosman, by the MTT colorimetric method for determining cytotoxicity of part of compounds of the present invention, the results are shown in Table 3:
Table 3Compound
1, compound
3, compound
6Cytotoxicity
Embodiment 6:
Reference literature (Wei Wei, Wu Ximei, Li Yuanjian chief editor, modern pharmacology experimental technique.) study various dose part of compounds of the present invention to the restraining effect of platelet aggregation, it the results are shown in Table 4:
Table
4Compound
1, compound
3, compound
6Restraining effect to platelet aggregation
Embodiment 7:
Reference literature (Joon-Su Shin, et al. Bioorg. Med. Chem. Lett. 1999, the hypoglycemic activity of method research part of compounds of the present invention 9:869), it the results are shown in Table 5:
Table
5Compound
1, compound
3, compound
6Hypoglycemic activity
| Active compound | Dosage mg/Kg | Blood sugar reduces (%) |
| Compound 1 | 0.8 | 80.1 |
| Compound 3 | 1.0 | 75.3 |
| Compound 6 | 2.0 | 74.9 |
Embodiment 8:
Contain general formula (
1) the tablet of compound, can be by method preparation well known in the art:
General formula (
1) compound 70mg
Magnesium Stearate 10mg
Talcum powder 10mg
Lactose 25mg
Starch 35mg
Embodiment 9:
Contain general formula (
1) the capsule of compound, can be by method preparation well known in the art:
General formula (
1) compound 100mg
Magnesium Stearate 20mg
Talcum powder 20mg
Lactose 30mg
Starch 20mg
Polyvinylpyrrolidone 10mg.
Claims (5)
1. the present invention relates to a class and contain nicotinic acid, acetylsalicylic acid curcumin ester derivative manufacture method and uses thereof, its general structure is as follows,
Wherein: general formula (
1) middle R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12, R
13, R
14, R
15, R
16, R
17, R
18Can be identical or different: can be hydrogen, halogen, hydroxyl, sulfydryl or the alkyl that contains 1-8 carbon atom, alkoxyl group, acyl alkoxyl group or contain alkynyl, the thiazolinyl of 2-6 carbon atom or contain the cycloalkyl of 3-9 carbon atom or aralkyl, phenyl, cyano group alkyl, 4-nitro alkyl, carboxyl, alkylhalide group, list or polyhydroxy alkyl, alkyl-thio-alkyl, alkyl sulfonyl alkyl, acyloxy alkyl, acyl group alkyl, sulfonic group, but R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10In at least one is R and R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10In at least one is R
'
2. a class as claimed in claim 1 contains nicotinic acid, acetylsalicylic acid curcumin ester derivative manufacture method and uses thereof, and the preferred compound of the present invention comprises compound
1, compound
2, compound
3, compound
4, compound
5, compound
6,
Its structure is as above schemed shown in (1-6).
3. contain nicotinic acid, acetylsalicylic acid curcumin ester derivative manufacture method and uses thereof such as the described class of claim 1-2, the preparation method of this compounds is as follows: with curcumine and derivative thereof in sulfur oxychloride or Acetyl Chloride 98Min. solvent in 55 ~ 80 ℃ of lower and acetylsalicylic acid and derivatives reaction thereof after 2 ~ 20 hours, with ethyl acetate extraction 2-4 time, anhydrous sodium sulfate drying, then use ethyl acetate: sherwood oil=1:3 column chromatography, obtain monomeric compound, then namely obtain this compounds with nicotinic acid and derivatives reaction thereof, reaction formula is as follows:
Perhaps:
More than two kinds of methods all can finish preparation.
4. contain nicotinic acid, acetylsalicylic acid curcumin ester derivative manufacture method and uses thereof such as the described class of claim 1-2; the purposes of this compounds comprises (but being not limited to), as lipid regulating agent, hypoglycemic agents, hypotensor, anti-malignant-tumor agent, antiphlogiston, antiviral drug and neural system protection medicine.
5. contain nicotinic acid, acetylsalicylic acid curcumin ester derivative manufacture method and uses thereof such as the described class of claim 1-2, the prepared derivative of the present invention can be prepared into pharmaceutically acceptable any formulation, but be preferably tablet, capsule, pill, granule, syrup, emulsion, sustained release dosage, control-released agent, the oral liquid of oral administration, and water agent for injecting, pulvis and infusion solutions etc.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101170915A (en) * | 2005-05-03 | 2008-04-30 | 帝斯曼知识产权资产管理有限公司 | Aryl derivatives of curcumin, demethoxycurcumin, bisdemethoxycurcumin or curcuminisoxazolide and their use as animal feed additives |
| CN101671248A (en) * | 2008-09-08 | 2010-03-17 | 北京鼎国昌盛生物技术有限责任公司 | Long effective curcumin derivative and preparation method thereof |
| CN101805285A (en) * | 2009-02-13 | 2010-08-18 | 南华大学 | Nicotinic acid-contained curcumin ester derivative and preparation method and application thereof |
| WO2011082290A2 (en) * | 2009-12-31 | 2011-07-07 | Organomed Corporation | Formulations from natural products, turmeric, and aspirin |
| CN102675114A (en) * | 2012-04-09 | 2012-09-19 | 湖南中医药大学 | Curcumin-containing acetylsalicylate derivative, preparation method and application thereof |
-
2012
- 2012-09-27 CN CN2012103653922A patent/CN102898362A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101170915A (en) * | 2005-05-03 | 2008-04-30 | 帝斯曼知识产权资产管理有限公司 | Aryl derivatives of curcumin, demethoxycurcumin, bisdemethoxycurcumin or curcuminisoxazolide and their use as animal feed additives |
| CN101671248A (en) * | 2008-09-08 | 2010-03-17 | 北京鼎国昌盛生物技术有限责任公司 | Long effective curcumin derivative and preparation method thereof |
| CN101805285A (en) * | 2009-02-13 | 2010-08-18 | 南华大学 | Nicotinic acid-contained curcumin ester derivative and preparation method and application thereof |
| WO2011082290A2 (en) * | 2009-12-31 | 2011-07-07 | Organomed Corporation | Formulations from natural products, turmeric, and aspirin |
| CN102675114A (en) * | 2012-04-09 | 2012-09-19 | 湖南中医药大学 | Curcumin-containing acetylsalicylate derivative, preparation method and application thereof |
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