CN105753859A - Preparation method and pharmaceutical application of chlorogenic acid berberine conjugate - Google Patents
Preparation method and pharmaceutical application of chlorogenic acid berberine conjugate Download PDFInfo
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- CN105753859A CN105753859A CN201610150059.8A CN201610150059A CN105753859A CN 105753859 A CN105753859 A CN 105753859A CN 201610150059 A CN201610150059 A CN 201610150059A CN 105753859 A CN105753859 A CN 105753859A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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Abstract
The invention provides a preparation method of a derivative shown in a formula (I) and application of the derivative serving as a drug for treating 2-type diabetes and regulating blood sugar and blood fat.Pharmacological experiments find that the derivative has pharmaceutical activity various in value and particularly presents excellent effects of regulating blood sugar and blood fat of rats with 2-type diabetes in animal experiments.The derivative mainly functions in improving oral glucose tolerance, promoting insulin secretion, improving insulin resistance and lowering triglyceride amount.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to the application in the product of preparation prevention or treatment obesity and relevant disease or symptom of the chlorogenic acid berberine conjugates.
Background technology
The whole world probably has 12,000,000 people to die from cardiovascular diseases and apoplexy every year, and the atherosclerosis that hyperlipemia causes is to cause the main cause of coronary heart disease, hypertension and cerebrovascular disease.2002, only nearly 8,000,000,000 dollars of the global annual sales amount of atorvastatin (a kind of hypolipidemic) medicine, became the best-selling medicine in the world then.As can be seen here, research and development blood lipid-lowering medicine has great social benefit and market prospect.Chlorogenic acid can suppress the activity of 6-phosphoric acid Fructus Vitis viniferae acid enzyme in liver as antioxidant, and the driving force-Na+ electrochemical gradient of glucose Passive intake can be regulated, thus the transhipment of glucose is produced antagonistic effect, reduce the small intestinal absorbance to glucose, the generation of prevention diabetes.Aldose reductase is had and all has inhibitory action by chlorogenic acid, and 3,4,5-CQA inhibition is the highest, and aldose reductase inhibitor diabetic complication as: cataract, optic nerve, retinopathy, nephropathy etc. play a significant role, it was shown that 3,4,5-CQA has the medical value of potential treatment diabetic complication, good market prospects.
Berberine BBR (Berberine, BBR) is the main active of Rhizoma Coptidis, and in Rhizoma Coptidis, BBR content is the highest, accounts for 5.2-7.69%.Rhizoma Coptidis bitter in the mouth, has heat clearing away, removing toxic substances, pathogenic fire purging and controls effect of diabetes, early on the books in motherland's medicine ancient books and records." not Lu ": " main the five internal organs are cold and hot, let out and debate pus and blood, only quench one's thirst under for a long time, frightened, the profit that dewaters bone, adjust stomach thickness intestinal, benefit gallbladder, treat aphtha ".Its concocting method is also early on the books in pharmacopeia, Lei Gong's Treatise on Preparation and Broiling of Materia Medica: " all makes Rhizoma Coptidis, wipes upper meat hair with cloth, when then soaking second of the three ten-day periods of the hot season with pulp-water, filter out, dry use in willow fire." in recent years, BBR starts synthetic, its hydrochlorate conventional is as the dosage form of medicine, and this water-soluble dramatically increases, and can be greatly enhanced curative effect.2004, the result that the graduate scientist of China Medical Science delivers on NatureMedicine illustrated BBR and reduces effect of Triglycerides in Serum, cholesterol and low-density lipoprotein cholesterol；2006, Lee etc. made the blood sugar reducing function of BBR cause the attention of people in the Diabetes result delivered.In recent years, effect of BBR has been extended to the every aspect of metabolism related diseases especially: in the experiment of type 2 diabetes mellitus patient, high fat nursing mice and db/db mice, and BBR all shows that it reduces body weight, improves effect of insulin resistant and dysbolism of blood fat.More strikingly, BBR feeds the remarkable efficacy demonstrating its treatment fatty liver in mice at obesity mice and high fat.
Water solublity yet with chlorogenic acid is poor, and oral bioavailability is not high, limits giving full play to of its drug effect.And berberine hydrochloride water solublity is only small, fat-soluble less, gastrointestinal absorption is bad, causes that its oral administration biaavailability is low, have impact on its whole body therapeutic effect.Although, chlorogenic acid medicine, berberine has many similar pharmacologically actives, but all because of the low use limited to a certain extent clinically of bioavailability, therefore find a kind of bioavailability improving chlorogenic acid medicine and berberine and play both synergistic method and will have very important meaning clinically.
Summary of the invention
The present invention provides the derivative preparation method of formula (I) and it is as application in the medicine for the treatment of type 2 diabetes mellitus, adjustment blood glucose and blood fat.Found by the experiment of pharmacology's aspect, this analog derivative has the pharmaceutically active of various value, particularly its performance easily absorbed is not available for chlorogenic acid medicine, and specifically this analog derivative demonstrates excellent adjustment type 2 diabetes mellitus rat blood sugar and blood fat in zoopery.Its Main Function is embodied in can improve oral glucose tolerance, promote insulin secretion, improve insulin resistant, reduce the amount etc. of triglyceride.
The present invention provides the derivant of formula (I), and structure is as follows:
It is characterized in that in formula (I), R=H or C1～C18 straight or branched alkane.
The derivative preparation method of formula (I), comprises the following steps:
(1) berberine hydrochloride is dissolved in 0.01～4mol/L inorganic alkali solution；
(2) in the solution of step (1) gained, formula (I) described respective acids compound solution, 50-75 DEG C of heated and stirred 1-10h are added；
(3) product carries out sucking filtration, filtrate while hot be recycled to original volume 1/3, cooling crystallization, filter, be drying to obtain formula (I) described compound；
Inorganic alkali solution in step (1): it is characterized in that berberine hydrochloride and inorganic base molar ratio are 1:1～1:4, it is preferable that 1:0.90～1.10；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide；Solution is 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 80% alcoholic solution；
In step (2), respective acids compound solution refers to, refers to that respective acids compound is dissolved in 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 80% alcoholic solution；
The present invention provides the derivant of formula (I) to make acceptable dosage form clinically through common process or the pharmaceutically acceptable excipient of indirect addition, is used for clinically treating type 2 diabetes mellitus, regulating blood glucose and blood fat.
Specific embodiment
By following example to better illustrate the present invention.But the present invention is not by the restriction of following embodiment.
Embodiment 1
The synthesis of chlorogenic acid berberine conjugates
Take berberine hydrochloride 4.44g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 0.4mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.28g chlorogenic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain chlorogenic acid berberine conjugates 7.6g, yield 87.3%.
Embodiment 2
The synthesis of chlorogenic acid berberine conjugates
Take berberine hydrochloride 4.44g, add in 250ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 0.5mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.32g chlorogenic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain chlorogenic acid berberine conjugates 7.65g, yield 87.9%.
Embodiment 3
The synthesis of chlorogenic acid berberine conjugates
Take berberine hydrochloride 4.44g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 0.8mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.35g chlorogenic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain chlorogenic acid berberine conjugates 7.68g, yield 88.3%.
Embodiment 4
The synthesis of chlorogenic acid berberine conjugates
Take berberine hydrochloride 4.44g, add in 250ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 1mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.31 chlorogenic acids, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain chlorogenic acid berberine conjugates 7.95g, yield 91.4%.
Embodiment 5
The synthesis of chlorogenic acid berberine conjugates
Take berberine hydrochloride 4.44g, add in 250ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 2mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.28g chlorogenic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain chlorogenic acid berberine conjugates 7.21g, yield 82.8%.
Embodiment 6
The synthesis of chlorogenic acid berberine conjugates
Take berberine hydrochloride 4.44g, add in 250ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.31g chlorogenic acid, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain chlorogenic acid berberine conjugates 7.65g, yield 87.9%.ESI-MS(M++H)m/zcalcdforC20H16NO4 +337.13found337.17；ESI-MS(M++H)m/zcalcdforC16H18O9355.31found355.35。
Embodiment 7 Chinese hamster is fed, after high fat hypercholesterolemia (HFHC) food 10 days, to be orally administered to compound described in embodiment, measures that T-CHOL in blood, glycerol three is cruel and the level of low density lipoprotein, LDL-C after 25 days.It table is mean+SD.Administering mode: every day is administered orally, totally 25 days；Every treated animal number: n=7.Taking hematometry cholesterol, glycerol three is cruel and the level of low density lipoprotein, LDL, and carries out statistical procedures, and result is in Table 1
The effect for reducing blood fat that table 1 embodiment compound is used in combination hamster
Experimental result shows, chlorogenic acid berberine conjugates lipid-lowering effect is substantially better than chlorogenic acid and berberine monomer.
Claims (6)
1. the present invention provides the derivant of formula (I), and structure is as follows:
It is characterized in that in formula (I), R=H or C1～C18 straight or branched alkane.
2. the preparation method of formula (I) compound described in claim 1, comprises the following steps:
(1) berberine hydrochloride is dissolved in 0.01～5mol/L inorganic alkali solution；
(2) in the solution of step (1) gained, formula (I) described respective acids compound solution, 60-70 DEG C of heated and stirred 1-8h are added；
(3) product carries out sucking filtration, filtrate while hot be recycled to original volume 1/3, cooling crystallization, filter, be drying to obtain formula (I) described compound.
3. the inorganic alkali solution in the step (1) described in claim 2: it is characterized in that berberine hydrochloride and inorganic base molar ratio are 1:1～1:3, it is preferable that 1:0.95～1.05；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide；Solution is 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 70% alcoholic solution.
4. respective acids compound solution described in the step (2) described in claim 2, refers to that respective acids compound is dissolved in 0-100% (volume ratio) methanol, ethanol, aqueous isopropanol, it is preferable that 70% alcoholic solution.
5. formula (I) compound described in claim 1 makes acceptable dosage form clinically through common process or the pharmaceutically acceptable excipient of indirect addition, including injection, oral agents, it is preferable that oral formulations.
6. formula (I) compound described in claim 1 makes acceptable dosage form clinically through common process or the pharmaceutically acceptable excipient of indirect addition, is used for clinically treating type 2 diabetes mellitus, regulating blood glucose and blood fat.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610150059.8A CN105753859A (en) | 2016-03-15 | 2016-03-15 | Preparation method and pharmaceutical application of chlorogenic acid berberine conjugate |
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| CN201610150059.8A CN105753859A (en) | 2016-03-15 | 2016-03-15 | Preparation method and pharmaceutical application of chlorogenic acid berberine conjugate |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101695520A (en) * | 2008-12-30 | 2010-04-21 | 天津医科大学 | Preparation method of medicament for treating diabetes |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
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2016
- 2016-03-15 CN CN201610150059.8A patent/CN105753859A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101695520A (en) * | 2008-12-30 | 2010-04-21 | 天津医科大学 | Preparation method of medicament for treating diabetes |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
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