CN105732609A - Preparation method and medical application of berberine hydrochloride conjugate - Google Patents
Preparation method and medical application of berberine hydrochloride conjugate Download PDFInfo
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- CN105732609A CN105732609A CN201610076091.6A CN201610076091A CN105732609A CN 105732609 A CN105732609 A CN 105732609A CN 201610076091 A CN201610076091 A CN 201610076091A CN 105732609 A CN105732609 A CN 105732609A
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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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Abstract
The invention discloses a preparation method and medical application of a berberine hydrochloride conjugate, and belongs to the field of biological medicine.A hydrochloride derivative and berberine are salified through chemical synthesis, so that the problem that hydrochloride derivative medicine is poor in water solubility and low in oral bioavailability, and consequently full play of the medicinal effect of the hydrochloride derivative medicine is restricted is solved.Besides, berberine hydrochloride is poor in water solubility and poorer in lipid solubility and can not be well absorbed by the gastrointestinal tract, consequently, the oral bioavailability of berberine hydrochloride is low, and the holistic treatment effect of berberine hydrochloride is affected.The hydrochloride derivative shows an excellent effect of regulating the blood glucose and blood lipid of type-2 diabetes rats in animal experiments and has the main effects of improving oral glucose tolerance, promoting insulin secretion, improving insulin resistance, reducing the amount of triglyceride and the like.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to nicotinic acid derivates application in the product of preparation prevention or treatment obesity and relevant disease or symptom.
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.Nicotinic acid is converted into nicotiamide in vivo, nicotinamide adenine dinucleotide (nadide) and nicotinamide-adenine dinucleotide phosphate (coenzyme II) is formed again with ribose adenine etc., required for lipidic amino acid, albumen, purine metabolism, the Oxidation of Tissue respiration and glycogenolysis institute.Nicotinic acid can lower the utilization of coenzyme A；Affected the delivery of blood cholesterol by the synthesis of suppression very low density lipoprotein (VLDL) (VLDL), heavy dose can reduce serum cholesterol and triglyceride concentration.Nicotinic acid has peripheral vasodilation effect.The treatment of II-patients with type Ⅰ DM and metabolism syndrome also there are good effect, 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 nicotinic 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, nicotinic acid class 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 nicotinic acid class 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 nicotinic acid class 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:
In formula (I), R is following functional group, but is not limited to this.
R1=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 0.01～5mol/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；
Inorganic alkali solution in step (1): 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；
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 70% 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 nicotinic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 100ml there-necked flask, add 100ml 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 1.25g nicotinic 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 nicotinic acid berberine conjugates 3.9g, yield 85%.
Embodiment 2
The synthesis of nicotinic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 100ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 0.6mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 1.3g nicotinic 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 nicotinic acid berberine conjugates 4.1g, yield 89.5%.
Embodiment 3
The synthesis of nicotinic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 100ml there-necked flask, add 100ml 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 2.0g nicotinic 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 nicotinic acid berberine conjugates 4.0g, yield 87.3%.ESI-MS(M++H)m/zcalcdforC20H16NO4 +337.13found337.17；ESI-MS(M++H)m/zcalcdforC6H4NO2 -122.02found122.05。
Embodiment 4
The synthesis of 2-pyridine carboxylic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 100ml 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 1.3g2-pyridine carboxylic 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 2-pyridine carboxylic acid berberine conjugates 4.1g, yield 88.6%.
Embodiment 5
The synthesis of 2-pyridine carboxylic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 100ml 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 2.0g2-pyridine carboxylic 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 2-pyridine carboxylic acid berberine conjugates 4.0g, yield 87.4%.ESI-MS(M++H)m/zcalcdforC20H16NO4 +337.13found337.14；ESI-MS(M++H)m/zcalcdforC6H4NO2 -122.02found122.08。
Embodiment 6
The synthesis of .gamma.-pyridinecarboxylic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 100ml 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 1.3g .gamma.-pyridinecarboxylic 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 .gamma.-pyridinecarboxylic acid berberine conjugates 4.1g, yield 89.6%.ESI-MS(M++H)m/zcalcdforC20H16NO4 +337.13found337.18；ESI-MS(M++H)m/zcalcdforC6H4NO2 -122.02found122.07。
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
Table 1 embodiment compound effect for reducing blood fat
Experimental result shows, nicotinic acid class berberine conjugates lipid-lowering effect is substantially better than nicotinic 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 is
R1=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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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10577379B1 (en) | 2018-12-05 | 2020-03-03 | Jiangxi Fushine Pharmaceutical Co., Ltd. | Fenofibric acid salt with berberine or its analogues, crystalline forms, methods of preparation, and applications thereof |
| CN115073446A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Berberine type alkaloid oxidized pyrazine formic acid quaternary ammonium salt and application thereof in preparing medicines |
| CN115073447A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Berberine type pyridine carboxylic acid quaternary ammonium salt compound and application thereof in preparing medicines |
| CN115068473A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Application of berberine type pyridine carboxylic acid quaternary ammonium salt compound in resisting virus infection diseases |
| WO2022194136A1 (en) * | 2021-03-15 | 2022-09-22 | 中国医学科学院药物研究所 | Diphenyl alkane compound and preparation method therefor, and pharmaceutical composition and use thereof |
-
2016
- 2016-01-30 CN CN201610076091.6A patent/CN105732609A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| DAVUDTABTS S.B.ET.AL: "Preparation of berberine salts of physiologicall active acids", 《DOKLADY AKADEMII NAUK TADZHIKSKOI SSR》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10577379B1 (en) | 2018-12-05 | 2020-03-03 | Jiangxi Fushine Pharmaceutical Co., Ltd. | Fenofibric acid salt with berberine or its analogues, crystalline forms, methods of preparation, and applications thereof |
| CN115073446A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Berberine type alkaloid oxidized pyrazine formic acid quaternary ammonium salt and application thereof in preparing medicines |
| CN115073447A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Berberine type pyridine carboxylic acid quaternary ammonium salt compound and application thereof in preparing medicines |
| CN115068473A (en) * | 2021-03-15 | 2022-09-20 | 中国医学科学院药物研究所 | Application of berberine type pyridine carboxylic acid quaternary ammonium salt compound in resisting virus infection diseases |
| WO2022194136A1 (en) * | 2021-03-15 | 2022-09-22 | 中国医学科学院药物研究所 | Diphenyl alkane compound and preparation method therefor, and pharmaceutical composition and use thereof |
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Application publication date: 20160706 |