CN105801663A - Preparation method and medical application of ursolic acid and berberine conjugate - Google Patents
Preparation method and medical application of ursolic acid and berberine conjugate Download PDFInfo
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- CN105801663A CN105801663A CN201610147839.7A CN201610147839A CN105801663A CN 105801663 A CN105801663 A CN 105801663A CN 201610147839 A CN201610147839 A CN 201610147839A CN 105801663 A CN105801663 A CN 105801663A
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- ursolic acid
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- berberine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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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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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparation method of a derivative in the formula (I) and application of the derivative to treatment of diabetes mellitus type 2 and adjustment of blood glucose.Pharmacological experiments show that the derivative has various valuable bioactivities, especially the bioactivity that the derivative is easy to absorb, which ursolic acid and berberine monomer do not have.Particularly, the derivative shows excellent blood glucose adjustment of mice suffering from diabetes mellitus type 2 in animal experiments.The derivative mainly has the effects of reducing blood glucose after dinner, stimulating insulin expression and secretion and preventing insulin resistance.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to the preparation of ursolic acid berberine conjugates, the application in the product of prevention or treatment diabetes and relevant disease.
Background technology
At present, China's diabetics increases increasingly in city, small towns and rich rural population, and the diabetics of more than 20 years old has reached 11%, separately has people's impaired glucose regulation of 15%, sum of the two accounts for the 1/4 of above-mentioned population, and research and development hypoglycemic drug has great social benefit and market prospect.
The rat diabetes that streptozotocin (STZ) is caused by ursolic acid can suppress amount of drinking water, urine volume, blood glucose and glucose in urine amount effectively, and serum insulin levels and rat body weight can be improved, it is possible to reduce high lipid food and feed blood glucose and the insulin level of mice and improve glucose tolerance.Ursolic acid is alpha-amylase inhibitor, it is suppressed that carbohydrate digestive enzyme activity in digestive tract, carbohydrate inversion can be delayed to become glucose, post-prandial glycemia also can be suppressed to raise.
Berberine (Berberine, BBR) is the main active of Rhizoma Coptidis, and BBR content in Rhizoma Coptidis is the highest, accounts for 5.2-7.69%.Thinking that berberine not easily absorbs after oral, blood drug level maintains soon, and clinic is mainly used in the treatment of the intestinal infection (including bacillary dysentery) that dysentery bacterium, escherichia coli, S. aureus L-forms etc. cause more in the past.Along with deepening continuously of research, find that it has blood sugar lowering, blocks the pharmacological actions such as alpha-receptor, blood fat reducing, antiinflammatory, antitumor in recent years successively.Animal experiment study is it was also found that berberine can reduce the blood glucose of normal mouse, alloxan diabetes mice, and effect is relatively strong, the persistent period is also longer, has the feature of sulfonylureas and biguanide compound concurrently；Berberine can improve the glucose tolerance of KK mice simultaneously.Reducing blood glucose study mechanism to show, berberine can suppress gluconeogenesis and promote glycogen degradation, and strengthens secretion and the sensitivity of insulin, thus improving insulin to play hypoglycemic activity.Clinical research in recent years also demonstrates that, berberine has treatment diabetes effect, is particularly suited for the treatment of type 2 diabetes mellitus.
Water solublity yet with ursolic acid is poor, and oral administration biaavailability is low, limits giving full play to of its drug effect.Berberine hydrochloride water solublity is only small, and fat-soluble less, gastrointestinal absorption is bad, causes that its oral administration biaavailability is low, reduces its therapeutic effect.Although ursolic acid has many similar biological activitys to berberine, but all because bioavailability is low, the two use clinically is somewhat limited, and therefore finds a kind of bioavailability improving ursolic acid and berberine and plays 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 treatment type 2 diabetes mellitus, the application regulating blood glucose.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 ursolic acid berberine monomer, and specifically this analog derivative demonstrates excellent adjustment type 2 diabetes mellitus rat blood sugar effect in zoopery.Its Main Function is embodied in can reduce post-prandial glycemia, stimulate insulin expression and secretion, antagonism insulin resistant etc..
The present invention provides the derivant of formula (I), and structure is as follows:
It is characterized in that in formula (I), R1=HC1～C18Side chain or branched paraffin.
1. the preparation method of formula (I) compound described in, comprises the following steps:
(1) berberine hydrochloride is dissolved in 0.1～5mol/L inorganic alkali solution；
(2) in the solution of step (1) gained, add formula (I) described ursolic acid solution, heat at 40-80 DEG C stirring 1-5h；
(3) by product cooling crystallization, filter, be drying to obtain formula (I) described compound.
2. the 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 1:1～1.05；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide；Solvent is 10-30 times of (weight ratio of berberine hydrochloride) methanol, ethanol, isopropanol, ethanol/water, methanol/water, isopropanol/water solution, it is preferable that 50-80% alcoholic solution.
3. ursolic acid solution described in step (2), refers to that ursolic acid is dissolved in 1-20 times of (weight ratio of ursolic acid) methanol, ethanol, isopropanol, ethanol/water, methanol/water, isopropanol/water solution, it is preferable that 50-80% 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.
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
Take berberine hydrochloride 3.6g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 7～8 with the sodium hydroxide solution of 3mol/L, be warming up to 60～70 DEG C, magnetic agitation is dissolved, add 4.9g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.2g, yield 85%.
Embodiment 2
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml methanol, regulate pH to 7～8 with the sodium hydroxide solution of 3mol/L, be warming up to 60～70 DEG C, magnetic agitation is dissolved, add 5.0g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.8g, yield 90%.
Embodiment 3
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, adding 100ml isopropanol, the sodium hydroxide solution of 3mol/L regulates pH to 7～8, is warming up to 60～70 DEG C, magnetic agitation is dissolved, add 5.0g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.7g, yield 89%
Embodiment 4
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml70% ethanol, regulate pH to 7～8 with the sodium hydroxide solution of 3mol/L, be warming up to 60～70 DEG C, magnetic agitation is dissolved, add 4.8g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.9, yield 91%.
Embodiment 5
Take berberine hydrochloride 3.8g, add in 250ml there-necked flask, adding 100ml70% methanol, the sodium hydroxide solution of 3mol/L regulates pH to 7～8, is warming up to 60～70 DEG C, magnetic agitation is dissolved, add 4.9g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.6g, yield 88%.
Embodiment 6
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml70% isopropanol, regulate pH to 7～8 with the sodium hydroxide solution of 3mol/L, be warming up to 60～70 DEG C, magnetic agitation is dissolved, add 4.7g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.7g, yield 89%.
Embodiment 7
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml70% ethanol, regulate pH to 7～8 with the potassium hydroxide solution of 3mol/L, be warming up to 60～70 DEG C, magnetic agitation is dissolved, add 4.9g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.4g, yield 87%.
Embodiment 8
Take berberine hydrochloride 3.8g, add in 250ml there-necked flask, add 100ml70% ethanol, regulate pH to 7～8 with the aqua calcis of 3mol/L, be warming up to 60～70 DEG C, magnetic agitation is dissolved, add 5.0g ursolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain ursolic acid berberine conjugates 7.1g, yield 82%.
ESI-MS(M++H)m/zcalcdforC20H18NO4 +337.12found337.26；
ESI-MS(M++H)m/zcalcdforC30H47O3456.35found456.32。
The hypoglycemic activity of embodiment 9 ursolic acid berberine conjugates
Blood sugar lowering is tested: choose clean level Wistar male rat 100, after normal diet feeds 2 weeks, and tail vein injection streptozotocin；After 3 days, take blood measuring blood glucose.Choosing the rat that blood glucose value is 10-25 μm of ol/mL is modeling success rat, and then successful for modeling rat is divided into 5 groups (often groups 10).Distilled water (normal group) is fed for one group for filling；Two groups is hyperglycemia model (matched group)；Three groups is ursolic acid group, fills and feeds trial drug (120mg/Kg)；Four groups of berberine groups, fill and feed trial drug (150mg/Kg)；Five groups is ursolic acid berberine conjugates group, fills and feeds trial drug (100mg/Kg)；Fill continuously after feeding 15 days, measure Blood Glucose content.
Blood sugar lowering experimental result:
Experimental result shows, ursolic acid berberine conjugates hypoglycemic effect is substantially better than ursolic acid and berberine set of monomers.
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), R1=HC1～C18Side chain or branched paraffin.
2. the preparation method of formula (I) compound described in, comprises the following steps:
(1) berberine hydrochloride is dissolved in 0.1～5mol/L inorganic alkali solution；
(2) in the solution of step (1) gained, add formula (I) described ursolic acid solution, heat at 40-80 DEG C stirring 1-5h；
(3) by product cooling crystallization, filter, be drying to obtain formula (I) described compound.
3. the 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 1:1～1.05；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide；Solvent is 10-30 times of (weight ratio of berberine hydrochloride) methanol, ethanol, isopropanol, ethanol/water, methanol/water, isopropanol/water solution, it is preferable that 50-80% alcoholic solution.
4. ursolic acid solution described in step (2), refers to that ursolic acid is dissolved in 1-20 times of (weight ratio of ursolic acid) methanol, ethanol, isopropanol, ethanol/water, methanol/water, isopropanol/water solution, it is preferable that 50-80% 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. the derivant of the formula (I) 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610147839.7A CN105801663A (en) | 2016-03-15 | 2016-03-15 | Preparation method and medical application of ursolic acid and berberine conjugate |
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| CN201610147839.7A CN105801663A (en) | 2016-03-15 | 2016-03-15 | Preparation method and medical application of ursolic acid and berberine conjugate |
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Cited By (2)
| 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 |
| WO2022170017A1 (en) * | 2021-02-04 | 2022-08-11 | Virginia Commonwealth University | Ursolic acid preparations and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219141A (en) * | 2008-01-17 | 2008-07-16 | 宁光 | Use of berberine in treating metabolism complex |
| CN105294676A (en) * | 2015-11-30 | 2016-02-03 | 贾本真 | Berberine double salt and preparation method and application thereof |
| WO2016015634A1 (en) * | 2014-07-29 | 2016-02-04 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof |
-
2016
- 2016-03-15 CN CN201610147839.7A patent/CN105801663A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219141A (en) * | 2008-01-17 | 2008-07-16 | 宁光 | Use of berberine in treating metabolism complex |
| WO2016015634A1 (en) * | 2014-07-29 | 2016-02-04 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof |
| CN105294676A (en) * | 2015-11-30 | 2016-02-03 | 贾本真 | Berberine double salt and preparation method and application thereof |
Cited By (2)
| 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 |
| WO2022170017A1 (en) * | 2021-02-04 | 2022-08-11 | Virginia Commonwealth University | Ursolic acid preparations and uses thereof |
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Application publication date: 20160727 |