CN105777846A - Preparation method and medical application of OA (oleanolic acid) and BBR (berberine) conjugate - Google Patents
Preparation method and medical application of OA (oleanolic acid) and BBR (berberine) conjugate Download PDFInfo
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- CN105777846A CN105777846A CN201610150096.9A CN201610150096A CN105777846A CN 105777846 A CN105777846 A CN 105777846A CN 201610150096 A CN201610150096 A CN 201610150096A CN 105777846 A CN105777846 A CN 105777846A
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- oleanolic acid
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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
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
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- General Health & Medical Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparation method of a derivative shown in the formula (I) and an application of the derivative in treatment of type 2 diabetes and regulation of blood glucose. Pharmacological experiments show that the derivative has drug activities of various values, particularly the easily absorptive performance which is not possessed by OA (oleanolic acid) and BBR (berberine), and the derivative shows an outstanding regulating effect on blood glucose of a rat with type 2 diabetes in an animal experiment; main effects of the derivative are as follows: the oral glucose tolerance can be improved, the insulin secretion can be promoted, the insulin resistance can be improved and the like.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to the preparation of oleanolic acid berberine conjugates and the application in the product of prevention or treatment diabetes and relevant disease.
Background technology
At present, China's diabetics increases increasingly, 2007～2008 years, the Diabetes Epidemiological Investigation that diabetology branch of Chinese Medical Association (CDS) carries out in China some areas shows, in the crowd of more than 20 years old, diabetes prevalence is 9.7%, the ratio of prediabetes is 15.5%, diabetics only has 40% acquisition diagnosis, the diabetes Investigation on economic burden that CDS carried out in 2007～2008 years finds, compared with euglycemia crowd, the natural law that diabetics is in hospital increases by 1 times, physician office visits increases by 2.5 times, health care costs adds 2.4 times, research and development hypoglycemic drug has great social benefit and market prospect.
Oleanolic acid (oleanolicacid, OA) dose dependent reduces normal mouse blood sugar level, and OA reduces at dose dependent while rat blood sugar, also correspondingly improves plasma insulin and C-peptide level.The mouse blood sugar that subcutaneous injection OA can significantly resist exogenous glucose or epinephrine causes raises.The mouse blood sugar that alloxan is caused raises obvious preventive and therapeutic action.OA and ursolic acid are alpha-amylase inhibitors, and OA and ursolic acid mixture (2:1) suppress the IC of this enzyme50(half-inhibition concentration) is 2.01mg/L (4.4 μMs).OA also Inhibiting α-glucosidase is active, and activity is significantly stronger than acarbose.
Berberine BBR (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 intestinal infection (including bacillary dysentery) 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, arrhythmia, blood fat reducing, 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 Spontaneous Diabetic KK mice, and effect is relatively strong, the persistent period is also longer, has the feature of sulfonylureas and biguanide compound concurrently.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 oleanolic 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, limits its therapeutical effect.Although oleanolic 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 oleanolic 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 oleanolic acid and berberine, and this derivant demonstrates excellent adjustment type 2 diabetes mellitus rat blood sugar effect in zoopery.Its Main Function is embodied in can improve oral glucose tolerance, promote insulin secretion, improve 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 oleanolic acid, 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. oleanolic acid solution described in step (2), refers to that oleanolic acid is dissolved in 1-20 times of (weight ratio of oleanolic acid) methanol, ethanol, isopropanol, ethanol/water, methanol/water, isopropanol/water solution, it is preferable that 50-80% alcoholic solution.
4. formula (I) compound described in 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.
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 4.0g, add in 250ml there-necked flask, add 100ml ethanol, regulate pH to 8～9 with the sodium hydroxide of 3mol/L, be warming up to 60～70 DEG C, stirring and dissolving, add 5.5g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 8.7g, yield 90%.
Embodiment 2
Take berberine hydrochloride 4.1g, add in 250ml there-necked flask, add 100ml methanol, regulate pH to 8～9 with the sodium hydroxide of 3mol/L, be warming up to 60～70 DEG C, stirring and dissolving, add 5.6g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 7.8g, yield 83%.
Embodiment 3
Take berberine hydrochloride 3.7g, add in 250ml there-necked flask, add 100ml isopropanol, regulate pH to 8～9 with the sodium hydroxide of 3mol/L, be warming up to 60～70 DEG C, stirring and dissolving, add 5.2g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 7.5g, yield 86%.
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 of 3mol/L, be warming up to 60～70 DEG C, stirring and dissolving, add 5.3g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 8.0g, yield 92%.
Embodiment 5
Take berberine hydrochloride 3.8g, add in 250ml there-necked flask, add 100ml70% methanol, regulate pH to 7～8 with the sodium hydroxide of 3mol/L, be warming up to 60～70 DEG C, stirring and dissolving, add 5.3g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 7.7g, yield 89%.
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 of 3mol/L, be warming up to 60～70 DEG C, stirring and dissolving, add 5.2g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 7.3g, yield 84%.
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 4.8g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 7.3g, yield 86%.
Embodiment 8
Take berberine hydrochloride 3.7g, 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 4.9g oleanolic acid, keep this temperature stirring 1～2h, naturally cool to room temperature, crystallize, filter, be drying to obtain oleanolic acid berberine conjugates 7.0g, yield 82%.ESI-MS(M++H)m/zcalcdforC20H18NO4 +337.12found337.22；ESI-MS(M++H)m/zcalcdforC30H47O3456.35found456.42。
The hypoglycemic activity of embodiment 9 oleanolic 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 group (matched group)；Three groups is oleanolic acid group, fills and feeds trial drug (120mg/Kg)；Four groups is berberine group, fills and feeds trial drug (150mg/Kg)；Five groups is oleanolic acid berberine conjugates group, fills and feeds trial drug (100mg/Kg)；Fill continuously after feeding 15 days, take hematometry Blood Glucose content.Blood sugar lowering experimental result:
Experimental result shows, oleanolic acid berberine conjugates hypoglycemic effect is substantially better than oleanolic 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 oleanolic acid, 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. oleanolic acid solution described in step (2), refers to that oleanolic acid is dissolved in 1-20 times of (weight ratio of oleanolic 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.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610150096.9A CN105777846A (en) | 2016-03-15 | 2016-03-15 | Preparation method and medical application of OA (oleanolic acid) and BBR (berberine) conjugate |
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| CN201610150096.9A CN105777846A (en) | 2016-03-15 | 2016-03-15 | Preparation method and medical application of OA (oleanolic acid) and BBR (berberine) conjugate |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102716134A (en) * | 2012-06-07 | 2012-10-10 | 中国人民解放军第四军医大学 | Application of oleanolic acid to medicine for treating obesity |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
| EP2923701A1 (en) * | 2014-03-27 | 2015-09-30 | Neopharmed Gentili S.r.l. | Formulation for the treatment and control of metabolic syndrome and correlated disorders |
| CN105294676A (en) * | 2015-11-30 | 2016-02-03 | 贾本真 | Berberine double salt and preparation method and application thereof |
-
2016
- 2016-03-15 CN CN201610150096.9A patent/CN105777846A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
| CN102716134A (en) * | 2012-06-07 | 2012-10-10 | 中国人民解放军第四军医大学 | Application of oleanolic acid to medicine for treating obesity |
| EP2923701A1 (en) * | 2014-03-27 | 2015-09-30 | Neopharmed Gentili S.r.l. | Formulation for the treatment and control of metabolic syndrome and correlated disorders |
| CN105294676A (en) * | 2015-11-30 | 2016-02-03 | 贾本真 | Berberine double salt and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 高大威: "齐墩果酸抗糖尿病作用及其机理研究", 《燕山大学工学博士学位论文》 * |
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Application publication date: 20160720 |