CN105693715A - Preparation and medical application of diacerein berberine conjugate - Google Patents
Preparation and medical application of diacerein berberine conjugate Download PDFInfo
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- CN105693715A CN105693715A CN201610150121.3A CN201610150121A CN105693715A CN 105693715 A CN105693715 A CN 105693715A CN 201610150121 A CN201610150121 A CN 201610150121A CN 105693715 A CN105693715 A CN 105693715A
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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 provides a preparation method of a conjugate in formula (I) and application thereof in drugs for treating hyperglycemia, hyperlipidemia, obesity, bacterial infection, peptic ulcers, arthritis, heart failure, arrhythmia, platelet aggregation, high blood pressure and the like. In pharmacology experiments, it is found that the conjugate has drug activity of various values, especially, diacerein drugs do not have the performance that the conjugate is easily absorbed, and specifically, the conjugate has excellent mouse blood sugar adjusting and bacterial infection adjusting effects in animal experiments.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to the application in treatment hypertension, adjustment blood pressure product of a kind of pril berberine conjugates。
Background technology
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。Thought more in the past oral after not easily absorb, intestinal infection that dysentery bacterium, escherichia coli, staphylococcus aureus are caused, eye conjunctivitis, suppurative otitis media etc. are effective, and clinic is mainly used in the treatment of intestinal infection。Along with going deep into of research, find that it has the pharmacological actions such as arrhythmia, vasodilator, protection cardiac muscle, antiplatelet aggregation, blood sugar lowering, blood fat reducing, antiinflammatory, antiviral, antitumor in recent years successively。
Traditionally, SF-277 is a kind of new interleukin inhibitor, for alleviating and change the chronic effect of osteoarthritis symptoms and the state of an illness。CN1395484 discloses SF-277 or its pharmaceutically acceptable conjugates for preparing psoriasis and relevant disease thereof。CN102526013 discloses a kind of medicinal group of composition and use thereof, and this pharmaceutical composition contains SF-277, it is shown that the mucosa injury that excellent prevention and treatment a variety of causes cause。Diabetics due to the shortage of insulin, the internal complication that simultaneously can show a series of metabolism disorder。Important vital organ, as heart, kidney, peripheral nervous tissue and retina etc. are likely to occur the damage of serious structure and function, wherein diabetic nephropathy is one of modal complication of diabetes, and diabetic nephropathy is the one of the main reasons of chronic renal insufficiency end-stage renal failure (i.e. uremia)。Diabetic nephropathy up to now, still lacks effective medicine。
Water solublity yet with diacetyl rhein is poor, and oral administration biaavailability is low, 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, diacetyl rhein 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 diacetyl rhein medicine and berberine and play both synergistic method and will have very important meaning clinically。
Summary of the invention:
The present invention provides the conjugates preparation method of formula (I) and it is as the application in the medicines such as treatment hyperglycemia, hyperlipidemia, obesity, antibacterial infection, peptic ulcer, arthritis, heart failure, arrhythmia, platelet aggregation, hypertension。Found by the experiment of pharmacology's aspect, such conjugates has the pharmaceutically active of various value, particularly its performance easily absorbed is not available for diacetyl rhein medicine, and specifically such conjugates demonstrates excellent adjustment rat blood sugar in zoopery, antibacterial infects。
The present invention provides the conjugates of formula (I), and structure is as follows:
It is characterized in that, in formula (I), R is
R1=HC1～C18 side chain or branched paraffin
1. the preparation method of formula (I) compound described in, comprises the following steps:
(1) berberine hydrochloride is dissolved in 0.01～5mol/L inorganic alkali solution；
(2) in the solution of step (1) gained, formula (I) described respective acids compound solution is added, at 60-70 DEG C of heated and stirred 1-5h；
(3) by product cooling crystallization, filter, be drying to obtain formula (I) described compound。
2. the inorganic alkali solution in step (1) described in: it is characterized in that berberine hydrochloride and inorganic base molar ratio are 1:1～1:3, it is preferable that 1:1～1.1；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide；Solution is 0-100% (volume ratio) methanol, ethanol, isopropanol, methanol/water, ethanol/water, isopropanol/water solution, it is preferable that 40%-70% alcoholic solution。
3. respective acids compound solution described in the step (2) described in, refer to that respective acids compound is dissolved in 0-100% (volume ratio) methanol, ethanol, isopropanol, methanol/water, ethanol/water, isopropanol/water solution, it is preferable that 40%-70% 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 conjugates 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 antibacterial infection, hyperglycemia and complication thereof。
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 diacetyl rhein berberine conjugates
Take berberine hydrochloride 3.7g, add in 500ml there-necked flask, add 50% ethanol 100ml, 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 3.7g diacetyl rhein, keeps this temperature stirring 1-5h, it is cooled to room temperature, crystallize, filtration, dry, obtain diacetyl rhein berberine conjugates 5.8g, yield 82%。
Embodiment 2
The synthesis of diacetyl rhein berberine conjugates
Take berberine hydrochloride 3.7g, add in 500ml there-necked flask, add 60% ethanol 100ml, regulate pH to 7-8 with the potassium hydroxide of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 3.9g diacetyl rhein, keeps this temperature stirring 1-5h, it is cooled to room temperature, crystallize, filtration, dry, obtain diacetyl rhein berberine conjugates 6.1g, yield 87%。
Embodiment 3
The synthesis of diacetyl rhein berberine conjugates
Take berberine hydrochloride 3.7g, add in 500ml there-necked flask, add 60% ethanol 100ml, regulate pH to 7-8 with the potassium carbonate of 3mol/l, it is warming up to 60-70 DEG C, stirring and dissolving, adds 4.0g diacetyl rhein, keeps this temperature stirring 1-5h, it is cooled to room temperature, crystallize, filtration, dry, obtain diacetyl rhein berberine conjugates 6.3g, yield 89%。
Embodiment 4
The synthesis of diacetyl rhein berberine conjugates
Take berberine hydrochloride 3.7g, add in 500ml there-necked flask, add 60% ethanol 100ml, 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 7.4g diacetyl rhein, keeps this temperature stirring 1-5h, it is cooled to room temperature, crystallize, filtration, dry, obtain diacetyl rhein berberine conjugates 6.3g, yield 89%。
Embodiment 5
The synthesis of diacetyl rhein berberine conjugates
Take berberine hydrochloride 3.7g, add in 500ml there-necked flask, add 60% ethanol 100ml, 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 11g diacetyl rhein, keeps this temperature stirring 1-5h, it is cooled to room temperature, crystallize, filtration, dry, obtain diacetyl rhein berberine conjugates 6.2g, yield 88%。ESI-MS (M++H)m/zcalcdforC20H18NO4 +337.12found337.15；ESI-MS (M++H)m/zcalcdforC19H11O8368.05found368.06。
The antibacterial activity in vitro of embodiment 6 diacetyl rhein berberine conjugates
Staphylococcus aureus, escherichia coli, group B streptococcus, streptococcus pneumoniae compound concentration be 2000 μ g/ml, antibacterial process is provided with the comparison of corresponding dissolved matrix, adopts lysoplate assay and tube dilution method to measure。MIC assay method: take sterile test tube 13, it is arranged in a row, except the 1st pipe adds the 1.8MH bacterium solution of broth dilution 1000 times, all the other are pipe addition MH meat soup 1ml often, adds antibacterials stock solution 0.2ml mixing at the 1st pipe, then draws 1ml to the 2nd pipe, 1ml to the 3rd pipe is drawn again after mixing, so doubling dilution is managed to the 12nd continuously, and absorption 1ml discards from the 12nd pipe, the growth control that the 13rd pipe is not drug containing。Cultivate 24h for 37 DEG C, with the least concentration without bacterial growth for minimal inhibitory concentration (MIC), minimum inhibitory concentration (MIC), unit μ g/mln=6,
Known through antibacterial activity in vitro test experiments result, staphylococcus aureus, escherichia coli, group B streptococcus, streptococcus pneumoniae are had stronger antibacterial action by diacetyl rhein berberine conjugates, its MIC is below diacetyl rhein and berberine, illustrate that diacetyl rhein, berberine exist synergism, enhance the antibacterial activity of diacetyl rhein berberine conjugates pair。
The hypoglycemic activity of embodiment 7 chrysophanic acid berberine ion-pair compound
Blood sugar lowering is tested: choose clean level mice 100, after balance is fed 3 days, and tail vein injections alloxan；After 3 days, take blood measuring blood glucose。Choosing the mice that blood glucose value is 10-25 μm of le/mL is modeling success mice, and then successful for modeling mice divides three major types totally 5 groups (often group 10)。One class is high sugar model control group, fills and feeds distilled water (matched group)；Two classes are hyperglycemia matched group；Three classes respectively diacetyl rhein, berberine group, fill and feed trial drug (100mg/Kg)；Four classes are diacetyl rhein berberine conjugates, fill and feed trial drug (100mg/Kg)；Fill continuously after feeding 15 days, measure Blood Glucose content。
Blood sugar lowering experimental result
Experimental result shows, diacetyl rhein berberine conjugates hypoglycemic effect is substantially better than diacetyl rhein and berberine monomer。
Claims (6)
1. the present invention provides the conjugates of formula (I), and structure is as follows:
It is characterized in that, in formula (I), R is
R1=HC1～C18 side chain or branched paraffin。
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 is added, at 60-70 DEG C of heated and stirred 1-5h；
(3) by product 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 1:1～1.1；Wherein inorganic base is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate；Solution is 0-100% (volume ratio) methanol, ethanol, isopropanol, methanol/water, ethanol/water, isopropanol/water solution, it is preferable that 40%-70% alcoholic solution。
4. respective acids compound solution described in the step (2) described in claim 2, refer to that respective acids compound is dissolved in 0-100% (volume ratio) methanol, ethanol, isopropanol, methanol/water, ethanol/water, isopropanol/water solution, it is preferable that 40%-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, clinically for preventing and treat the complication of antibacterial infection, hyperglycemia and diabetes generation thereof。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610150121.3A CN105693715A (en) | 2016-03-15 | 2016-03-15 | Preparation and medical application of diacerein berberine conjugate |
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| CN201610150121.3A CN105693715A (en) | 2016-03-15 | 2016-03-15 | Preparation and medical application of diacerein berberine conjugate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146488A (en) * | 2016-06-29 | 2016-11-23 | 合肥华方医药科技有限公司 | The Preparation method and use of 9 substituted double-functional group berberinc derivates |
| CN109833292A (en) * | 2019-02-23 | 2019-06-04 | 河南省人民医院 | A kind of diacerein eye drops and application thereof |
| CN112830924A (en) * | 2019-11-25 | 2021-05-25 | 北京中医药大学 | Preparation of multiple-drug-resistant staphylococcus aureus carrier-free nano-drug resistant by rhein and isoquinoline alkaloids |
Citations (3)
| 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 |
| CN103965062A (en) * | 2013-01-29 | 2014-08-06 | 上海源力生物技术有限公司 | Water-soluble choline salts of rhein and rhein derivative, preparation method and application of choline salts in medicine |
| CN104771400A (en) * | 2015-03-17 | 2015-07-15 | 朱孝云 | Oral pharmaceutical composition of diacerein and berberine, and applications thereof |
-
2016
- 2016-03-15 CN CN201610150121.3A patent/CN105693715A/en active Pending
Patent Citations (3)
| 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 |
| CN103965062A (en) * | 2013-01-29 | 2014-08-06 | 上海源力生物技术有限公司 | Water-soluble choline salts of rhein and rhein derivative, preparation method and application of choline salts in medicine |
| CN104771400A (en) * | 2015-03-17 | 2015-07-15 | 朱孝云 | Oral pharmaceutical composition of diacerein and berberine, and applications thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146488A (en) * | 2016-06-29 | 2016-11-23 | 合肥华方医药科技有限公司 | The Preparation method and use of 9 substituted double-functional group berberinc derivates |
| CN106146488B (en) * | 2016-06-29 | 2019-02-05 | 合肥华方医药科技有限公司 | The Preparation method and use of the double-functional group berberinc derivate of 9- substitutions |
| CN109833292A (en) * | 2019-02-23 | 2019-06-04 | 河南省人民医院 | A kind of diacerein eye drops and application thereof |
| CN112830924A (en) * | 2019-11-25 | 2021-05-25 | 北京中医药大学 | Preparation of multiple-drug-resistant staphylococcus aureus carrier-free nano-drug resistant by rhein and isoquinoline alkaloids |
| CN112830924B (en) * | 2019-11-25 | 2023-10-20 | 北京中医药大学 | Preparation of rhein and isoquinoline alkaloid anti-multiple drug resistant staphylococcus aureus carrier-free nano-drug |
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