CN105693813A - Preparation and medical application of glycyrrhizic acid berberine coupling compound - Google Patents
Preparation and medical application of glycyrrhizic acid berberine coupling compound Download PDFInfo
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- CN105693813A CN105693813A CN201610150099.2A CN201610150099A CN105693813A CN 105693813 A CN105693813 A CN 105693813A CN 201610150099 A CN201610150099 A CN 201610150099A CN 105693813 A CN105693813 A CN 105693813A
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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
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/256—Polyterpene radicals
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Abstract
The invention provides a preparing method of a derivative of the formula (I) and application of the derivative to drugs for treating hyperlipidemia and lowering lipid. It is found through pharmacology experiments that the derivative has multi-value drug activity and especially the easy absorbing property which is not possessed by glycyrrhizic acid drugs, and specifically, the derivative shows an excellent effect of adjusting blood lipid of hyperlipidemia rats in the animal experiments. The derivative has the main effects of promoting decrease of cholesterol content, promoting obvious reduction of phospholipid, inhibiting the inflammatory reaction of the organism and the blood vessel wall and preventing occurrence and development of arteriosclerosis.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to the application in treatment hyperlipidemia, reduction blood fat product of a kind of Radix Glycyrrhizae acids berberine conjugates。
Background technology
Between past 20 years, the food consumption of people and diet structure there occurs very big change, and the sickness rate that the most active effects thus brought is exactly hyperlipidemia constantly promotes。In the blood safety seminar a few days ago held, expert estimates, in the middle of the adult in more than 30 years old, the whole nation, the sickness rate of hyperlipidemia is at about 10%-20%, and hyperlipemia number is up to 90,000,000。The relevant statistics of Ministry of Public Health displays that, last year just has one to die from cardiovascular and cerebrovascular disease in the middle of every 3 dead Chinese, and hyperlipidemia causes that atherosclerosis is the arch-criminal of cardiovascular and cerebrovascular disease。Namely foreign scholar proved as far back as the seventies, and glycyrrhizic acid has reduction animal lipid effect, and is being clinically used for the treatment of hypercholesterolemia。
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。
Water solublity yet with Radix Glycyrrhizae acids 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, Radix Glycyrrhizae acids 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 Radix Glycyrrhizae acids medicine and berberine and play both synergistic method and will have very important meaning clinically。
Summary of the invention:
The present invention provide the derivative preparation method of formula (I) and its as treatment hyperlipidemia, reduce application in the medicine of 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 Radix Glycyrrhizae acids medicine, and specifically this analog derivative demonstrates excellent adjustment hyperlipemia rat blood fat in zoopery。Its Main Function is embodied in and promotes cholesterol level to reduce, and phospholipid is decreased obviously, it is suppressed that the inflammatory reaction of body and blood vessel wall, it is prevented that atherosclerotic generation and development。
The present invention provides the derivant of formula (I), and structure is as follows:
In formula (I), R is
R1=H or C1～C18 straight or branched alkane。
1. 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；
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 1:1.0～1.05；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；
3. 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 hyperlipidemia, reducing 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 glycyrrhizic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml 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 8.2g glycyrrhizic 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 glycyrrhizic acid berberine conjugates 9.3g, yield 80%。
Embodiment 2
The synthesis of glycyrrhizic acid berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml 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 8.9g glycyrrhizic 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 glycyrrhizic acid berberine conjugates 9.7g, yield 84%。
Embodiment 3
The synthesis of glycyrrhizic acid berberine conjugates
Take berberine hydrochloride 3.7g, 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 9.5g glycyrrhizic 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 glycyrrhizic acid berberine conjugates 10.2g, yield 92%。ESI-MS (M++H)m/zcalcdforC20H18NO4 +337.12found337.26；ESI-MS (M++H)m/zcalcdforC42H62O16823.40found823.34。
Embodiment 4
The synthesis of enoxolone berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml 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 4.7g enoxolone, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain enoxolone berberine conjugates 6.5g, yield 81%。
Embodiment 5
The synthesis of enoxolone berberine conjugates
Take berberine hydrochloride 3.7g, add in 250ml 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 5.2g enoxolone, keeps this temperature stirring 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain enoxolone berberine conjugates 6.9g, yield 86%。ESI-MS (M++H)m/zcalcdforC20H18NO4 +337.12found337.26；ESI-MS (M++H)m/zcalcdforC30H46O4471.34found471.38。
The effect for reducing blood fat of embodiment 6 Radix Glycyrrhizae acids berberine conjugates
Lipid-lowering test: choose hamster and feed, after high fat hypercholesterolemia (HFHC) food 10 days, to be orally administered to compound described in embodiment, measures after 25 days that T-CHOL in blood, glycerol three is cruel and the level of low density lipoprotein, LDL-C。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, Radix Glycyrrhizae acids berberine conjugates lipid-lowering effect is substantially better than glycyrrhizic 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 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, 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 1:1.0～1.05；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 preventing and treating hyperlipidemia, reduce blood fat。
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| CN201610150099.2A CN105693813A (en) | 2016-03-15 | 2016-03-15 | Preparation and medical application of glycyrrhizic acid berberine coupling compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146489A (en) * | 2016-06-30 | 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 |
| CN114306640A (en) * | 2022-01-27 | 2022-04-12 | 南方医科大学南方医院 | Method for increasing solubility of berberine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563073A (en) * | 2004-04-06 | 2005-01-12 | 南开大学 | Method for preparing enoxolone |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
-
2016
- 2016-03-15 CN CN201610150099.2A patent/CN105693813A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563073A (en) * | 2004-04-06 | 2005-01-12 | 南开大学 | Method for preparing enoxolone |
| CN103319479A (en) * | 2012-03-20 | 2013-09-25 | 王从品 | Rheinic acid berberine ion pair compound, preparation method and applications |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146489A (en) * | 2016-06-30 | 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 |
| CN106146489B (en) * | 2016-06-30 | 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 |
| CN114306640A (en) * | 2022-01-27 | 2022-04-12 | 南方医科大学南方医院 | Method for increasing solubility of berberine |
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