CN105566318A - Preparation method and medical application of statin berberine conjugate - Google Patents
Preparation method and medical application of statin berberine conjugate Download PDFInfo
- Publication number
- CN105566318A CN105566318A CN201610076077.6A CN201610076077A CN105566318A CN 105566318 A CN105566318 A CN 105566318A CN 201610076077 A CN201610076077 A CN 201610076077A CN 105566318 A CN105566318 A CN 105566318A
- Authority
- CN
- China
- Prior art keywords
- berberine
- formula
- compound
- solution
- statin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method and medical application of a statin berberine conjugate. A statin compound and berberine are chemically synthesized into salt, and the problems that water solubility of statin medicine is poor, oral bioavailability is low, and full play of efficacy is restricted are solved. The problems that water solubility of berberine hydrochloride is low, lipid solubility is low, malabsorption of the gastrointestinal tract is caused, oral bioavailability is low, and the whole-body treatment effect is influenced are also solved. The statin berberine conjugate is mainly applied to products for preventing and/or treating diseases or symptoms related to hyperlipidemia. The invention further relates to products used for preventing and/or treating the diseases or the symptoms related to hyperlipidemia.
Description
Technical field
The present invention relates to berberinc derivate and statins conjugates preparation method, the application in the product of prevention or treatment hyperlipidemia and relative disease or symptom.
Background technology
The whole world probably has 1,200 ten thousand people to die from cardiovascular diseases and cerebral apoplexy every year, and the atherosclerosis that hyperlipidaemia causes causes the major 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 develop blood lipid-lowering medicine and there are great social benefit and market outlook.Statins (statins) is hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, this type of medicine is by competitive inhibition endogenous cholesterol synthesis rate-limiting enzyme (HMG-CoA) reductase enzyme, block hydroxyl first valeric acid pathways metabolism in cell, intracellular cholesteryl is synthesized reduce, thus feedback irritation cell film surface (being mainly liver cell) low-density lipoprotein (lowdensitylipoprotein, LDL) acceptor quantity and activity increase, make serum cholesterol remove increase, level reduces.Statins also can suppress liver to synthesize Apolipoprotein B-100, thus reduces and be rich in triglyceride level AV, the synthesis of lipoprotein and secretion.。
Berberine BBR (Berberine, BBR) is the main active ingredient of the coptis, and in the coptis, BBR content is the highest, accounts for 5.2-7.69%.Coptis bitter, has heat-clearing, removing toxic substances, purging intense heat 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 purulence blood, only quench one's thirst for a long time, frightened, except water conservancy bone, adjust the thick intestines of stomach, beneficial courage, treat aphtha ".Its concocting method is also early on the books in pharmacopeia, Lei Gong's Treatise on Preparation and Broiling of Materia Medica: " allly make the coptis, wipe upper meat hair, time then with pulp-water leaching second of the three ten-day periods of the hot season, filter out, in willow fire, dry use with cloth." in recent years, BBR starts synthetic, its hydrochloride conventional is as the formulation of medicine, and this water-soluble significantly increases, and can greatly heighten the effect of a treatment.2004, the result that the graduate scientist of China Medical Science delivers on NatureMedicine illustrated effect that BBR reduces 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 result that Diabetes delivers.In recent years, effect of BBR has been extended to the every aspect of metabolism related diseases especially: feed in the experiment of mouse and db/db mouse at diabetes B patient, high fat, and BBR all shows it to be reduced body weight, improve effect of insulin resistant and dysbolism of blood fat.More strikingly, BBR feeds in mouse the remarkable efficacy demonstrating its treatment fatty liver at obesity mice and high fat,
But water-soluble poor due to statins, oral administration biaavailability is low, limits giving full play to of its drug effect.And berberine hydrochloride is water-soluble very little, fat-soluble less, gastrointestinal absorption is bad, causes its oral administration biaavailability low, have impact on its whole body therapeutic effect.Although, statins, Berberine has many similar pharmacologically actives, but the use all limited to a certain extent clinically because bioavailability is low, therefore find a kind of improve fibrate and Berberine bioavailability and synergistic method both playing will have very important meaning clinically.
Summary of the invention
The invention provides the derivative preparation method of formula (I) and it is as purposes in the product of prevention and/treatment and hyperlipidemia diseases related or symptom.The invention still further relates to for preventing and the product of/treatment and hyperlipidemia diseases related or symptom.The invention provides the derivative of formula (I), structure is as follows:
In formula (I), R is following structure, but is not limited thereto.
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, the described respective acids compound solution of formula (I) is added, 60-70 DEG C of heated and stirred 1-8h;
(3) reaction product is carried out suction filtration, filtrate to be while hot recycled to original volume 1/3, cooling crystallization, to filter, to 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, preferred 1:0.95 ~ 1.05; Wherein mineral alkali is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide; Solution is 0-100% (volume ratio) methyl alcohol, ethanol, aqueous isopropanol, preferably 70% ethanolic soln;
In step (2), respective acids compound solution refers to, refers to that respective acids compound is dissolved in 0-100% (volume ratio) methyl alcohol, ethanol, aqueous isopropanol, preferably 70% ethanolic soln;
The derivative that the invention provides formula (I) is through common process or indirectly add pharmaceutically acceptable vehicle and make and can accept formulation clinically, is used for the treatment of diabetes B clinically, regulates blood sugar and blood fat.
Specific embodiment
By following examples better the present invention to be described.But the present invention is not by the restriction of following embodiment.
The synthesis of embodiment 1 fluvastatin Berberine conjugates
Get berberine hydrochloride 3.7g, add in 100ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the aqueous sodium hydroxide solution of 3mol/l, be warming up to 60-70 DEG C, stirring and dissolving, then add 4.2g fluvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain fluvastatin special Berberine conjugates 6.3g, yield 84.6%.
The synthesis of embodiment 2 fluvastatin Berberine conjugates
Get berberine hydrochloride 3.7g, add in 100ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the aqueous sodium hydroxide solution of 0.3mol/l, be warming up to 60-70 DEG C, stirring and dissolving, then add 4.3g fluvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain fluvastatin Berberine conjugates 6.1g, yield 81.9%.
The synthesis of embodiment 3 fluvastatin Berberine conjugates
Get berberine hydrochloride 3.7g, add in 100ml there-necked flask, add 100ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 1mol/l, be warming up to 60-70 DEG C, stirring and dissolving, then add 4.5g fluvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain fluvastatin Berberine conjugates 5.6g, yield 91.3%.ESI-MS(M
++H)m/zcalcdforC
20H1
6NO
4 +337.13found337.26；ESI-MS(M
++H)m/zcalcdforC
24H
26FNO
4412.54found412.65。
The synthesis of embodiment 4 Simvastatin Berberine conjugates
Get 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, be warming up to 60-70 DEG C, stirring and dissolving, then add 4.5g Simvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain fluvastatin Berberine conjugates 6.6g, yield 85.8%.
The synthesis of embodiment 5 Simvastatin Berberine conjugates
Get berberine hydrochloride 3.7g, add in 100ml there-necked flask, add 150ml ethanol, regulate pH to 7-8 with the sodium hydroxide of 2mol/l, be warming up to 60-70 DEG C, stirring and dissolving, then add 4.4g Simvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain Simvastatin Berberine conjugates 6.7g, yield 87.1%.ESI-MS(M
++H)m/zcalcdforC
20H1
6NO
4 +337.13found337.26；ESI-MS(M
++H)m/zcalcdforC
25H
38O
5419.34found419.35。
The synthesis of embodiment 6 pitavastatin acid Berberine conjugates
Get 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, be warming up to 60-70 DEG C, stirring and dissolving, then add the acid of 4.2g pitavastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain pitavastatin acid Berberine conjugates 6.1g, yield 81%.ESI-MS(M
++H)m/zcalcdforC
20H1
6NO
4 +337.13found337.26；ESI-MS(M
++H)m/zcalcdforC
25H
23FNO
4422.34found422.29。
The synthesis of embodiment 7 atorvastatin acid Berberine conjugates
Get 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, be warming up to 60-70 DEG C, stirring and dissolving, then add the acid of 5.6g atorvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain atorvastatin acid Berberine conjugates 8.3g, yield 93%.ESI-MS(M
++H)m/zcalcdforC
20H1
6NO
4 +337.13found337.26；ESI-MS(M
++H)m/zcalcdforC
33H
35FN
2O
5559.64found559.65。
The synthesis of embodiment 8 Rosuvastatin Berberine conjugates
Get 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, be warming up to 60-70 DEG C, stirring and dissolving, then add 4.8g Rosuvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain Rosuvastatin Berberine conjugates 6.4g, yield 78.6%.
The synthesis of embodiment 9 Rosuvastatin Berberine conjugates
Get 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, be warming up to 60-70 DEG C, stirring and dissolving, then add 5.0g Rosuvastatin, keep this temperature to stir 1-2h, filtered while hot, filtrate is concentrated into original volume 1/3rd, cooling crystallization, filters, is drying to obtain Rosuvastatin Berberine conjugates 7.3g, yield 89.6%.ESI-MS(M
++H)m/zcalcdforC
20H1
6NO
4 +337.13found337.26；ESI-MS(M
++H)m/zcalcdforC
22H
28N
3O
6SF782.01found482.00。
Embodiment 10 Chinese hamster is fed with high fat hypercholesterolemia (HFHC) food after 10 days, orally gives compound described in embodiment, within 25 days, measures the level of the cruel and low-density lipoprotein-C of total cholesterol in blood, glycerine three afterwards.It is mean+SD in table.Administering mode: every day is oral, totally 25 days; Every treated animal number: n=7.Get hematometry cholesterol, the level of the cruel and low-density lipoprotein of glycerine three, and carry out statistical procedures, the results are shown in Table 1
Table 1 embodiment compound reducing blood lipid
Claims (6)
1. the invention provides the derivative of formula (I), structure is as follows:
it is characterized in that, in formula (I), R can be following functional group, but is not limited thereto;
R1=H or C1 ~ C18 straight or branched alkane.
2. the preparation method of formula according to claim 1 (I) compound, 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, the described respective acids compound solution of formula (I) is added, 60-70 DEG C of heated and stirred 1-8h;
(3) reaction product is carried out suction filtration, filtrate to be while hot recycled to original volume 1/3, cooling crystallization, to filter, to be drying to obtain formula (I) described compound.
3. the inorganic alkali solution in step according to claim 2 (1): it is characterized in that berberine hydrochloride and inorganic base molar ratio are 1:1 ~ 1:3, preferred 1:0.95 ~ 1.05; Wherein mineral alkali is one or more in sodium hydroxide, potassium hydroxide, calcium hydroxide; Solution is 0-100% (volume ratio) methyl alcohol, ethanol, aqueous isopropanol, preferably 70% ethanolic soln.
4. respective acids compound solution described in step according to claim 2 (2), refers to that respective acids compound is dissolved in 0-100% (volume ratio) methyl alcohol, ethanol, aqueous isopropanol, preferably 70% ethanolic soln.
5. formula according to claim 1 (I) compound is through common process or indirectly add pharmaceutically acceptable vehicle and make and can accept formulation clinically, comprises injection, oral preparation, preferred oral preparation.
6. formula according to claim 1 (I) compound is through common process or indirectly add pharmaceutically acceptable vehicle and make and can accept formulation clinically, clinically for preventing and the product of/treatment and hyperlipidemia diseases related or symptom.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610076077.6A CN105566318A (en) | 2016-01-30 | 2016-01-30 | Preparation method and medical application of statin berberine conjugate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610076077.6A CN105566318A (en) | 2016-01-30 | 2016-01-30 | Preparation method and medical application of statin berberine conjugate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105566318A true CN105566318A (en) | 2016-05-11 |
Family
ID=55877008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610076077.6A Pending CN105566318A (en) | 2016-01-30 | 2016-01-30 | Preparation method and medical application of statin berberine conjugate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105566318A (en) |
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 |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012073256A1 (en) * | 2010-11-29 | 2012-06-07 | Cadila Healthcare Limited | Salts of rosuvastatin |
| CN104327070A (en) * | 2014-09-30 | 2015-02-04 | 中南大学 | Preparation method and application of substituted indole acetic acid berberine salt |
-
2016
- 2016-01-30 CN CN201610076077.6A patent/CN105566318A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012073256A1 (en) * | 2010-11-29 | 2012-06-07 | Cadila Healthcare Limited | Salts of rosuvastatin |
| CN104327070A (en) * | 2014-09-30 | 2015-02-04 | 中南大学 | Preparation method and application of substituted indole acetic acid berberine salt |
Non-Patent Citations (1)
| Title |
|---|
| 苏晓叶等: "辛伐他汀联合黄连素治疗高脂血症60 例", 《中国中医药现代远程教育》 * |
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 |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2084132B1 (en) | Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate | |
| CN102670673B (en) | The application of Flos abelmoschi manihot active component in the medicine of preparation control metabolic disease | |
| WO2008012603A1 (en) | Positively charged water-soluble prodrugs of diflunisal and related compounds with very fast skin penetration rate | |
| CN105732609A (en) | Preparation method and medical application of berberine hydrochloride conjugate | |
| JP2009543857A (en) | Positively charged water-soluble prodrug of ibuprofen | |
| WO2012000377A1 (en) | Pharmaceutical composition comprising levocarnitine and dobesilate | |
| KR20110117257A (en) | Triacetyl-3-hydroxyphenyladenosine and its use for regulating blood fat | |
| CN101823956B (en) | Diisopropylamine fenofibrate, preparation method of same, medicinal composition and use of same | |
| WO2008012605A1 (en) | Positively charged water-soluble prodrugs of ketoprofen and related compounds with very fast skin penetration rate | |
| CN105566318A (en) | Preparation method and medical application of statin berberine conjugate | |
| CN104592025A (en) | Ferulate compound and preparation method thereof | |
| CN103239725A (en) | Compound preparation for treating cardiovascular and cerebrovascular diseases | |
| CN105712989A (en) | Preparation method of cinnamic acid type berberine conjugate and medical application | |
| CN105732610A (en) | Pharmaceutical application of phenoxy acid derivative | |
| CN106083842B (en) | The Preparation method and use of the double-functional group berberinc derivate of 9- substitutions | |
| CN104774236A (en) | Fatty acid-bile acid conjugates having fat lowering activity, and medical uses thereof | |
| CN106146489B (en) | The Preparation method and use of the double-functional group berberinc derivate of 9- substitutions | |
| WO2006102788A1 (en) | The complex antihyperlipidemics | |
| CN105693813A (en) | Preparation and medical application of glycyrrhizic acid berberine coupling compound | |
| CN1672728A (en) | Extract of star of bethlehem and its prepn process, medicinal composition and use | |
| CN106146488B (en) | The Preparation method and use of the double-functional group berberinc derivate of 9- substitutions | |
| CN1293874C (en) | Traditional chinese medicine Monascus purpureus went using Lovastatin salt as main active and its preparation component | |
| CN1398861A (en) | Prepn and application in preparing medicine of Fraxinus general coumarin | |
| CN102040603B (en) | The purposes of the adjacent methoxycarbonyl benzyl tetrahydro Berberine of bromination N-and treatment hyperlipidemia thereof | |
| WO2020063262A1 (en) | Application of 3'-deoxyinosine in preparation of drug, food or health product for multiple disease |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160511 |
|
| RJ01 | Rejection of invention patent application after publication |