CN106188035A - The Preparation method and use of 9 substituted double-functional group berberinc derivates - Google Patents
The Preparation method and use of 9 substituted double-functional group berberinc derivates Download PDFInfo
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- CN106188035A CN106188035A CN201610517945.XA CN201610517945A CN106188035A CN 106188035 A CN106188035 A CN 106188035A CN 201610517945 A CN201610517945 A CN 201610517945A CN 106188035 A CN106188035 A CN 106188035A
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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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- Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract
The present invention provides the preparation method of a kind of 9 substituted double-functional group berberinc derivates, belong to the field of chemical synthesis, 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 simple function group medicine, and specifically this analog derivative demonstrates excellent adjusting hypertension rat blood pressure effect in zoopery.Its Main Function is embodied in and can block the angiotensinⅡ that various approach produces and be combined with its specific receptor, thus weakens or blocks its boosting.
Description
Technical field
The present invention relates to food pharmaceutical technical field, be specifically related to 9-position substituted double-functional group berberinc derivate in system
Application in the product of standby prevention or treatment hypertension and relevant disease or symptom.
Background technology
Hypertension is modal cardiovascular and cerebrovascular disease, is the public health problem of whole world maximum, analyzes according to WHO, arrive
The year two thousand twenty, because the death of hypertension-induced occupies the 1st of all non-death that catches.Survey data, China more than 18 years old
Adult hypertension prevalence is 18.8%, estimates that current China there are about 200,000,000 hyperpietics, just has 2 people in every 10 adults
Suffer from hypertension, account for the 1/5 of whole world hypertension total number of persons.In China's Hypertensive Population, the overwhelming majority is light, medium and high blood
Pressure (accounting for 90%), mild hypertension accounts for more than 60%.But, population of China normal arterial pressure (< 120/80mmHg) proportion is not
To 1/2.The horizontal crowd of In Prehypertensive accounts for the ratio of total Adult Groups and constantly increases, especially young and middle-aged, from 1991
Year 29% increase to 2002 34%, be China's Prevalence of Hypertension persistently raise increase severely with number of patients main come
Source.Estimate that China increases hyperpietic 10,000,000 people every year newly.The sales volume of global sartans in 2007 has reached 19,400,000,000
Dollar, occupy the 2.72% of whole world drug market.Sartans by antagonizing angiotensin II receptor blocking circulation and
The arterial vasoconstriction caused by angiotensin, sympathetic activation and pressure receptor sensitivity in local organization increase equivalence
Answer thus play the effect reduced blood pressure.Heavily absorb and Reverse cardiac and vascular smooth muscle additionally by reducing renal tubules water, sodium
Hypertrophy and reach hypotensive effect.Preferable to hypertension therapeutic effect, good market prospects.
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 and be difficult to inhale after being administered orally
Receipts, the intestinal infection causing dysentery bacterium, escherichia coli, staphylococcus aureus, eye conjunctivitis, suppurative otitis media etc. have
Effect, clinic is mainly used in the treatment of intestinal infection.Along with research go deep into, find the most successively its have arrhythmia,
The pharmacological actions such as vasodilator, protection cardiac muscle, antiplatelet aggregation, blood sugar lowering, blood fat reducing, antiinflammatory, antiviral, antitumor.
Berberine hydrochloride water solublity is the least, and fat-soluble less, gastrointestinal absorption is bad, causes its oral administration biaavailability
Low, have impact on its whole body therapeutic effect.Although husky smooth class, berberine have many similar pharmacologically actives, but all because of biology
The low use limited to a certain extent clinically of availability, therefore finds a kind of life improving sartans and berberine
Thing availability also plays both synergistic method and will have very important meaning clinically.
Summary of the invention
The present invention relates to the Preparation method and use of a kind of 9-position substituted double-functional group berberinc derivate, such derives
Thing has the pharmaceutically active of various value, and particularly its performance easily absorbed is not available for simple function group medicine, specifically
This analog derivative of ground demonstrates excellent adjusting hypertension rat blood pressure effect in zoopery.Its Main Function is embodied in and can hinder
The angiotensinⅡ that disconnected various approach produce is combined with its specific receptor, thus weakens or block its boosting.The present invention
The derivant of offer formula (I), structure is as follows:
It is characterized in that, in formula (I), wherein m, n are the integer of 1-10；X is
One in C, O, S, NH, C=O, COO, C=ONH；Z is F-、Cl-、Br-、I-Or physiology can accept into other of salt bear from
Son；R is
In one.
The preparation method of described formula (I) compound, comprises the following steps:
(1) berberine hydrochloride is taken off 9 methyl and prepare berberrubine；
(2) to the berberrubine of step (1) gained withEtherificate prepares compound
(3) to the berberrubine etherate of step (2) gained withCondensation preparation formula (I) compound.Described step
Suddenly in (2) structural formula, m, n are the integer of 1-10, and X is the one in C, O, S, NH, C=O, COO, C=ONH, Y is F, Cl, Br,
I, Z are F-、Cl-、Br-、I-Or physiology can accept into other anion of salt.
In described step (3) structural formula, R is
In one.
Described formula (I) compound is made clinically may be used through common process or the pharmaceutically acceptable excipient of indirect addition
Accept dosage form, including injection, oral agents, preferred oral preparation.
Described formula (I) compound is made clinically may be used through common process or the pharmaceutically acceptable excipient of indirect addition
Accept dosage form, be used for clinically preventing and treating hypertension.
Detailed description of the invention
By following example to better illustrate the present invention.But the present invention is not limited by following embodiment.
Embodiment 1
A) synthesis of berberrubine
Adding berberine 7.4g in 250mL circle flask is 20-30mmHg in vacuum, heats under the conditions of 190-200 DEG C
About 30min, the most dimmed redness of yellow solid, vacuum desiccator is cooled to room temperature, silica gel column chromatography purification, obtains dark red toner
End 4.7g, yield 75%.
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
In 25mL round-bottomed flask, add berberrubine 3.2g (10mmol), add 30mLDMF and dissolve, 70 DEG C of heating, add
Entering ethylene bromohyrin 4.4g (20mmol), TLC follows the tracks of reaction, adds 100mL absolute ether, separates out solid, filter after reaction completely,
Silica gel column chromatography purification, obtains 9-O-3-hydroxy-ethyl berberine hydrobromate 3.3g, yield 76%
C) synthesis of eprosartan-9-O-acetas berberine
425mg (1mmol) eprosartan, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 446mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain eprosartan-9-O-acetas berberine 658mg, yield 85%.ESI-MS(M+H)+m/z calcd C44H42N3O8S+
for 773.28found773.27。
Embodiment 2
A) synthesis of berberrubine
A) identical with embodiment 1
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
B) identical with embodiment 1
C) synthesis of valsartan-9-O-acetas berberine
436mg (1mmol) valsartan, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 446mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain valsartan-9-O-acetas berberine 659mg, yield 86%.ESI-MS(M+H)+m/z calcd C45H47N6O7 +for
784.35found784.35。
Embodiment 3
A) synthesis of berberrubine
A) identical with embodiment 1
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
B) identical with embodiment 1
C) synthesis of Candesartan-9-O-acetas berberine
440mg (1mmol) Candesartan, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 446mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain Candesartan-9-O-acetas berberine 694mg, yield 88%.ESI-MS(M+H)+m/z calcd C45H38N7O7 +
for789.28found789.28。
Embodiment 4
A) synthesis of berberrubine
A) identical with embodiment 1
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
B) identical with embodiment 1
C) synthesis of telmisartan-9-O-acetas berberine
515mg (1mmol) telmisartan, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 446mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain telmisartan-9-O-acetas berberine 694mg, yield 87%.ESI-MS(M+H)+ m/z calcd C54H48N5O6 +
for863.36found863.37。
Embodiment 5
A) synthesis of berberrubine
A) identical with embodiment 1
B) synthesis of 9-O-3-hydroxy-ethyl berberine hydrobromate
B) identical with embodiment 1
C) synthesis of Azilsartan-9-O-acetas berberine
515mg (1mmol) Azilsartan, dichloromethane 20ml, 178mg (1.1mmol) is added in 25mL round-bottomed flask
CDI, stir 10min, add 9-O-3-hydroxy-ethyl berberine hydrobromate 456mg (1mmol), be stirred at room temperature, TLC with
Track reacts, and adds 20ml water, stirring, extraction, organic facies, is dried, filter after reaction completely, and concentrating under reduced pressure, silica gel column chromatography is pure
Change, obtain Azilsartan-9-O-acetas berberine 694mg, yield 83%.ESI-MS(M+H)+m/z calcd C46H38N5O9 +
for805.27found805.27。
The hypotensive activity of embodiment 6 9-position substituted double-functional group berberinc derivate
Blood pressure lowering is tested: choosing spontaneous hypertensive rat 200, adaptability is supported 1 week, and single oral gavage is administered, and uses
Softron intelligence non-invasive blood pressure measuring detection rat blood pressure.Choosing the rat that pressure value is 125-190mmHg is that modeling success is big
Mus, is then divided into 7 groups (often groups 10) by successful for modeling rat.Administration group, fills and feeds trial drug (8mg/Kg)；Fill continuously and feed
After 15 days, measure rat blood pressure height.
Blood pressure lowering experimental result
Experimental result shows, 9-position substituted double-functional group berberinc derivate hypoglycemic effect is substantially better than berberine list
Body.
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), wherein m, n are the integer of 1-10；X is C, O, S,
One in NH, C=O, COO, C=ONH；Z is F-、Cl-、Br-、I-Or physiology can accept into other anion of salt；R isIn one.
2. the preparation method of formula (I) compound described in claim 1, comprises the following steps:
(1) berberine hydrochloride is taken off 9 methyl and prepare berberrubine；
(2) to the berberrubine of step (1) gained withEtherificate prepares compound
(3) to the berberrubine etherate of step (2) gained withCondensation preparation formula (I) compound.
3., in step (2) structural formula described in claim 2, m, nn are the integer of 1-10, and X is C, O, S, NH, C=O, COO, C
One in=ONH, Y is F, Cl, Br, I, and Z is F-、Cl-、Br-、I-Or physiology can accept into other anion of salt.
4., in step (3) structural formula described in claim 2, R is
In one.
5. formula (I) compound described in claim 1 is made through common process or the pharmaceutically acceptable excipient of indirect addition
Can accept dosage form clinically, including injection, oral agents, preferred oral preparation.
6. formula (I) compound described in claim 1 is made through common process or the pharmaceutically acceptable excipient of indirect addition
Can accept dosage form clinically, be used for clinically preventing and treating hypertension.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163433A (en) * | 2021-12-21 | 2022-03-11 | 哈尔滨医科大学 | Berberine derivative and preparation method and application thereof |
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|---|---|---|---|---|
| WO2011006000A1 (en) * | 2009-07-08 | 2011-01-13 | Haiyan Liu | Berberine derivatives useful for modulating lipid levels and their methods of synthesis |
| CN102030746A (en) * | 2009-09-30 | 2011-04-27 | 中山大学 | Preparation method and application of 9-bit substituent double-functional group berberine derivatives |
| CN102659777A (en) * | 2012-05-07 | 2012-09-12 | 雷海民 | Antitumor medicament |
| CN102746292A (en) * | 2011-04-18 | 2012-10-24 | 中国医学科学院医药生物技术研究所 | Cyclized berberine derivatives, preparation method and uses thereof |
| CN103450187A (en) * | 2013-08-10 | 2013-12-18 | 湖州师范学院 | Tetrahydro-berberrubine derivative and preparation method and application thereof |
| CN105622602A (en) * | 2016-01-30 | 2016-06-01 | 合肥华方医药科技有限公司 | Method for preparing sartans and berberine conjugates and medical application thereof |
-
2016
- 2016-06-30 CN CN201610517945.XA patent/CN106188035B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011006000A1 (en) * | 2009-07-08 | 2011-01-13 | Haiyan Liu | Berberine derivatives useful for modulating lipid levels and their methods of synthesis |
| CN102030746A (en) * | 2009-09-30 | 2011-04-27 | 中山大学 | Preparation method and application of 9-bit substituent double-functional group berberine derivatives |
| CN102746292A (en) * | 2011-04-18 | 2012-10-24 | 中国医学科学院医药生物技术研究所 | Cyclized berberine derivatives, preparation method and uses thereof |
| CN102659777A (en) * | 2012-05-07 | 2012-09-12 | 雷海民 | Antitumor medicament |
| CN103450187A (en) * | 2013-08-10 | 2013-12-18 | 湖州师范学院 | Tetrahydro-berberrubine derivative and preparation method and application thereof |
| CN105622602A (en) * | 2016-01-30 | 2016-06-01 | 合肥华方医药科技有限公司 | Method for preparing sartans and berberine conjugates and medical application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163433A (en) * | 2021-12-21 | 2022-03-11 | 哈尔滨医科大学 | Berberine derivative and preparation method and application thereof |
| CN114163433B (en) * | 2021-12-21 | 2022-11-25 | 哈尔滨医科大学 | Berberine derivative and preparation method and application thereof |
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