CN102225962A - New derivative bonded by berberine and cholic acid at 9th position of berberine and preparation method thereof - Google Patents
New derivative bonded by berberine and cholic acid at 9th position of berberine and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a new derivative bonded by berberine and cholic acid at the 9th position of berberine in formula (I) and a preparation method thereof. The invention also relates to a method for preparing a compound of the derivative and the application of the compound in the invention as medicine in treating tumors. In formula (I), R1 stands for hydroxy and carbonyl, while R2 and R3 stand for hydrogen, hydroxyl and carbonyl.
Description
Technical field
The present invention relates to the preparation method of a class berberinc derivate and the application in antineoplaston.
Background technology
From M.-E. Xia Waliai in 1826 and G. Pei Ertan extracted Berberine first from the Xanthoxylonclava bark since, the medicine scholar discovered the Berberine has a broad antifungal spectrum, and pharmacological effects such as reducing blood-fat, hypoglycemic, anti-peptic ulcer are arranged.The traditional Chinese medical science is used the coptis, golden cypress, Root of Chinese Barberry etc. always and is done clearing heat and detoxicating medicine, and its main component is a Berberine.1966, berberine hydrochloride has been collected by Japanese officina and the Weibull Berberine is used for the treatment of intestinal tract infections.Along with further investigation, seventies Japan scholar proposes Berberine and derivative has antitumor action.In recent years, many researchists actively put on the Application and Development of Berberine, and research thinks that the interior hydrolysis of berberinc derivate body has generated quaternary ammonium salt, can enter tumour cell, suppresses the tumour cell dna replication dna as topoisomerase enzyme inhibitor.Because Berberine intestinal absorption effect is relatively poor, and its bioavailability is had certain influence
Berberine is water-soluble, is insoluble in numerous organic solvents, and side effect is little.Because the treatment process difference can obtain quaternary ammonium formula, aldehyde formula and three kinds of multi-form Berberines of pure formula, and is wherein the most stable with the quaternary ammonium formula.In order to improve Berberine analog derivative anti-tumor activity, enhanced stability and fat-soluble increases bioavailability simultaneously, reduces its toxic side effect as much as possible, to there being the Berberine than strong water-soluble to carry out structural modification research, can be effectively the barberry bases useful for drug delivery of aequum be arrived target tissue.
By the liver targeted drug delivery technology chemotherapeutic agent optionally is invested in liver, can alleviates or avoid its systemic toxic side effect.Cholic acid is the specific natural aglucon of endogenic liver cell, it is present unique oral hepatic targeting drug carrier, bio-compatibility is preferably arranged, enter liver by the active transport approach by intestinal absorption, having the organ specificity of height and higher turn-over capacity, therefore, is the liver target that targeting vector not only can be realized medicine with the cholic acid, reduce side effect, and can improve bioavailability of medicament.
In recent years, people are to being that the research of the hepatic targeting drug of carrier deepens continuously with the cholic acid, bibliographical information polypeptide, lipid lowerers, antiviral drug, antitumour drug, antidiabetic drug and nitrate esters medicine etc. and cholic acid bonded hepatic targeting drug arranged.Experimental study such as cell and animal shows that after medicine and the cholic acid coupling, liver increases to some extent to being absorbed in varying degrees of medicine, has reduced the toxic side effect of medicine to a certain extent.Kramer etc. utilize Chlorambucil as model drug and cholic acid coupling, and Chlorambucil is connected to 3 hydroxyls of cholic acid, obtain cholic acid-Chlorambucil conjugates, have investigated the liver target and the anti-tumor activity of conjugates.The result shows that former medicine has only faint effect to liver cholic acid transporter, and corresponding cholic acid conjugates strongly inhibited the liver of taurocholate absorb, illustrating between conjugates and cholic acid transporter has stronger interaction.People such as Monte form glycine cholic acid-cis-platinum inner complex with glycine cholic acid and cis-platinum coupling, in vivo test show that this inner complex can be absorbed by tumour cell and absorbed dose apparently higher than former medicine.As natural cholic acid, can advance the circulation of people's liver sausage, increase the little intestinal absorption and the choleresis of former medicine, have only on a small quantity and get rid of by urine.Simultaneously, also can effectively suppress the growth of external and interior tumor cell, have certain anti-tumor activity, see [2006 15 the 3rd phases of volume of Chinese Journal of New Drugs].
In sum, the conjugates of former medicine and cholic acid has the transport features of cholic acid, and the liver that can increase medicine absorbs, and reaches the target purpose.
Summary of the invention
The object of the present invention is to provide a class fully to keep the antineoplastic pharmacologically active of Berberine, improve drug targeting, solve the berberinc derivate of problems such as it is fat-soluble poor, and target is poor, and bioavailability is low.
Another object of the present invention provides the preparation method of such berberinc derivate.
In order to finish purpose of the present invention, the contriver has carried out a large amount of creationary researchs, filling under the antineoplastic pharmacologically active prerequisite of maintenance Berberine, it is fat-soluble poor to solve it, target is poor, bioavailability is low, etc. problem, has finally found and can generate the berberinc derivate with liver target by Berberine and chlolic acid derivatives reaction
The new berberinc derivate of the present invention is represented with following general formula (I):
Wherein
R
1Be hydroxyl, carbonyl;
R
2Be hydrogen, hydroxyl, carbonyl;
R
3Be hydrogen, hydroxyl, carbonyl;
The preparation method of the fat-soluble berberinc derivate that the present invention is new:
It is characterized in that the Berberine shown in the formula (II)
Heating generates intermediate berberrubine (III).
With chlolic acid derivatives shown in (IV) formula
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
React to generate chlolic acid derivatives (V) with N-hydroxy-succinamide
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
With glycine reactant to generate chlolic acid derivatives (VI)
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
With the dihalo hydrocarbon reaction to generate chlolic acid derivatives (VII)
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
With berberinc derivate shown in (III) formula and the reaction of (VII) chlolic acid derivatives shown in the formula to generate the described berberinc derivate of claim 1 (I)
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5.
Advantage of the present invention: berberinc derivate of the present invention has not only kept O-O and N on the Berberine reactive site five-ring
+Stability, and fat-soluble good, increased bioavailability of medicament, fully kept the antineoplastic pharmacologically active of Berberine.
Embodiment:
Embodiment 1: glycocholic acid-9-propoxy-Berberine synthetic: (C1)
(1) berberrubine is synthetic
Adding Berberine 744mg (2mmol) in the 250mL round-bottomed flask is 20-30mmHg in vacuum tightness, heat 30min under the 195-210 ℃ of condition, yellow solid deepening redness gradually, be cooled to room temperature in the vacuum drier, purification by silica gel column chromatography gets the garnet powder, yield 73%, molecular weight: 322, structure is as follows:
(2) the cholic acid Acibenzolar is synthetic:
In the 50mL round-bottomed flask, add cholic acid 204mg (0.5mmol), add methylene dichloride 10mL, add N-hydroxy-succinamide 115mg, dropwise add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide 766mg (4mmol) dichloromethane solution 10mL, follow the tracks of reaction by TLC.In reaction solution, add chloroform 30ml after reacting completely, use 50ml saturated aqueous common salt, the saturated NaHCO of 50ml successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder.Yield 60%; Molecular weight: 515; Structural formula is as follows:
(3) glycocholic acid is synthetic:
In the 25mL round-bottomed flask, add cholic acid Acibenzolar 257mg (0.5mmol), 1mL DMSO dissolving adds glycine 45mg (0.6mmol), 100 μ L triethylamines, TLC follows the tracks of reaction, add the 20mL anhydrous diethyl ether after reacting completely, separate out white solid, decompress filter, vacuum-drying, productive rate 98%, molecular weight: 465, structure is as follows:
(4) glycocholic acid-3-bromine propyl ester is synthetic:
Add glycocholic acid 233mg (0.5mmol) in the 25mL round-bottomed flask, add the 1mLDMF dissolving, add 200 μ L 1, the 3-dibromopropane adds K
2CO
3276mg (2mmol), TLC follows the tracks of reaction, and after reacting completely, decompress filter adds chloroform 50mL in the filtrate, use 50mL distilled water, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder, yield 60%; Molecular weight: 585, structure is as follows:
(5) glycocholic acid-9-propoxy-Berberine is synthetic: (C1)
In the 25mL round-bottomed flask, add berberrubine 161mg (0.5mmol), add 3mL DMF dissolving, add glycocholic acid-3-bromine propyl ester 468mg (0.8mmol), 60 ℃ of heating, TLC follows the tracks of reaction, add anhydrous diethyl ether after reacting completely, separate out yellow solid, decompress filter, vacuum-drying, silica gel column chromatography obtains target product, yield 34%; Molecular weight: 827, structural formula is as follows:
Embodiment 2: sweet ammonia Felacrinos-9-propoxy-Berberine synthetic: (C2)
(1) berberrubine is synthetic
Identical with (1) among the embodiment 1.
(2) the Felacrinos Acibenzolar is synthetic:
In the 50mL round-bottomed flask, add Felacrinos 201mg (0.5mmol), add methylene dichloride 10mL, add N-hydroxy-succinamide 115mg, dropwise add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide 766mg (4mmol) dichloromethane solution 10mL, follow the tracks of reaction by TLC.In reaction solution, add chloroform 30mL after reacting completely, use 50mL saturated aqueous common salt, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder.Yield 98%; Molecular weight: 509; Structural formula is as follows:
(3) sweet ammonia Felacrinos is synthetic:
In the 25mL round-bottomed flask, add Felacrinos Acibenzolar 257mg (0.5mmol), 1mL DMSO dissolving adds glycine 45mg (0.6mmol), 100 μ L triethylamines, TLC follows the tracks of reaction, add the 20mL anhydrous diethyl ether after reacting completely, separate out white solid, decompress filter, vacuum-drying, productive rate 97%, molecular weight: 459, structure is as follows:
(4) sweet ammonia Felacrinos-3-bromine propyl ester is synthetic:
Add sweet ammonia Felacrinos 230mg (0.5mmol) in the 25mL round-bottomed flask, add 1 mLDMF dissolving, add 200 μ L1, the 3-dibromopropane adds K
2CO
3276mg (2mmol), TLC follows the tracks of reaction, and after reacting completely, decompress filter adds chloroform 50mL in the filtrate, use 50mL distilled water, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder, yield 93%; Molecular weight: 579, structure is as follows:
(5) sweet ammonia Felacrinos-9-propoxy-Berberine is synthetic: (C2)
In the 25mL round-bottomed flask, add berberrubine 161mg (0.5mmol), add 3mL DMF dissolving, add sweet ammonia Felacrinos-3-bromine propyl ester 463mg (0.8mmol), 60 ℃ of heating, TLC follows the tracks of reaction, add anhydrous diethyl ether after reacting completely, separate out yellow solid, decompress filter, vacuum-drying, silica gel column chromatography obtains target product, yield 41%; Molecular weight: 821, structural formula is as follows:
Embodiment 3: glycodesoxycholic acid-9-propoxy-Berberine synthetic: (C3)
(1) berberrubine is synthetic
Identical with (1) among the embodiment 1.
(2) the Felacrinos Acibenzolar is synthetic:
In the 50mL round-bottomed flask, add Septochol 196mg (0.5mmol), add methylene dichloride 10mL, add N-hydroxy-succinamide 115mg, dropwise add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide 766mg (4mmol) dichloromethane solution 10mL, follow the tracks of reaction by TLC.In reaction solution, add chloroform 30mL after reacting completely, use 50mL saturated aqueous common salt, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder.Yield 98%; Molecular weight: 509; Structural formula is as follows:
(3) glycodesoxycholic acid is synthetic:
In the 25mL round-bottomed flask, add Septochol Acibenzolar 255mg (0.5mmol), 1mL DMSO dissolving adds glycine 45mg (0.6mmol), 100 μ L triethylamines, TLC follows the tracks of reaction, add the 20mL anhydrous diethyl ether after reacting completely, separate out white solid, decompress filter, vacuum-drying, productive rate 95%, molecular weight: 449, structure is as follows:
(4) glycodesoxycholic acid-3-bromine propyl ester is synthetic:
Add glycodesoxycholic acid 225mg (0.5mmol) in the 25mL round-bottomed flask, add the 1mLDMF dissolving, add 200 μ L 1, the 3-dibromopropane adds K
2CO
3276mg (2mmol), TLC follows the tracks of reaction, and after reacting completely, decompress filter adds chloroform 50mL in the filtrate, use 50mL distilled water, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder, yield 93%; Molecular weight: 569, structure is as follows:
(5) glycodesoxycholic acid-9-propoxy-Berberine is synthetic: (C3)
In the 25mL round-bottomed flask, add berberrubine 161mg (0.5mmol), add 3mL DMF dissolving, add glycodesoxycholic acid-3-bromine propyl ester 455mg (0.8mmol), 60 ℃ of heating, TLC follows the tracks of reaction, add anhydrous diethyl ether after reacting completely, separate out yellow solid, decompress filter, vacuum-drying, silica gel column chromatography obtains target product, yield 39%; Molecular weight: 811, structural formula is as follows:
Embodiment 4: glycochenodeoxycholate-9-propoxy-Berberine synthetic: (C4)
(1) berberrubine is synthetic
Identical with (1) among the embodiment 1.
(2) the gallodesoxycholic acid Acibenzolar is synthetic:
In the 50mL round-bottomed flask, add gallodesoxycholic acid 196mg (0.5mmol), add methylene dichloride 10mL, add N-hydroxy-succinamide 115mg, dropwise add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide 766mg (4mmol) dichloromethane solution 10mL, follow the tracks of reaction by TLC.In reaction solution, add chloroform 30mL after reacting completely, use 50mL saturated aqueous common salt, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder.Yield 90%; Molecular weight: 509; Structural formula is as follows:
(3) glycochenodeoxycholate is synthetic:
In the 25mL round-bottomed flask, add gallodesoxycholic acid Acibenzolar 255mg (0.5mmol), 1mL DMSO dissolving adds glycine 45mg (0.6mmol), 100 μ L triethylamines, TLC follows the tracks of reaction, add the 20mL anhydrous diethyl ether after reacting completely, separate out white solid, decompress filter, vacuum-drying, productive rate 95%, molecular weight: 449, structure is as follows:
(4) glycochenodeoxycholate-3-bromine propyl ester is synthetic:
Add glycochenodeoxycholate 225mg (0.5mmol) in the 25mL round-bottomed flask, add the 1mLDMF dissolving, add 200 μ L 1, the 3-dibromopropane adds K
2CO
3276mg (2mmol), TLC follows the tracks of reaction, and after reacting completely, decompress filter adds chloroform 50mL in the filtrate, use 50mL distilled water, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder, yield 86%; Molecular weight: 569, structure is as follows:
(5) glycochenodeoxycholate-9-propoxy-Berberine is synthetic: (C4)
In the 25mL round-bottomed flask, add berberrubine 161mg (0.5mmol), add 3mL DMF dissolving, add glycochenodeoxycholate-3-bromine propyl ester 455mg (0.8mmol), 60 ℃ of heating, TLC follows the tracks of reaction, add anhydrous diethyl ether after reacting completely, separate out yellow solid, decompress filter, vacuum-drying, silica gel column chromatography obtains target product, yield 34%; Molecular weight: 811, structural formula is as follows:
Embodiment 5: sweet ammonia Ursodeoxycholic Acid (UDCA)-9-propoxy-Berberine synthetic: (C5)
(1) berberrubine is synthetic
Identical with (1) among the embodiment 1.
(2) the Ursodeoxycholic Acid (UDCA) Acibenzolar is synthetic:
In the 50mL round-bottomed flask, add Ursodeoxycholic Acid (UDCA) 196mg (0.5mmol), add methylene dichloride 10mL, add N-hydroxy-succinamide 115mg, dropwise add 1-ethyl-3-(3-dimethylamine propyl) carbodiimide 766mg (4mmol) dichloromethane solution 10mL, follow the tracks of reaction by TLC.In reaction solution, add chloroform 30mL after reacting completely, use 50mL saturated aqueous common salt, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder.Yield 84%; Molecular weight: 509; Structural formula is as follows:
(3) sweet ammonia Ursodeoxycholic Acid (UDCA) is synthetic:
In the 25mL round-bottomed flask, add Ursodeoxycholic Acid (UDCA) Acibenzolar 255mg (0.5mmol), 1mL DMSO dissolving adds glycine 45mg (0.6mmol), 100 μ L triethylamines, TLC follows the tracks of reaction, add the 20mL anhydrous diethyl ether after reacting completely, separate out white solid, decompress filter, vacuum-drying, productive rate 95%, molecular weight: 449, structure is as follows:
(4) sweet ammonia Ursodeoxycholic Acid (UDCA)-3-bromine propyl ester is synthetic:
Add sweet ammonia Ursodeoxycholic Acid (UDCA) 225mg (0.5mmol) in the 25mL round-bottomed flask, add the 1mLDMF dissolving, add 200 μ L1, the 3-dibromopropane adds K
2CO
3276mg (2mmol), TLC follows the tracks of reaction, and after reacting completely, decompress filter adds chloroform 50mL in the filtrate, use 50mL distilled water, the saturated NaHCO of 50mL successively
3Solution extraction 3 times, anhydrous MgSO
4Drying, decompress filter is removed MgSO
4Back concentrating under reduced pressure, silica gel column chromatography separating purification gets white powder, yield 86%; Molecular weight: 569, structure is as follows:
(5) sweet ammonia Ursodeoxycholic Acid (UDCA)-9-propoxy-Berberine is synthetic: (C5)
In the 25mL round-bottomed flask, add berberrubine 161mg (0.5mmol), add 3mL DMF dissolving, add sweet ammonia Ursodeoxycholic Acid (UDCA)-3-bromine propyl ester 455mg (0.8mmol), 60 ℃ of heating, TLC follows the tracks of reaction, add anhydrous diethyl ether after reacting completely, separate out yellow solid, decompress filter, vacuum-drying, silica gel column chromatography obtains target product, yield 30%; Molecular weight: 811, structural formula is as follows:
Claims (5)
1. described berberinc derivate is represented with following general formula (I):
Wherein
R
1Be hydroxyl, carbonyl;
R
2Be hydrogen, hydroxyl, carbonyl;
R
3Be hydrogen, hydroxyl, carbonyl.
2. berberinc derivate according to claim 1, wherein R
1Be hydroxyl, carbonyl; R
2, R
3Be hydrogen, hydroxyl, carbonyl.
3. the preparation method of the described berberinc derivate of claim 1:
It is characterized in that the Berberine shown in the formula (II)
Heating generates intermediate berberrubine (III).
With chlolic acid derivatives shown in (IV) formula
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
React to generate chlolic acid derivatives (V) with N-hydroxy-succinamide
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
With glycine reactant to generate chlolic acid derivatives (VI)
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
With the dihalo hydrocarbon reaction to generate chlolic acid derivatives (VII)
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5;
With berberinc derivate shown in (III) formula and the reaction of (VII) chlolic acid derivatives shown in the formula to generate the described berberinc derivate of claim 1 (I)
Wherein
R
1Definition with claim 3;
R
2Definition with claim 4;
R
3Definition with claim 5.
4. the compound of claim 1-5 is as the purposes in the preparation antitumor drug.
5. the compound of claim 1-5 is used for the treatment of the application of activeconstituents of the medicine of tumour as preparation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016184103A1 (en) * | 2015-05-18 | 2016-11-24 | 华南理工大学 | Cholic acid modified glucosamine derivative and preparation method and use |
| CN108137575A (en) * | 2015-04-06 | 2018-06-08 | 深圳君圣泰生物技术有限公司 | Ursodesoxycholic acid and jamaicin or the conjugated compound and its composition and its method of l-cn |
| CN112341514A (en) * | 2019-08-06 | 2021-02-09 | 杜心赟 | Deoxycholic acid compound, pharmaceutical composition and application thereof |
| CN114539343A (en) * | 2022-03-10 | 2022-05-27 | 江苏东南纳米材料有限公司 | Preparation method of glycocholic acid |
-
2011
- 2011-04-21 CN CN2011101001578A patent/CN102225962A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108137575A (en) * | 2015-04-06 | 2018-06-08 | 深圳君圣泰生物技术有限公司 | Ursodesoxycholic acid and jamaicin or the conjugated compound and its composition and its method of l-cn |
| EP3280712A4 (en) * | 2015-04-06 | 2019-01-09 | Shenzhen Hightide Biopharmaceutical, Ltd. | Conjugate compounds of ursodeoxycholic, berberine or l-carnitine, and compositions and methods thereof |
| WO2016184103A1 (en) * | 2015-05-18 | 2016-11-24 | 华南理工大学 | Cholic acid modified glucosamine derivative and preparation method and use |
| CN112341514A (en) * | 2019-08-06 | 2021-02-09 | 杜心赟 | Deoxycholic acid compound, pharmaceutical composition and application thereof |
| WO2021023100A1 (en) * | 2019-08-06 | 2021-02-11 | 杜心赟 | Deoxycholic acid compounds, pharmaceutical compositions and uses thereof |
| CN112341514B (en) * | 2019-08-06 | 2023-11-21 | 杜心赟 | Deoxycholic acid compound, pharmaceutical composition and application thereof |
| CN114539343A (en) * | 2022-03-10 | 2022-05-27 | 江苏东南纳米材料有限公司 | Preparation method of glycocholic acid |
| CN114539343B (en) * | 2022-03-10 | 2024-03-19 | 江苏东南纳米材料有限公司 | Preparation method of glycocholic acid |
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Application publication date: 20111026 |