CN101104618B - Long chain alkyl berberine salt derivative, synthetic method and use - Google Patents
Long chain alkyl berberine salt derivative, synthetic method and use Download PDFInfo
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- CN101104618B CN101104618B CN200710078505A CN200710078505A CN101104618B CN 101104618 B CN101104618 B CN 101104618B CN 200710078505 A CN200710078505 A CN 200710078505A CN 200710078505 A CN200710078505 A CN 200710078505A CN 101104618 B CN101104618 B CN 101104618B
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Abstract
The present invention relates to a class of chemically named long chain alkyl berberine salt derivatives (hydrochloride or Bromate or iodate or hydrofluoric acid salt), and the molecular structural formula is stated above, wherein, X is equal to F-, Cl-, Br-, I-, SO42-, NO3-, PO43-, citric acid radical, acetic acid radical or lactic acid radical. R1, R2, R3, R4, R5 see table above. The class of the substances is provided with obvious hypoglycemic and hypolipidemic activities which are significantly higher than that of berberine salt, so that the invention is a very promising new compound withhypoglycemic and hypolipidemic medicinal values.
Description
Technical field
The present invention relates to a class new compound and a medicinal use thereof, be specifically related to a kind of derivative of long chain alkyl berberine salt.
Background technology
Berberine (Berberine) claims berberine again, is a kind of traditional natural antibacterial active substance that extracts from the coptis, is mainly used in the medicine for treatment that the intestinal bacteria sexuality is dyed clinically.In recent years pharmacological research finds that berberine hydrochloride and some structural derivative thereof have antibiotic, and anti-inflammatory is antitumor, multiple pharmacologically actives such as hypoglycemic and reducing blood-fat.Therefore, further investigation and the structure of modification work to the berberine hydrochloride pharmacological action excites wide spread interest.Structure activity study result to Berberine shows, at 8 introducing alkyl (methane is to octane) of Berberine molecule, perhaps introduces alkyl (methane is to butane) for 9, and its anti-microbial activity increases.Applicant's early-stage Study result shows that behind 8 introducing chain alkyls (ethane is to 12 alkyl), its anti-microbial activity increases, and during to 8 alkyl berberines, the anti-microbial activity maximum descends then; Reach the synthetic of 3 alkoxyl groups about the synthetic of 9 long-chain alkoxy bases (carbon chain lengths is more than 6), and the research of active aspect, do not appear in the newspapers as yet; Especially about the research of modified derivative reducing blood-fat of Berberine alkyl and hypoglycemic aspect, do not see any bibliographical information especially.
Summary of the invention
The objective of the invention is to propose long chain alkyl berberine salt derivative, the purposes of its reducing blood-fat and hypoglycemic aspect is disclosed, hypoglycemic and the hypolipidemic activity of this compounds is apparently higher than berberine hydrochloride, and its activity increases along with the increase of alkyl chain length, and its toxicity (LD
50) descend along with the increase of alkyl company commander degree.
The present invention relates to the new chemical substance of a class, its chemical name is long chain alkyl berberine salt derivative (hydrochloride or bromate or iodate or a hydrofluoride), and its molecular structural formula is as follows:
Wherein, X=F
-, Cl
-, Br
-, I
-, SO
4 2-, NO
3 -, PO
4 3-, citrate, acetate, lactate.R
1, R
2, R
3, R
4, R
5See the following form
Wherein, when selecting R
1+ R
2=-CH
2-; R
3=H or F or Cl or Br or I; R
5=CH
3R
6=C
nH2n+1, n=12～20 o'clock are long-chain 8-alkyl berberine salt, its synthetic method is as follows:
(1) is reaction solvent with anhydrous tetrahydro furan, ether or dioxane, under nitrogen protection, presses (X-C with magnesium chips and haloalkane
nH2n+1, n=10～20; X=F
-, Cl
-, Br
-, I) 1～1.5: 1 mol ratio prepares corresponding Grignard reagent, 5～100: 1 of the weightmeasurement ratio of solvent and haloalkane;
(2) in berberine hydrochloride, add anhydrous tetrahydro furan or ether or dioxane, make into and under nitrogen protection, carry out ice bath behind the berberine hydrochloride suspension and cool to-20～20 ℃, the mol ratio of berberine salt and haloalkane is 1: 1～10 in the berberine hydrochloride, and the weightmeasurement ratio of solvent and Berberine is 1～500: 1;
(3) under nitrogen protection and ice bath, Grignard reagent is added in the Berberine suspension, stir simultaneously, remove ice bath after adding, reflux finishes its reaction.
(4) separate the acquisition supernatant liquor, vacuum concentration is used methanol crystallization after becoming solid, obtains 8-alkyl dihydroberberine bromate intermediate;
(5) 8-alkyl dihydroberberine bromate intermediate is used the bromine water oxidation in acetic acid, the mol ratio of the two is 1: 1～2, obtains 8-alkyl berberine halate product;
(6) 8-alkyl berberine halate is dissolved in the acetic acid, uses the halogen oxidation, and the mol ratio of the two is 1: 1～20, obtains 8-alkyl-12-halo Berberine halate product.
Whether this product can utilize thin-layer chromatography to differentiate is pure substance, the thin-layer chromatography condition: silica gel G making sheet, and developping agent is: benzene: ethyl acetate: Virahol: methyl alcohol: ammoniacal liquor (6: 3: 1.5: 1.5: 0.5); Agents useful for same is analytical pure.
Sample after the purification adopts Perkin Elmer one type infrared spectrophotometer to measure IR spectrogram (KBr compressing tablet); UV analyzes and adopts Hitachi U-1800 type ultraviolet spectrophotometer to measure UV spectrum;
1HNMR,
13CNMR analyzes hydrogen spectrum and the carbon spectrum that adopts Bruker 300 type nmr determination compounds, and solvent is DMSO-d
6,
1Be designated as TMS in the HNMR mensuration.
Below be the structural characterization result of berberine hydrochloride:
Rf＝0.43，UV(CH
3OH)λmax：348(0.284)，266(0.322)nm；
1HNMR(DMSO-d
6)δ：3.21(t，2H，5-CH
2)，4.07，4.09(each s，6H，-OCH
3)，4.93(d，2H，6-CH
2)，6.12(s，2H，-OCH
2O-)，7.091(s，1H，4-CH)，7.80(s，1H，1-CH)，8.00(d，1H，11-CH)，8.21(d，1H，12-CH)，8.94(s，1H，13-CH)，9.89(s，1H，8-CH)；
13CNMR(DMSO-d
6)δ：26.65，49.63，57.08，61.57，101.10，105.82，107.54，120.29，121.19，121.41，124.68，125.25，130.78，132.67，137.83，145.57，147.63，149.66，152.44，160.17.IR(KBr)v：3413，3017，3000，2946，2909，2846，1634，1619，1601，1567，1509，1480，1458cm
-1。
The structural characterization result of the 8-tetradecyl berberine hydrochloride of above-mentioned acquisition is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, and Rf=0.76, productive rate are 65.6%.MP＝173～174℃；UV(CH
3OH)λmax：348(0.295)，266(0.333)nm；
1HNMR(DMSO-d
6)δ：0.86(t，3H，-CH
3)，1.31(m，8H，-(CH2)
4-)，1.58(m，2H，-CH
2-)，1.77(m，2H，Ar-CH
2-)，3.15(t，2H，5-CH
2)，3.75(t，2H，Ar-CH
2-)，4.03，4.06(each s，6H，-OCH
3)，4.81(d，2H，6-CH
2)，6.17(s，2H，-OCH
2O-)，7.11(s，1H，4-CH)，7.73(s，1H，1-CH)，8.02(d，1H，11-CH)，8.19(d，1H，12-CH)，8.80(s，1H，13-CH)；
13CNMR(DMSO-d
6)δ：13.80，21.93，26.53，27.78，28.48，28.53，29.20，31.10，32.15，49.52，56.94，61.45，101.85，105.65，107.54，120.07，121.08，121.28，124.60，125.07，130.63，132.52，137.67，145.51，147.49，149.48，152.37，160.96.IR(KBr)v：3435，3036，3007，2953，2921，2852，1630，1617，1602，1550，1509，1485，1466cm
-1。
The structural characterization data of contrast berberine hydrochloride and 8-tetradecyl berberine hydrochloride are found, in the Berberine molecule after the modification, except that 8 proton peak disappear, newly occur the corresponding peak of alkyl in addition.The site that shows modification but is a 8-alkyl berberine hydrochloride.
Above-mentioned data show that the compound that obtains is 8-tetradecyl berberine hydrochloride really.Utilize same spectroscopic data, can prove and to synthesize 8-hexadecyl berberine hydrochloride, 8-octadecyl berberine hydrochloride, 8-eicosyl berberine hydrochloride according to the method described above.
The structural characterization result of the 8-tetradecyl of above-mentioned acquisition-12-bromo Berberine bromate is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, and Rf=0.78, productive rate are 65.6%.MP＝177～178℃；UV(CH
3OH)λmax：348(0.295)，266(0.333)nm；
1HNMR(DMSO-d
6)δ：0.86(t，3H，-CH
3)，1.31(m，8H，-(CH2)
4-)，1.58(m，2H，-CH
2-)，1.77(m，2H，Ar-CH
2-)，3.15(t，2H，5-CH
2)，3.75(t，2H，Ar-CH
2-)，4.03，4.06(each s，6H，-OCH
3)，4.81(d，2H，6-CH
2)，6.17(s，2H，-OCH
2O-)，7.11(s，1H，4-CH)，7.73(s，1H，1-CH)，8.02(d，1H，11-CH)，8.80(s，1H，13-CH)；
13CNMR(DMSO-d
6)δ：13.80，21.93，26.53，27.78，28.48，28.53，29.20，31.10，32.15，49.52，56.94，61.45，101.85，105.65，107.54，120.07，121.08，121.28，124.60，125.07，130.63，132.52，137.67，145.51，147.49，149.48，152.37，160.96.IR(KBr)v：3435，3036，3007，2953，2921，2852，1630，1617，1602，1550，1509，1485，1466cm
-1。
The structural characterization data of contrast 8-tetradecyl Berberine bromate and 8-tetradecyl-12-bromo Berberine bromate find that in the Berberine molecule after the modification, except that 12 proton peak disappeared, other peak positions did not change.Show new compound 8-tetradecyl-12-bromo Berberine bromate really.
Utilize same spectroscopic data, can prove and to synthesize 8-alkyl-12-halo Berberine halate according to the method described above.
In the structural formula, work as R
1+ R
2=-CH
2-; R
3=H or F or Cl or Br or I; R
4=C
nH2n+1, n=6～20; R
5During=H, be long-chain 9-alkoxyl group berberine salt, its synthetic method is as follows:
(1), be reaction solvent with DMF, berberrubine is joined among the DMF, after the rising temperature for dissolving, add the haloalkane of 1～10 times of mol ratio, after mixing, back flow reaction 2～5 hours.
(2), after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 9-alkoxyl group berberine salt crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 9-alkoxyl group berberine salt.
(3) 9-alkoxyl group berberine salt is dissolved in the acetic acid, uses the halogen oxidation, and the mol ratio of the two is 1: 1～20, obtains 9-alkoxyl group-12-halo Berberine halate product.
The structural characterization result of the 9-hexyloxy Berberine oxymuriate of above-mentioned acquisition is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, and Rf=0.78, productive rate are 63.6%.MP＝168～169℃；UV(CH
3OH)λmax：348(0.295)，266(0.333)nm；
1HNMR(DMSO-d
6)δ：0.86(t，3H，-CH
3)，1.32(m，10H，-(CH2)
5-)，1.77(m，2H，Ar-CH
2-)，3.15(t，2H，5-CH
2)，3.75(t，2H，Ar-CH
2-)，4.03(s，3H，-OCH
3)，4.23(s，2H，-OCH
2-)，6.17(s，2H，-OCH
2O-)，7.11(s，1H，4-CH)，7.73(s，1H，1-CH)，8.02(d，1H，11-CH)，8.19(d，1H，12-CH)，8.80(s，1H，13-CH)，9.89(s，1H，8-CH)；
13CNMR(DMSO-d
6)δ：13.80，21.93，26.53，27.78，28.48，28.53，29.20，31.10，32.15，49.52，56.94，61.45，101.85，105.65，107.54，120.07，121.08，121.28，124.60，125.07，130.63，132.52，137.67，145.51，147.49，149.48，152.37，160.96.IR(KBr)v：3435，3036，3007，2953，2921，2852，1630，1617，1602，1550，1509，1485，1466cm
-1。
The structural characterization data of contrast berberine hydrochloride and 9-hexyloxy berberine hydrochloride are found, in the Berberine molecule after the modification, the corresponding peak of alkyl just newly occurred.Showing that modification does not directly act on the ring, but increased alkyl at 9, is 9-hexyl Berberine bromate really.
Utilize same spectroscopic data, can prove the 9-alkoxyl group berberine salt that can synthesize other according to the method described above.
The structural characterization result of the 9-hexyloxy of above-mentioned acquisition-12-Berberine oxymuriate is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, and the Rf=0.83 productive rate is 55.6%.MP＝168～169℃；UV(CH
3OH)λmax：348(0.295)，266(0.333)nm；
1HNMR(DMSO-d
6)δ：0.86(t，3H，-CH
3)，1.32(m，10H，-(CH2)
5-)，1.77(m，2H，Ar-CH
2-)，3.15(t，2H，5-CH
2)，3.75(t，2H，Ar-CH
2-)，4.03(s，3H，-OCH
3)，4.23(s，2H，-OCH
2-)，6.17(s，2H，-OCH
2O-)，7.11(s，1H，4-CH)，7.73(s，1H，1-CH)，8.02(d，1H，11-CH)，8.80(s，1H，13-CH)，9.89(s，1H，8-CH)；
13CNMR(DMSO-d
6)δ：13.80，21.93，26.53，27.78，28.48，28.53，29.20，31.10，32.15，49.52，56.94，61.45，101.85，105.65，107.54，120.07，121.08，121.28，124.60，125.07，130.63，132.52，137.67，145.51，147.49，149.48，152.37，160.96.IR(KBr)v：3435，3036，3007，2953，2921，2852，1630，1617，1602，1550，1509，1485，1466cm
-1。
The structural characterization data of contrast 9-hexyloxy berberine hydrochloride and 9-hexyloxy-12-chloro berberine hydrochloride find that new compound is except that 12 protons disappear, and other groups do not change.The hexyloxy of the 9-really-12-chloro berberine hydrochloride that shows synthetic.
Utilize same spectroscopic data, can prove the 9-alkoxyl group-12-chloro berberine hydrochloride that can synthesize other according to the method described above.
In the structural formula, work as R
1=C
nH2n+1, n=0～20; R
2=CH
3R
3=H or F or Cl or Br or I; R
4=CH
3R
5==CH
3The time, being long-chain 3-alkoxyl group jateorhizine salt, its synthetic method is as follows:
(1), be reaction solvent with DMF, jateorhizine is joined among the DMF, after the rising temperature for dissolving, add the haloalkane of 1～10 times of mol ratio, after mixing, back flow reaction 2～5 hours.
(2), after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-alkoxyl group berberine salt crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-alkoxyl group berberine salt.
(3) 3-alkoxyl group berberine salt is dissolved in the acetic acid, uses the halogen oxidation, and the mol ratio of the two is 1: 1～20, obtains 3-alkoxyl group-12-halo Berberine halate product.
The structural characterization result of the 3-butoxy Berberine oxymuriate of above-mentioned acquisition is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, and Rf=0.66, productive rate are 73.6%.MP＝158～159℃；UV(CH
3OH)λmax：348(0.295)，266(0.333)nm；
1HNMR(DMSO-d
6)δ：0.86(t，3H，-CH
3)，1.32(m，4H，-(CH2)
2-)，1.77(m，2H，Ar-CH
2-)，3.15(t，2H，5-CH
2)，3.75(t，2H，Ar-CH
2-)，4.04，4.06，4.08(s，9H，-OCH
3)，4.33(s，2H，-OCH
2-)，7.11(s，1H，4-CH)，7.73(s，1H，1-CH)，8.02(d，1H，11-CH)，8.19(d，1H，12-CH)，8.80(s，1H，13-CH)，9.89(s，1H，8-CH)；
13CNMR(DMSO-d
6)δ：13.80，21.93，26.53，27.78，28.48，28.53，29.20，31.10，32.15，49.52，56.94，61.45，101.85，105.65，107.54，120.07，121.08，121.28，124.60，125.07，130.63，132.52，137.67，145.51，147.49，149.48，152.37，160.96.IR(KBr)v：3435，3036，3007，2953，2921，2852，1630，1617，1602，1550，1509，1485，1466cm
-1。
The structural characterization data of contrast berberine hydrochloride and 3-butoxy berberine hydrochloride are found, in the Berberine molecule after the modification, the corresponding peak of alkyl just newly occurred.Showing that modification does not directly act on the ring, but increased alkyl at 3, is 3-hexyl Berberine bromate really.
Utilize same spectroscopic data, can prove the 3-alkoxyl group berberine salt that can synthesize other according to the method described above.
The structural characterization result of the 3-butoxy of above-mentioned acquisition-12-Berberine oxymuriate is as follows:
Yellow powder shape solid is dissolved in methyl alcohol, and Rf=0.69, productive rate are 70.6%.MP＝162～163℃；UV(CH
3OH)λmax：348(0.295)，266(0.333)nm；
1HNMR(DMSO-d
6)δ：0.86(t，3H，-CH
3)，1.32(m，4H，-(CH2)
2-)，1.77(m，2H，Ar-CH
2-)，3.15(t，2H，5-CH
2)，3.75(t，2H，Ar-CH
2-)，4.04，4.06，4.08(s，9H，-OCH
3)，4.33(s，2H，-OCH
2-)，7.11(s，1H，4-CH)，7.73(s，1H，1-CH)，8.02(d，1H，11-CH)，8.80(s，1H，13-CH)，9.89(s，1H，8-CH)；
13CNMR(DMSO-d
6)δ：13.80，21.93，26.53，27.78，28.48，28.53，29.20，31.10，32.15，49.52，56.94，61.45，101.85，105.65，107.54，120.07，121.08，121.28，124.60，125.07，130.63，132.52，137.67，145.51，147.49，149.48，152.37，160.96.IR(KBr)v：3435，3036，3007，2953，2921，2852，1630，1617，1602，1550，1509，1485，1466cm
-1。
The structural characterization data of contrast 3-butoxy berberine hydrochloride and 3-butoxy-12-chloro berberine hydrochloride find that new compound is except that 12 protons disappear, and other groups do not change.The butoxy of the 3-really-12-chloro berberine hydrochloride that shows synthetic.
Utilize same spectroscopic data, can prove the 3-alkoxyl group-12-chloro berberine hydrochloride that can synthesize other according to the method described above.
This compounds has following characteristics:
1, except that jateorhizine, all be the synthetic novel substance first time.
2, the alkyl chain length along with derivative increases, and the activity of its reducing blood-fat and hypoglycemic increases; After the length of alkyl chain is greater than 8 (8 and 9), its reducing blood-fat and hypoglycemic activity are apparently higher than Berberine; The reducing blood-fat of 3 alkyl derivatives (containing jateorhizine) and hypoglycemic activity are also apparently higher than Berberine.
3, the alkyl chain length along with derivative increases its toxicity (LD
50) descend; After alkyl chain length was greater than 10, its toxicity was less than Berberine.
4, this compound yield height, price is low, has fabulous value of exploiting and utilizing.
Berberine itself is the good blood lipid-lowering medicine of a kind of effect, and the patient can reach lipid-lowering effect by direct oral Berberine sheet.The present invention finds, the hypolipemic function of long chain alkyl berberine derivative is apparently higher than berberine salt, and be the analogue of Berberine, because fat-soluble increase more helps absorption of human body, its molecular mechanism of action is identical with Berberine, therefore, the long chain alkyl berberine derivative is made the blood lipid-lowering medicine tablets and other formulations use separately, perhaps use simultaneously with other blood lipid-lowering medicines, perhaps use simultaneously with other Chinese medicines and Chinese patent medicine, its lipid-lowering effect will be better.Therefore the long chain alkyl berberine derivative can be used as a kind of new raw material medicine development and use of reducing blood-fat.
Berberine itself is the good ofhypoglycemic medicine of a kind of effect, the patient can direct oral Berberine sheet reaches the effect of hypoglycemic, especially use simultaneously with other antidiabetic drugs such as diabetes pill or the basicly stable back drug use as follow-up maintenance curative effect of hypoglycemic, effect is fine.Show after deliberation through the applicant, the function of polysaccharide of long chain alkyl berberine derivative is apparently higher than berberine salt, and be the analogue of Berberine, because fat-soluble increase, more help absorption of human body, its molecular mechanism of action may be identical with Berberine, therefore, the alkyl berberine derivative is made tablets and other formulations to be used separately, perhaps use simultaneously with other ofhypoglycemic medicines, perhaps use simultaneously with other Chinese medicines and Chinese patent medicine, perhaps as the medication between the convalescence of the stable back of conditions of patients, its hypoglycemic effect will be better.Therefore the alkyl berberine derivative can be used as a kind of new raw material medicine development and use of hypoglycemic.
The compounds of this invention can composition form be used for the patient of relative disease by the mode of administrations such as oral, injection or external application.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc., make liquid preparation such as water oil-suspending agent or syrup etc.; When being used for drug administration by injection, can be made into injection solution or oil-suspending agent etc.; Be used for external application and can make emplastrum or liniment.More than various formulations can be according to the conventional production method preparation of pharmaceutical field.
The amount of application of The compounds of this invention can be according to variations such as the type of route of administration, patient's age, body weight, the disease for the treatment of and severity.
Embodiment
Following embodiment can make those skilled in the art more fully understand the present invention, but does not limit the present invention with this.
Embodiment 1:8-tetradecyl berberine hydrochloride.
It is prepared as follows:
1., dry all reaction glassware, take by weighing dried magnesium chips 0.1mol and put in the 250mL three-necked flask, be reaction solvent with anhydrous tetrahydro furan 40mL, under nitrogen protection, add the chloro n-tetradecane of 0.1mol, prepare corresponding Grignard reagent.
2., the dry berberine hydrochloride that takes by weighing 0.1mol places the 500mL three-necked flask, adds the 100mL anhydrous tetrahydro furan, makes into behind the berberine hydrochloride suspension under nitrogen protection ice bath to-10 ℃.
3., the Grignard reagent with preparation under nitrogen protection and ice bath slowly joins in the Berberine suspension, stirs simultaneously, the removal ice bath makes and gets back to room temperature adding after, reflux 2h afterreaction finishes.
4., reaction solution is centrifugal, get supernatant liquor after, add tetrahydrofuran (THF) again and extract, repeated multiple times, with the extraction situation of thin-layer method monitoring reaction product, to raw material point very little till.The centrifuged supernatant vacuum concentration is used methanol crystallization after becoming solid, and crystal is 8-tetradecyl dihydroberberine hydrochloride.
5., measure 0.01mol Br with transfer pipet
2Dissolve in the 10mL Glacial acetic acid, take by weighing and two liquid are mixed reflux 1h after 0.01mol 8-tetradecyl dihydroberberine hydrochloride dissolves in the 100mL Glacial acetic acid.
6., the reaction solution cooled and filtered, precipitation is with 10% Na
2S
2O
5Solution washing, last water washing and precipitating, precipitation methanol crystallization, i.e. 8-tetradecyl berberine hydrochloride.
Embodiment 2:8-octadecyl Berberine bromate
Its preparation process is as follows:
1., dry all reaction glassware, take by weighing dried magnesium chips 0.12mol and put in the 250mL three-necked flask, be reaction solvent with anhydrous diethyl ether 100mL, under nitrogen protection, add the bromo Octadecane of 0.06mol, prepare corresponding Grignard reagent.
2., the dry berberine hydrochloride that takes by weighing 0.03mol places the 500mL three-necked flask, adds the 100mL anhydrous diethyl ether, makes into behind the berberine hydrochloride suspension under nitrogen protection ice bath to 0 ℃.
3., the Grignard reagent with preparation under nitrogen protection and ice bath slowly joins in the Berberine suspension, stirs simultaneously, the removal ice bath makes and gets back to room temperature adding after, reflux 2h afterreaction finishes.
4., reaction solution is centrifugal, get supernatant liquor after, add ether extraction again, repeated multiple times, with the extraction situation of thin-layer method monitoring reaction product, to raw material point very little till.The centrifuged supernatant vacuum concentration is used methanol crystallization after becoming solid, and crystal is 8-octadecyl dihydroberberine bromate.
5., measure 0.015mol Br with transfer pipet
2Dissolve in the 10mL Glacial acetic acid, take by weighing and two liquid are mixed reflux 1h after 0.01mol 8-octadecyl dihydroberberine bromate dissolves in the 100mL Glacial acetic acid.
6., the reaction solution cooled and filtered, precipitation is with 10% Na
2S
2O
5Solution washing, last water washing and precipitating, precipitation methanol crystallization, i.e. 8-octadecyl Berberine bromate.
Embodiment 3:8-hexadecyl-12-bromo Berberine bromate
Its preparation process is as follows:
0.1 mole of 8-hexadecyl Berberine bromate is dissolved in 100 milliliters of acetic acid, adds 0.5 mole of bromine, reaction is 30 minutes under the room temperature, is cooled to-10 ℃, filters; Precipitation is dissolved in that recrystallization once obtains 8-hexadecyl-12-bromo Berberine bromate product in the ethanol.
The own alkoxyl group Berberine of embodiment 4:9-iodate
Its preparation process is as follows:
1., 0.1 mole of berberrubine is dissolved among 100 milliliters of DMF, be warmed up to 80 ℃, stir the iodo normal hexane that slowly adds 0.1 mole down, after adding, back flow reaction 2 hours;
2., after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as the own alkoxyl group berberine salt of 9-crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of the own alkoxyl group berberine salt of 9-.
Embodiment 5:9-eicosane oxygen base berberine hydrochloride
Its preparation method is as follows:
1., 0.1 mole of berberrubine is dissolved among 100 milliliters of DMF, be warmed up to 80 ℃, stir the chloro eicosane that slowly adds 1 mole down, after adding, back flow reaction 5 hours;
2., after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 9-eicosane oxygen base berberine hydrochloride crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 9-eicosane oxygen base berberine hydrochloride.
Embodiment 6:9-dodecyloxy-12-chloro berberine hydrochloride
Its preparation method is as follows:
Say 0.1 mole of 9-ten and the alkoxyl group berberine hydrochloride is dissolved in 100 milliliters of acetic acid, add 2 moles of chlorine, reaction is 30 minutes under the room temperature, is cooled to 0 ℃, filters; Precipitation is dissolved in that recrystallization once obtains 9-dodecyloxy-12-chloro berberine hydrochloride product in the ethanol.
Embodiment 7:3-butoxy Berberine fluorate
The preparation method is as follows:
1., 0.1 mole of jateorhizine is dissolved among 100 milliliters of DMF, be warmed up to 80 ℃, stir the fluoro normal butane that slowly adds 1 mole down, after adding, back flow reaction 4 hours;
2., after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-butoxy Berberine fluorate crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-butoxy Berberine fluorate.
Embodiment 8:3-n-Hexadecane oxygen base Berberine bromate
Preparation process is as follows:
1., 0.1 mole of jateorhizine is dissolved among 100 milliliters of DMF, be warmed up to 80 ℃, stir the bromo n-hexadecane that slowly adds 0.3 mole down, after adding, back flow reaction 4 hours;
2., after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-n-Hexadecane oxygen base Berberine bromate crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-n-Hexadecane oxygen base Berberine bromate.
Embodiment 9:3-n-Hexadecane Oxy-1 2-bromo Berberine bromate
The preparation method:
0.1 mole of 3-n-Hexadecane oxygen base Berberine iodate is dissolved in 100 milliliters of acetic acid, adds 0.3 mole of iodine, reaction is 30 minutes under the room temperature, is cooled to 10 ℃, filters; Precipitation is dissolved in that recrystallization once obtains 3-n-Hexadecane Oxy-1 2-iodo Berberine iodate product in the ethanol.
The reducing blood-fat and the hypoglycemic medicinal tablet of embodiment 10:8-eicosyl berberine salt:
Get 10 gram 8-eicosyl berberine salts (medicine), add spherulitic lactose (auxiliary material) 70 grams, Magnesium Stearate (auxiliary material) 15 grams, Microcrystalline Cellulose (auxiliary material) 5 grams, be suppressed into the tablet of 0.5 gram a slice after mixing.Be every pastille 50mg.Oral, promptly can be used as reducing blood-fat and hypoglycemic medicine.
The reducing blood-fat and the hypoglycemic medicinal tablet of embodiment 11:9-dodecyloxy-12-bromo berberine salt:
Get 10 gram 9-dodecyloxy-12-bromo berberine salts (medicine), add spherulitic lactose (auxiliary material) 80 grams, Magnesium Stearate (auxiliary material) 5 grams, Microcrystalline Cellulose (auxiliary material) 5 grams, be suppressed into the tablet of 0.5 gram a slice after mixing.Be every pastille 50mg.Oral, promptly can be used as reducing blood-fat and hypoglycemic medicine.
The reducing blood-fat and the hypoglycemic medicinal tablet of embodiment 12:3-fourth alkoxyl group berberine salt:
Get 10 gram 3-fourth alkoxyl group berberine salts (medicine), add spherulitic lactose (auxiliary material) 80 grams, Magnesium Stearate (auxiliary material) 5 grams, Microcrystalline Cellulose (auxiliary material) 5 grams, be suppressed into the tablet of 0.5 gram a slice after mixing.Be every pastille 50mg.Oral, promptly can be used as reducing blood-fat and hypoglycemic medicine.
Embodiment 13: the lipid-lowering effect of long chain alkyl berberine salt derivative:
1., experimentation on animals: 190 of healthy adult male Wistar rats (every 150～220g), the rat feeding basal feed was observed 5～10 days under experimental situation; Get tail blood then, measure serum total cholesterol (TC) and triglyceride level (TG) level.Beginning each treated animal from formal experiment uses high lipid food (78.8% basal feed, 1% cholesterol, 10% yolk powder and 10% lard, 0.2% cholate) instead and feeds and to raise 7～10 days, get tail blood, measuring serum TC, the TG level is raised before the high lipid food than to determine whether to form hyperlipemia model with feeding.Built up the rat of hyperlipidemia model, according to serum total cholesterol (TC) level, be divided into 19 groups at random, experimental group is irritated according to the dosage of 5mg/kg, 15mg/kg, 30mg/kg respectively and is fed sample when giving high lipid food; High fat control group is given the solvent with volume; Fed 30 days continuously, fasting is 16 hours when experiment finishes, and surveys serum TC, the TG level.
2., lipid-lowering test the results are shown in Table 1 and table 2
The reducing blood-fat of table 1, alkyl berberine salt derivative (TC) experimental result
The reducing blood-fat of table 4, alkyl berberine salt derivative (TG) experimental result
Result from table can see that alkyl berberine salt derivative has tangible hypolipidemic activity, and its hypolipidemic activity is apparently higher than Berberine.
Embodiment 14: the blood sugar decreasing effect of alkyl berberine salt derivative:
1., experimental technique: get 200 of kunming mices, be divided into 20 groups at random, every group 10, organize in contrast for 1 group, set up diabetes model by 200mg/Kg injection tetraoxypyrimidine, select the mouse of modeling success behind the 48h for other 19 groups, the reason of on average making a living respectively salt solution group, low metering group, middle metering and high metering group, each dosage group is irritated according to 5mg/kg, 15mg/kg, 30mg/kg respectively and is fed, and continuous irrigation is fed and measured blood sugar after 30 days, respectively organizes blood sugar.
2., the results are shown in following table 5
The hypoglycemic experimental result of table 5, tetradecyl berberine salt derivative
| The date group | Berberine salt | 8-tetradecyl berberine hydrochloride | 9-octadecane Oxy-1 2-bromo Berberine bromate | 3-butoxy Berberine fluorate | 3-octyloxy-12-chloro berberine hydrochloride |
| Normal control | 6.4±2.3 | 6.4±2.3 | 6.4±2.3 | 6.4±2.3 | 6.4±2.3 |
| High sugar contrast | 14.8±3.8 | 14.8±3.8 | 14.8±3.8 | 14.8±3.8 | 14.8±3.8 |
| Low dosage | 14.3±3.9 | 9.5±3.1 | 9.6±3.0 | 8.9±2.3 | 9.5±3.0 |
| Middle dosage | 12.1±3.4 | 8.7±2.8 | 7.9±2.5 | 7.8±2.1 | 9.0±2.9 |
| High dosage | 11.5±4.1 | 7.8±2.4 | 7.1±2.1 | 6.8±1.9 | 8.1±2.7 |
From hypoglycemic experimental result, the hypoglycemic ability of alkyl berberine derivative all is better than berberine salt.
Embodiment 15: the The acute toxicity tests of alkyl berberine salt derivative:
1., experimental technique (improvement karber's method): get 330 of kunming mices, be divided into 33 groups at random, 10 every group; Medicine is by high, medium and low three dosed administrations (concrete dosage needs trial test to determine: when guaranteeing low dosage, a small amount of mouse death is arranged, most of death during high dosage can not be dead entirely).Medicine is emulsion, a gastric infusion with disperseing collection to join.Raise and press the general condition raising.Observe the dead mouse situation after the administration in 7 days.Then, calculate by following formula:
LogLD
50＝XK-i×(∑P-0.5)
Wherein, XK be the maximum dose level group to numeral, i for the group distance; ∑ P is the mortality ratio sum.
2., the results are shown in following table 6
The acute toxicity test result of table 6, alkyl berberine salt derivative
| The date group | Berberine salt | 8-ethyl berberine hydrochloride | 8-butyl berberine hydrochloride | 8-hexyl berberine hydrochloride | The 8-octyl berberine hydrochloride |
| LD 50(mg/Kg) | 780 | 56 | 205 | 386 | 475 |
| 8-decyl berberine hydrochloride | 8-dodecyl berberine hydrochloride | 8-tetradecyl berberine hydrochloride | 8-hexadecyl berberine hydrochloride | 8-octadecyl berberine hydrochloride | 8-eicosyl berberine hydrochloride |
| 610 | 724 | 856 | 903 | 1108 | 1285 |
Data from table 6 can see, along with the increase of alkyl chain length, and its LD
50Rise rapidly, show that the acute toxicity of alkyl berberine derivative will significantly descend.
Claims (5)
1. long chain alkyl berberine salt derivative, its molecular structural formula is as follows:
Wherein, X=F
-, Cl
-, Br
-, I
-
R
1, R
2, R
3, R
4, R
5See the following form
2. the synthetic method of the described long chain alkyl berberine salt derivative of claim 1 is characterized in that: wherein long-chain 9-alkoxyl group berberine salt, i.e. R
1+ R
2=-CH
2-; R
3=H or F or Cl or Br or I; R
4=C
nH2n+1, n=6～20; R
5=H, synthetic method is as follows:
(1), be reaction solvent with DMF, berberrubine is joined among the DMF, heat up 80 ℃, after the dissolving, add the haloalkane of 1～10 times of mol ratio, after mixing, back flow reaction 2～5 hours;
(2), after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 9-alkoxyl group berberine salt crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 9-alkoxyl group berberine salt;
(3) 9-alkoxyl group berberine salt is dissolved in the acetic acid, uses the halogen oxidation, and the mol ratio of the two is 1: 1～20, obtains 9-alkoxyl group-12-halo Berberine halate product.
3. the synthetic method of the described long chain alkyl berberine salt derivative of claim 1 is characterized in that: wherein long-chain 3-alkoxyl group jateorhizine salt, i.e. R
1=C
nH2n+1, n=0～20; R
2=CH
3R
3=H or F or Cl or Br or I; R
4=CH
3R
5=H, synthetic method as follows:
(1), be reaction solvent with DMF, jateorhizine is joined among the DMF, after the rising temperature for dissolving, add the haloalkane of 1～10 times of mol ratio, after mixing, back flow reaction 2～5 hours;
(2), after reaction finishes, be cooled to-40～20 ℃, filter, be precipitated as 3-alkoxyl group berberine salt crude product.After a small amount of DMF washing, recrystallization is 1～3 time in the ethanol, obtains the pure product of 3-alkoxyl group berberine salt;
(3) 3-alkoxyl group berberine salt is dissolved in the acetic acid, uses the halogen oxidation, and the mol ratio of the two is 1: 1～20, obtains 3-alkoxyl group-12-halo Berberine halate product.
4. the application of the described long chain alkyl berberine salt derivative of claim 1 aspect the preparation blood lipid-lowering medicine.
5. the application of the described long chain alkyl berberine salt derivative of claim 1 aspect the preparation hypoglycemic drug.
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| CN102002081B (en) * | 2010-10-26 | 2013-04-10 | 中国药科大学 | 9-O-beta-D-glucosyl nandinine as well as preparation method and application thereof |
| CN102850346A (en) * | 2012-09-27 | 2013-01-02 | 四川大学 | Berberrubine 12-site derivatives as well as preparation method and applications thereof |
| CN103709270B (en) * | 2013-12-31 | 2015-07-15 | 中国科学院海洋研究所 | Chitosan-grafted alkyl substituted berberrubine derivative and preparation method thereof |
| CN106008560B (en) * | 2016-05-18 | 2018-04-20 | 中国医学科学院生物医学工程研究所 | A kind of preparation method and purposes of double berberinc derivates |
| CN106045989A (en) * | 2016-06-29 | 2016-10-26 | 合肥华方医药科技有限公司 | Preparation method and application of 9-substituted dual functional group berberine derivative |
| CN106905313B (en) * | 2017-03-14 | 2018-10-16 | 中国药科大学 | Nitric oxide donator type protoberberine analog derivative and its preparation method and application |
| CN109020968A (en) * | 2018-07-31 | 2018-12-18 | 南京中医药大学 | Jamaicin crystalline salt and preparation method thereof |
| CN112679492B (en) * | 2019-10-17 | 2022-03-18 | 中国科学院上海药物研究所 | Berberine derivative, preparation method and application thereof |
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