CN101870694A - 8,8-disubstituted-13,13a-dihyrdroberberine derivative as well as pharmaceutical composition and application thereof - Google Patents
8,8-disubstituted-13,13a-dihyrdroberberine derivative as well as pharmaceutical composition and application thereof Download PDFInfo
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Abstract
The invention provides a 8,8-disubstituted-13,13a-dihyrdroberberine derivative with a structure shown as the following general formula or a physiologically acceptable salt and application thereof and a pharmaceutical composition comprising the derivative. The 8,8-disubstituted-13,13a-dihyrdroberberine derivative has the effect of promoting the glucose absorption on muscle cells. Proved by in-vivo animal experiments, the compound has the effects on improving the carbohydrate tolerance and the insulin resistance, reducing weight, relieving fatty livers, and the like, has high bioavailability, enhances the in-vivo pesticide effect, and has stable structure under an acidic condition. The compound can be used for treating type-2 diabetes, obesity, fatty livers or complications thereof.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, more specifically, relate to and can be used as 8 of euglycemic agent, 8-two replaces-13,13a-dihydro berberine derivant and pharmaceutical composition thereof and medicinal use.
Background technology
From the fifties in last century, some experts and scholars and medical worker have carried out a large amount of antidiabetic experimentation on animalies and clinical trial to widely used berberine clinically, find that berberine also can treat diabetes and complication thereof except antibiotic.Recently, on the animal model in modern times, proved conclusively its antidiabetic effect, and discover that further its mechanism of action is the ratio by raising ADP/ATP, promote the AMPK phosphorylation, thereby promote muscle and fatty tissue absorption and utilization [Diabetes to glucose, 2006,55:2256-2264; Biochim.Biophys.Acta., 2006,1760:1682-1689].Pharmacological tests shows the onset dosage very big (560mg/kg every day) of berberine, for obtain active stronger, toxicity is lower and have the drug candidates of independent intellectual property right, is worth further composition optimizes.
The inventor has at first synthesized 3 series as follows: barberry bases (BBR analogues), dihydroberberine class (DHBBR analogues) and N-1 class (THBBR analogues) amount to more than 40 compound:
Carry out the test of glucose absorption and AMPK phosphorylation level on the L6 muscle cell, the activity of the promotion glucose absorption of discovery spectrum of berberine compounds and raising AMPK phosphorylation level is all than barberry alkaline error; The activity and the Berberine of dihydroberberine class are suitable; The activity of N-1 then reduces greatly, is about 30% of Berberine.The profit partition ratio logP of used Chemdraw ultra 10 computed in software barberry bases and dihydroberberine class is respectively-0.92 and 3.88.Press five rules of Lipinski ' s, the compound of 0＜logP＜5 generally has preferable oral administration biaavailability, person of the present invention DHBBR carried out the test of intravital anti-diabetic drug effect, raise at high fat and show on the multiple models such as inductive insulin resistant and obesity mice, rat than Berberine and improve curative effect more than 6 times: improve sugar tolerance and insulin resistant, alleviate obesity and reduce free fatty acid in the blood plasma and triglyceride level, alleviation fatty liver [Diabetes, 2008,57:1414-1418].
The inventor has carried out preliminary pharmacokinetic to BBR and DHBBR.After rat oral gavage gives BBR, in blood plasma, detect less than the original shape medicine, infer this medicine gastric infusion after, first pass metabolism takes place in the body or chemical transformation has taken place.After the filling stomach gave DHBBR, DHBBR can detect 5h in the blood plasma, and metabolite BBR plasma concentration can monitor 24h.AUC and C with BBR and DHBBR
MaxAdd and after carry out absolute bioavailability and calculate, with AUC
0-tCalculate, after rat oral gavage gave DHBBR, absolute bioavailability was 2.65%.
The oral administration biaavailability of DHBBR increases than BBR, but very low, and analyzing reason is that DHBBR easily is oxidized to BBR under the stomach acidity condition.Therefore be necessary to obtain active the reservation, have constitutionally stable dihydro berberine derivant under acidic conditions simultaneously again by further structural modification.
Summary of the invention
For addressing the above problem, the present invention has been proposed.
Therefore, the object of the present invention is to provide a class 8,8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt, it has under acidic conditions steady chemical structure, promote muscle cell to anti-diabetic activity in the activity of glucose absorption, high oral administration biaavailability, the strong body;
Another object of the present invention is to provide a kind of and comprise above-mentionedly 8,8-two replaces-13, the pharmaceutical composition of 13a-dihydro berberine derivant or its physiologically acceptable salt;
It is above-mentioned 8 that an also purpose of the present invention is to provide, and 8-two replaces-13, and 13a-dihydro berberine derivant or its physiologically acceptable salt are used for the treatment of purposes in the medicine of diabetes B, obesity, fatty liver or its complication in preparation.
The invention provides 8 shown in the following general formula (1), 8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt:
Wherein, R
1, R
2Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
1,
R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
4Alkyl;
R
4, R
5Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
4, R
5Be connected to become-O-CH
2-O-;
Perhaps
Shown in the following general formula (2) 8,8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt:
Wherein, R
1, R
2Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
1,
R
2Be connected to become-O-CH
2-O-;
R
3Be CN or COOR
6, R
6Be C
1-C
4Alkyl;
R
4, R
5Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
4, R
5Be connected to become-O-CH
2-O-;
Perhaps
Shown in the following general formula (3) 8,8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt:
Wherein, R
1, R
2Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
1,
R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
4Alkyl, C
1-C
4Acyloxy or aromatic base;
R
4, R
5Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
4, R
5Be connected to become-O-CH
2-O-.
In the preferred embodiment of the invention:
In general formula (1):
R
1, R
2Be H or C independently of one another
1-C
2Alkoxyl group, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
3Alkyl;
R
4, R
5Be C independently of one another
1-C
2Alkoxyl group;
In general formula (2):
R
1, R
2Be H or C independently of one another
1-C
2Alkoxyl group, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be CN or COOR
6, R
6Be C
1-C
2Alkyl;
R
4, R
5Be C independently of one another
1-C
2Alkoxyl group;
In general formula (3):
R
1, R
2Be H or C independently of one another
1-C
2Alkoxyl group, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
2Alkyl or phenyl;
R
4, R
5Be C independently of one another
1-C
2Alkoxyl group.
Further preferred, of the present invention 8,8-two replaces-13, and the 13a-dihydro berberine derivant is selected among the compound 1-10 as shown in the table:
Of the present invention 8,8-two replaces-13, and the 13a-dihydro berberine derivant can synthesize by following synthetic method:
8-oxygen substituted-dihydro Berberine refluxes in phosphorus oxychloride and obtains important intermediate 8-chlorine Berberine.8-chlorine Berberine and different grignard reagent reactions obtain 8 dialkyl group substituted-dihydro Berberines, i.e. general formula (1) compound; 8-chlorine Berberine and different primary amine reactions generate different group with imine moiety, i.e. general formula (3) compound; 8-chlorine Berberine and diethyl malonate or propane dinitrile reaction just can obtain 8 the dihydroberberine analogues that form two keys, i.e. general formula (2) compounds.
According to the present invention, the invention provides and comprise 8 of treatment effective dose, 8-two replacements-13, the pharmaceutical composition of 13a-dihydro berberine derivant or its physiologically acceptable salt, said composition may further include conventional auxiliary material pharmaceutically, for example vehicle, sweeting agent etc.
Of the present invention 8,8-two replaces-13, and 13a-dihydro berberine derivant or its physiologically acceptable salt have and promotes the activity of muscle cell to glucose absorption, can be used for preparing the medicine that is used for the treatment of diabetes B, obesity, fatty liver or its complication.
Of the present invention 8,8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt can be used for treating diabetes B, obesity, fatty liver or its complication, this methods of treatment comprises to patient treats 8 of significant quantity, 8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt.
Beneficial effect
The present invention designs and has synthesized 8,8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt, it has the effect that promotes glucose absorption to muscle cell, whole animal test shows, this compounds has the sugar tolerance of improvement and insulin resistant, alleviate obesity, alleviate effect such as fatty liver, and the bioavailability height, strengthened intravital drug effect, simultaneously Stability Analysis of Structures under acidic conditions.This compounds can be used for treating diabetes B, obesity, fatty liver and complication thereof.The compounds of this invention is synthetic simple, is easy to preparation, and synthesis material is abundant.
Description of drawings
Figure 1A is that wherein CH-con is the normal mouse group through compound 4 treatment obesity mices 4 all pneumoretroperitoneum injectable dextrose monohydrate tolerance (ipGTT) graphic representations, and HF-con is the obesity mice group, and HF-compound 4 is compound 4 treatment groups;
Figure 1B is that wherein CH-con is the normal mouse group through compound 4 treatment obesity mices 4 all pneumoretroperitoneum injectable dextrose monohydrate tolerance (ipGTT) area under curve, and HF-con is the obesity mice group, and HF-compound 4 is compound 4 treatment groups;
Fig. 2 is through compound 4 treatment obesity mices 4 all pneumoretroperitoneum insulin injection tolerances (ITT) graphic representations;
Fig. 3 A is the variation diagram through compound obesity mice body weight after 4 weeks of 4 treatments;
Fig. 3 B is the variation diagram through compound obesity mice subcutaneous lipids/body weight ratio after 4 weeks of 4 treatments;
Fig. 4 A is the variation diagram of the insulin content in the obesity mice blood plasma of compound after 44 weeks of treatment;
Fig. 4 B is the variation diagram of the content of triglyceride in the obesity mice blood plasma of compound after 44 weeks of treatment;
Fig. 4 C is the variation diagram of the content of triglyceride in the obesity mice liver of compound after 44 weeks of treatment;
Fig. 5 A is that wherein WT-con is the normal mouse group through the variation diagram of the db/db mouse postprandial blood sugar in 44 weeks of treatment of compound, and db/db-con is the diabetic mice group, and db/db-compound 4 is compound 4 treatment groups;
Fig. 5 B is that wherein WT-con is the normal mouse group through the variation diagram of the hungry blood sugar of db/db mouse in 44 weeks of treatment of compound, and db/db-con is the diabetic mice group, and db/db-compound 4 is compound 4 treatment groups;
Fig. 6 A is compound 4 and dihydroberberine (DHBBR) treatment db/db mouse 4 all pneumoretroperitoneum injectable dextrose monohydrate tolerance (ipGTT) graphic representations;
Fig. 6 B is compound 4 and dihydroberberine (DHBBR) treatment db/db mouse 4 all pneumoretroperitoneum injectable dextrose monohydrate tolerance (ipGTT) area under curve;
Fig. 7 treats the db/db mouse after 4 weeks, abdominal injection insulin tolerance (ITT) graphic representation through compound 4 and dihydroberberine (DHBBR);
Fig. 8 is the db/db mouse after 4 weeks of treatment through compound 4 and dihydroberberine (DHBBR), the variation diagram of the content of triglyceride in its blood plasma.
Embodiment
The present invention is further elaborated below in conjunction with specific embodiment, but the present invention is not limited to this.
In the following preparation example,
1H-NMR Varian Mercury AMX300 type Instrument measuring.MS uses VG ZAB-HS or VG-7070 type and Esquire 3000 plus-01005 to measure.All through distillation again, employed anhydrous solvent all is to obtain by the standard method drying treatment to all solvents before use.Unless otherwise indicated, it all is to carry out under argon shield and follow the tracks of with TLC that institute responds, during aftertreatment all through saturated common salt washing and anhydrous magnesium sulfate drying process.The purifying of product unless otherwise indicated all uses the column chromatography of silica gel, and employed silica gel is the 200-300 order, GF
254Be Haiyang Chemical Plant, Qingdao or the production of the rich silica gel company of Yantai edge.
The preparation embodiment
The preparation of 8-oxygen substituted-dihydro palmatine
Palmatine (5g, 13.2mmol, commercially available obtaining) is dissolved in 20% potassium hydroxide solution (100mL), stirs 6 hours at 80 ℃, and the cooling back adds dichloromethane extraction.With 2N dilute hydrochloric acid, water, saturated common salt washing, dry then concentrated, residue is recrystallization in methylene dichloride, methyl alcohol, obtains yellow needle-like crystal 8-oxygen substituted-dihydro palmatine (2.4g, productive rate 48%) successively for organic phase.
8-oxygen substituted-dihydro palmatine, C
21H
21NO
5, MW:367; Yellow needle-like crystal is soluble in chloroform and acetone.
1H?NMR(300MHz，CDCl
3)，δ7.31(1H，d，J＝7.8Hz，H-12)，7.24(1H，d，J＝7.8Hz，H-11)，7.20(1H，s，H-1)，6.73(1H，s，H-4)，6.71(1H，s，H-13)，4.27(2H，t，J＝6.3Hz，H-6)，4.00(3H，s，OMe)，3.94(3H，s，OMe)，3.90(3H，s，OMe)，3.89(3H，s，OMe)，2.93(2H，t，J＝6.3Hz，H-5)。
The preparation of 8-oxygen substituted-dihydro Berberine
Berberine (5g, 13.4mmol, commercially available obtaining) is dissolved in 20% potassium hydroxide solution (100mL), stirs 6 hours at 80 ℃, and the cooling back adds methylene dichloride and extracts.With 2N dilute hydrochloric acid, water, saturated common salt washing, dry then concentrated, residue is recrystallization in methylene dichloride, methyl alcohol, obtains yellow needle-like crystal 8-oxygen substituted-dihydro Berberine (2.3g, productive rate 49%) successively for organic phase.
8-oxygen substituted-dihydro Berberine, C
20H
17NO
5, MW:351; Yellow needle-like crystal is soluble in chloroform and acetone.
1H?NMR(300MHz，CDCl
3)，δ7.32(1H，d，J＝8.1Hz，H-12)，7.27(1H，d，J＝8.1Hz，H-11)，7.21(1H，s，H-1)，6.72(1H，s，H-4)，6.70(1H，s，H-13)，6.00(2H，s，-OCH
2O-)，4.29(2H，t，J＝6.3Hz，H-6)，4.00(3H，s，OMe)，3.94(3H，s，OMe)，2.89(2H，t，J＝6.3Hz，H-5)。
The preparation of 8-chlorine palmatine
8-oxygen substituted-dihydro palmatine (5g 13.6mmol) places phosphorous oxychloride (10mL) to reflux 2 hours, cooled and filtered, and filter cake obtains orange pulverulent solids 8-chlorine palmatine (4.3g, productive rate 75%) with chloroform and ether washing behind the drying under reduced pressure.This compound need not purifying, directly carries out next step reaction.
The preparation of 8-chlorine Berberine
8-oxygen substituted-dihydro Berberine (5g 14.2mmol) places phosphorous oxychloride (10mL) to reflux 2 hours, cooled and filtered, and filter cake obtains orange pulverulent solids 8-chlorine Berberine (4.5g, productive rate 78%) with chloroform and ether washing behind the drying under reduced pressure.This compound need not purifying, directly carries out next step reaction.
The preparation of 8-chlorine palmatine and 8-chlorine Berberine is referring to document: J.Pharm.Sci., 1979,68,705.
The preparation of compound 1
(1g 2.38mmol) is dissolved in the 30mL anhydrous diethyl ether 8-chlorine palmatine, and (3mL, 3mol/mL), the reaction mixture stirring and refluxing adds 2N dilute hydrochloric acid after 30 minutes, use dichloromethane extraction slowly to drip the methyl grignard reagent under the nitrogen protection.Organic layer with ammoniacal liquor alkalize after drying, concentrate, through column chromatography (sherwood oil/acetone=30: 1, volume ratio) purifying, obtain yellow powder shape crystalline compounds 1 (350mg, productive rate 36%).
1H NMR (300MHz, CDCl
3), δ 7.10 (1H, s, H-1), 6.69 and 6.58 (2H, d, J=7.5Hz, H-11,12), 6.47 (1H, s, H-4), 5.63 (1H, s, H-13), 3.90 (3H, s, OMe), 3.85 (3H, s, OMe), 3.73 (3H, s, OMe), 3.69 (3H, s, OMe), 3.23 (2H, m, H-6), 2.79 (2H, m, H-5), 1.52 (6H, s, CH
3).
The preparation of compound 2
(1g 2.47mmol) is dissolved in the 30mL anhydrous diethyl ether 8-chlorine Berberine, and (3mL, 3mol/mL), the reaction mixture stirring and refluxing adds 2N dilute hydrochloric acid after 30 minutes, use dichloromethane extraction slowly to drip the propyl group grignard reagent under the nitrogen protection.Organic layer with ammoniacal liquor alkalize after drying, concentrate, through column chromatography (sherwood oil/acetone=40: 1, volume ratio) purifying, obtain yellow powder shape crystalline compounds 2 (320mg, productive rate 28%).
Compound 2, C
26H
31NO
4, MW:421; The yellow powder crystal is soluble in chloroform and acetone.
1H?NMR(300MHz，CDCl
3)，δ7.11(1H，s，H-1)，6.69(1H，d，J＝8.1Hz，H-12)，6.56(1H，s，H-4)，6.52(1H，d，J＝8.1Hz，H-11)，5.93(2H，s，-OCH
2O-)，5.28(1H，s，H-13)，3.83(3H，s，OMe)，3.82(3H，s，OMe)，3.27(2H，t，J＝5.7Hz，H-6)，2.78(2H，t，J＝5.7Hz，H-5)，2.20(2H，m，CH
2)，1.78(2H，m，CH
2)，1.50(2H，m，CH
2)，1.28(2H，m，CH
2)，0.86(6H，t，J＝7.5Hz，CH
3)。
The preparation of compound 3
(1g 2.47mmol) is dissolved in the 30mL anhydrous diethyl ether 8-chlorine Berberine, and (3mL, 3mol/mL), the reaction mixture stirring and refluxing adds 2N dilute hydrochloric acid after 30 minutes, use dichloromethane extraction slowly to drip the ethyl grignard reagent under the nitrogen protection.Organic layer with ammoniacal liquor alkalize after drying, concentrate, through column chromatography (sherwood oil/acetone=40: 1, volume ratio) purifying, obtain yellow powder shape crystalline compounds 3 (330mg, productive rate 31%).
Compound 3, C
24H
27NO
4, MW:393; The yellow powder crystal is soluble in chloroform and acetone.
1H?NMR(300MHz，CDCl
3)，δ7.12(1H，s，H-1)，6.70(1H，d，J＝8.1Hz，H-12)，6.56(1H，s，H-4)，6.54(1H，d，J＝8.1Hz，H-11)，5.93(2H，s，-OCH
2O-)，5.29(1H，s，H-13)，3.80(6H，s，OMe)，3.26(2H，t，J＝5.4Hz，H-6)，2.79(2H，t，J＝5.4Hz，H-5)，2.23(2H，m，CH
2)，1.84(2H，m，CH
2)，0.88(6H，t，J＝7.5Hz，CH
3)。
The preparation of compound 4
(1g 2.47mmol) is dissolved in the 30mL anhydrous diethyl ether 8-chlorine Berberine, and (3mL, 3mol/mL), the reaction mixture stirring and refluxing adds 2N dilute hydrochloric acid after 30 minutes, use dichloromethane extraction slowly to drip the methyl grignard reagent under the nitrogen protection.Organic layer with ammoniacal liquor alkalize after drying, concentrate, through column chromatography (sherwood oil/acetone=30: 1, volume ratio) purifying, obtain yellow powder shape crystalline compounds 4 (350mg, productive rate 36%).
1H?NMR(300MHz，CDCl
3)，δ7.13(1H，s，H-1)，6.72and?6.62(2H，d，J＝7.5Hz，H-11，12)，6.56(1H，s，H-4)，5.93(2H，s，-OCH
2O-)，5.66(1H，s，H-13)，3.90(3H，s，OMe)，3.85(3H，s，OMe)，3.23(2H，m，H-6)，2.79(2H，m，H-5)，1.52(6H，s，CH
3)。
The preparation of compound 5
Propane dinitrile (0.6g 9.1mmol) is dissolved in the 20mL anhydrous tetrahydro furan, then add sodium hydride (0.2g, 8.3mmol).(1.5g, 3.56mmol), reaction mixture stirs and adds the ether dilution after 30 minutes, with methylene dichloride, water extraction to add 8-chlorine palmatine under nitrogen protection fast.Organic layer drying, concentrated, recrystallization obtains safran powder compounds 5 (1.1g, productive rate 63%) in methyl alcohol.
Compound 5, C
24H
21N
3O
4, MW:415; The safran powder is soluble in chloroform and acetone.
1H?NMR(300MHz，CDCl
3)，δ7.38(1H，d，J＝8.4Hz，H-12)，7.25(1H，d，J＝8.4Hz，H-11)，7.11(1H，s，H-1)，6.98(1H，s，H-4)，6.74(1H，s，H-13)，4.44(2H，t，J＝6.0Hz，H-5)3.99(3H，s，OMe)，3.97(3H，s，OMe)，3.84(3H，s，OMe)，3.79(3H，s，OMe)，2.97(2H，t，J＝6.0Hz，H-6)。
The preparation of compound 6
Diethyl malonate (1.2mL 8.3mmol) is dissolved in the 20mL anhydrous tetrahydro furan, then add sodium hydride (0.2g, 8.3mmol).(1.5g, 3.56mmol), reaction mixture stirs and adds the ether dilution after 30 minutes, with methylene dichloride, water extraction to add 8-chlorine palmatine under nitrogen protection fast.Organic layer drying, concentrated, recrystallization obtains garnet powder compounds 6 (1.05g, productive rate 72%) in methyl alcohol.
1H NMR (300MHz, CDCl
3), δ 7.67 (1H, s, H-1), 7.58 (2H, s, H-11 and 12), 7.20 (1H, s, H-4), 6.78 (1H, s, H-13), 4.68 (2H, t, J=6.0Hz, H-5) 4.08 (4H, m, CH
2), 3.94 (3H, s, OMe), 3.85 (3H, s, OMe), 3.78 (3H, s, OMe), 3.72 (3H, s, OMe), 2.94 (2H, t, J=6.0Hz, H-6), 1.09 (6H, t, J=6.9Hz, CH
3).
The preparation of compound 7
Propane dinitrile (0.6g 9.1mmol) is dissolved in the 20mL anhydrous tetrahydro furan, then add sodium hydride (0.2g, 8.3mmol).(1.5g, 3.7mmol), reaction mixture stirs and adds the ether dilution after 30 minutes, with methylene dichloride, water extraction to add 8-chlorine Berberine under nitrogen protection fast.Organic layer drying, concentrated, recrystallization obtains safran powder compounds 7 (1.1g, productive rate 63%) in methyl alcohol.
Compound 7, C
23H
17N
3O
4, MW:399; The safran powder is soluble in chloroform and acetone.
1H?NMR(300MHz，CDCl
3)，δ7.38(1H，d，J＝8.4Hz，H-12)，7.25(1H，d，J＝8.4Hz，H-11)，7.11(1H，s，H-1)，6.98(1H，s，H-4)，6.74(1H，s，H-13)，6.00(2H，s，-OCH
2O-)，4.44(2H，t，J＝6.0Hz，H-6)3.99(3H，s，OMe)，3.97(3H，s，OMe)，2.97(2H，t，J＝6.0Hz，H-5)。
The preparation of compound 8
Diethyl malonate (1.2mL 8.3mmol) is dissolved in the 20mL anhydrous tetrahydro furan, then add sodium hydride (0.2g, 8.3mmol).(1.5g, 3.7mmol), reaction mixture stirs and adds the ether dilution after 30 minutes, with methylene dichloride, water extraction to add 8-chlorine Berberine under nitrogen protection fast.Organic layer drying, concentrated, recrystallization obtains garnet powder compounds 8 (1.05g, productive rate 72%) in methyl alcohol.
1H NMR (300MHz, CDCl
3), δ 7.67 (1H, s, H-1), 7.58 (2H, s, H-11 and 12), 7.20 (1H, s, H-4), 6.78 (1H, s, H-13), 6.00 (2H, s ,-OCH
2O-), 4.68 (2H, t, J=6.0Hz, H-5) 4.08 (4H, m, CH
2), 3.94 (3H, s, OMe), 3.78 (3H, s, OMe), 2.94 (2H, t, J=6.0Hz, H-6), 1.09 (6H, t, J=6.9Hz, CH
3).
The preparation of compound 9
(1g 2.47mmol) is dissolved in the 30mL dry-out benzene 8-chlorine Berberine, slowly drips anhydrous methylamine (0.2mL) under the nitrogen protection, and the reaction mixture stirring at room adds 2N dilute hydrochloric acid after 1.5 hours, use dichloromethane extraction.Organic phase with ammoniacal liquor alkalize after drying, concentrate, recrystallization obtains yellow powder shape crystalline compounds 9 (430mg, productive rate 41%) in methyl alcohol.
Compound 9, C
21H
20N
2O
4, MW:364; The glassy yellow powder crystal is soluble in chloroform and acetone.
1H?NMR(300MHz，CDCl
3)，δ7.58(1H，d，J＝8.1Hz，H-12)，7.45(1H，d，J＝8.1Hz，H-11)，7.31(1H，s，H-1)，7.10(1H，s，H-4)，6.91(1H，s，H-13)，6.10(2H，s，-OCH
2O-)，4.54(2H，t，J＝7.5Hz，H-6)，4.30(3H，s，OMe)，4.18(3H，s，OMe)，3.51(3H，s，NCH
3)，3.15(2H，t，J＝7.5Hz，H-5)。
The preparation of compound 10
(1g 2.47mmol) is dissolved in the 30mL dry-out benzene 8-chlorine Berberine, slowly drips anhydrous aniline (0.2mL) under the nitrogen protection, and the reaction mixture stirring at room adds 2N dilute hydrochloric acid after 1.5 hours, use dichloromethane extraction.Organic phase with ammoniacal liquor alkalize after drying, concentrate, recrystallization obtains yellow powder shape crystalline compounds 10 (475mg, productive rate 43%) in methyl alcohol.
1H NMR (300MHz, CDCl
3), δ 7.55 (1H, d, J=8.1Hz, H-12), 7.42 (1H, d, J=8.1Hz, H-11), 7.37 (1H, s, H-1), 7.28-7.07 (5H, m, H on the phenyl ring), 7.02 (1H, s, H-4), 6.91 (1H, s, H-13), 6.08 (2H, s ,-OCH
2O-), 4.44 (2H, t, J=7.2Hz, H-6), 4.22 (3H, s, OMe), 4.10 (3H, s, OMe), 2.93 (2H, t, J=7.2Hz, H-5).
The preparation example of above dihydro berberine derivant is for referencial use, and other dihydro berberine derivant also can make with reference to aforesaid method.
Experimental example
Experimental example 1:
Use L6 muscle cell glucose uptake model, in the promoter action of external preliminary assessment part of compounds of the present invention to glucose absorption.
Experimental procedure:
After the L6 muscle cell that cultivation is broken up in 24 orifice plates is fully washed once with phosphoric acid buffer, hunger is 2 hours in the high sugared DMEM that contains 0.2% bovine serum albumin (BSA) (Dulbecco ' s Modified Eagle Media) substratum, with containing 5 μ M dihydro berberine derivant of the present invention, the high sugared DMEM substratum of 0.2%BSA continued to hatch 2.5 hours.After washing 2 times with the HBS that contains 5 μ M dihydro berberine derivants (HEPES buffered saline) solution, hatched 0.5 hour in the HBS solution for continuous of 5 μ M dihydro berberine derivants.Add [3H] isotope-labeled 2-deoxyglucose (being dissolved as concentration 1mM with HBS or KRP (Krebs Ringer phosphate), 5 μ Ci/mL odd-job liquid) in HBS solution, making its final concentration is 100 μ M, isotropic substance 0.5 μ Ci/mL.Hatch 10min at 37 ℃.Inhale rapidly and remove the cell Incubating Solution, cell is placed on ice, wash rapidly 3 times with ice-cold PBS.42 ℃ of drying in oven.Add 200 μ l, 0.1% TritonX-100,4 ℃ of gentle vibration 45min lysing cell.Get 150 μ L lysates, add 1.1mL scintillation solution scintillation counting.Get 10 μ l lysates and dilute 10 times with Bradford method survey protein concentration.Net result is represented with picomole/minute/milligram protein.
Judgment criteria:
Testing compound is dissolved among the DMSO, during concentration 5 μ M, than DMSO blank raising is arranged if calculate the glucose uptake amount of gained, and there are significant difference statistically in two groups of data, illustrates that then this compound has the effect that promotes glucose absorption.Active result represents the ratio of glucose uptake amount and DMSO blank with compound.
Test result:
Table 1 has shown when glucose concn is 5.0mM in L6 muscle cell glucose uptake model that to the facilitation effect of glucose transport, wherein BBR is a Berberine to part of compounds of the present invention when concentration 5 μ M.
Table 1:
As shown in table 1, results of screening clearly shows of the present inventionly 8 on the cell levels, and 8-two replaces-13, and the 13a-dihydro berberine derivant has the activity that promotes glucose absorption.The inventor has further selected 8,8-dimethyl-13, and 13a-dihydroberberine hydrochloride (compound 4) is made the pharmacodynamics test that following whole animal has been carried out in representative.Though following experimentation on animals only uses 8,8-dimethyl-13,13a-dihydroberberine hydrochloride is represented, and results of screening is pointed out other 8 significantly on the above-listed cell levels, and 8-two replaces-13, and the 13a-dihydro berberine derivant also should have similar effects.
Experimental example 2:
Adopt high performance liquid chromatography to study compound dihydroberberine (DHBBR), 4,8 and 9 stability under pH=3 citric acid-sodium citrate condition.
Liquid phase systems analysis condition: Waters 2695 liquid phase systems; Chromatographic column: XTerra MS C8,4.6 * 150mm, 5 μ m; The potassium dihydrogen phosphate of the preparation of buffering salt: 0.025mol/L [is got potassium primary phosphate 3.405g, is added water 1000mL, regulate pH value to 6.0 ± 0.1 with the 1mol/L potassium hydroxide solution, promptly; Moving phase: gradient elution, 0 to 20min, moving phase is from buffering salt-acetonitrile (70: 30, volume ratio) to buffering salt-acetonitrile (30: 70, volume ratio); Flow velocity: 1.0mL/min detects wavelength: 375nm; Concentration: 0.5mg/mL; Sampling volume: 20uL, column temperature: 30 degree.
With acetonitrile difference sample dissolution dihydroberberine (DHBBR), 4,8 and 9, add a small amount of pH3.0 citric acid-sodium citrate damping fluid more earlier, lucifuge was placed after 6 hours, measured the content of compound.
| Sample | Samples contg after 6 hours | Stability | |
| Dihydroberberine (DHBBR) | 47.5 | Difference | |
| 4 | 99.3 | Good | |
| 8 | 98.7％ | Good | |
| 9 | 97.6％ | Good |
Show from the stability experiment of above-claimed cpd dihydroberberine (DHBBR), 4,8 and 9 under pH=3 citric acid-sodium citrate condition, of the present invention 8,8-two replaces-13, and the 13a-dihydro berberine derivant is under acidic conditions, structure is more stable, is difficult for being oxidized to Berberine.
Experimental example 3:
Adopt the liquid chromatography-tandem mass spectrometry method to study Berberine, dihydroberberine (DHBBR) and 8,8-dimethyl Berberine (compound 4) is at the intravital absolute bioavailability of rat.
Dosage regimen
The rat vein administration: 12 of healthy SD rats, male and female half and half, body weight 200～250g is divided into three groups at random, and 4 every group, fasting 12h before the administration freely drinks water.Wherein one group of dosage with 20mg/kg gives Berberine through the rat tail vein injection, second group of dosage with 20mg/kg gives dihydroberberine through the rat tail vein injection, the 3rd group of dosage with 20mg/kg gives 8 through the rat tail vein injection, 8-dimethyl dihydroberberine (the administration volume is 10mL/kg) is after administration 0.083,0.167,0.50,1.0,2.0,3.0,4.0,6.0,8,12 and 24h through rat eye rear vein beard extracting vein blood 0.3mL, put in the heparinization test tube, 3000 rev/mins of centrifugal 10min, separated plasma ,-20 ℃ of preservations are to be measured.
The rat oral gavage administration: 12 of healthy SD rats, male and female half and half, body weight 200～250g is divided into three groups at random, and 4 every group, fasting 12h before the administration freely drinks water.Wherein one group of dosage with 20mg/kg is irritated stomach and is given Berberine, second group of dosage with 20mg/kg is irritated stomach and is given dihydroberberine, the 3rd group of dosage with 20mg/kg gives 8 through the rat tail vein injection, 8-dimethyl dihydroberberine (the administration volume is 10mL/kg), before administration and administration after 0.25,0.5,1.0,2.0,3.0,4.0,5.0,6.0,8.0,12 and 24h through rat eye rear vein beard extracting vein blood 0.3mL, put in the heparinization test tube, the centrifugal 10min of 3000rpm, separated plasma ,-20 ℃ of preservations are to be measured.
Conclusion
Press AUC
0-t(Area under the concentration, lower area of blood concentration-time curve.) calculate, rat oral gavage gives Berberine, dihydroberberine and 8, and behind the 8-dimethyl dihydroberberine, absolute bioavailability is respectively 0,2.65% and 38.5%.Therefore, illustrate 8, the oral absorption effect of 8-dimethyl dihydroberberine is better than Berberine, dihydroberberine greatly.
Experimental example 4:
Estimate the interior anti-diabetic of body and the anti-obesity activity of The compounds of this invention.
Experimental procedure:
1. high lipid food inductive insulin resistant obesity mice DIO model
Adopt normal male C 57 BL/6 J mouse (6 age in week), (Rodent diet with60 kcal% fat (Research diets, Inc)) feeds and 8 weeks formed the obvious insulin resistance symptom, and the glucose tolerance is obviously descended through high lipid food.The mouse of getting the modeling success is used for the evaluation of compound pharmacodynamics.Methylcellulose gum with 0.5% is made into uniform suspension with compound 4, gastric infusion every day (dosage is 15mg/kg/day).Write down body weight gain and feed situation every day.After treating for 4 weeks, hungry 6 hours, get hematometry basis blood glucose value (0 minute) from the tail vein, give abdominal injection glucose 2g/kg according to body weight then, measure blood glucose value at 15,30,60,90 and 120 minutes respectively, and calculate its area under curve AUC.After treating the animal recovering state, hungry 6 hours, according to body weight abdominal injection Regular Insulin 0.75U/kg, measured blood glucose value at 15,30,60,90 minutes respectively, do insulin tolerance test (ITT) curve.After treatment finishes, get interior fat and liver organization is weighed, and measure its content of triglyceride.
2. diabetes db/db mouse model
The db/db mouse is introduced from Jackson Laboratory, and blood sugar significantly raises after 8 ages in week, according to body weight and blood glucose value random packet, is used for the evaluation of compound pharmacodynamics.Methylcellulose gum with 0.5% is made into uniform suspension with compound 4 and dihydroberberine (DHBBR), gastric infusion every day (dosage of compound 4 and dihydroberberine is 50mg/kg/day).Each once to survey postprandial blood sugar and hungry blood sugar (hungry 6 hours) weekly.After treating for 4 weeks, hungry 6 hours of animal is got hematometry basis blood glucose value (0 minute) from the tail vein, gives abdominal injection glucose 1.5g/kg according to body weight then, measure blood glucose value at 15,30,60,90 and 120 minutes respectively, and calculate its area under curve AUC.After treating the animal recovering state, hungry 6 hours, according to body weight abdominal injection Regular Insulin 1U/kg, measured blood glucose value at 15,30,60,90,120 minutes respectively, do the ITT curve.After treatment finishes, get interior fat and liver organization is weighed, and measure its content of triglyceride.
Experimental result:
1. the chronic treatment curative effect of 4 pairs of high fat inductive insulin resistant obesities of compound (DIO) mouse
After treating for 4 weeks, give the glucose of 2g/kg by abdominal injection, as shown in Figure 1, the fatter control group of treatment group blood sugar increasing is few and blood sugar recovery is very fast, and there was significant difference in both blood sugar in the time of 90 minutes.Area is also significantly less than control group (*, P＜0.05) under the treatment group blood glucose curve.Explanation obviously improves through the tolerance of compound 4 treatment obesity mices to glucose.Insulin tolerance test shows (Fig. 2), and the treatment group gives more remarkable (*, P＜0.05) that the fatter control group of blood sugar descends behind the Regular Insulin, illustrates that compound 4 can strengthen the insulin sensitivity of DIO mouse.
Mouse after compound 4 treatments, its weight increase of DIO is significantly less than control group, is negative growth.And the ratio of subcutaneous lipids in body weight compared with control group and is significance decline (as shown in Figure 3) (*, P＜0.05).Illustrate that compound of the present invention has the opposing mouse by high lipid food inductive body weight gain and fat accumulation trend, has potential and treats fat curative effect.
Shown in Fig. 4 A, 4B and 4C, through the mouse of compound after 4 weeks of 4 chronic treatments, Regular Insulin in its blood plasma (HF-con vs HF-compound 4,1.66 (HF-con vs HF-compound 4,0.79 ± 0.04mmol/l vs 0.59 ± 0.04mmol/l) obviously descends for ± 0.22ng/ml vs 0.92 ± 0.05ng/ml) and triglyceride level TG content.Also obviously descend (*, P＜0.05 of content of triglyceride in the liver (HF-con vs HF-compound 4,24.85 ± 4.50 μ mol/g vs 15.93 ± 1.45 μ mol/g) in addition; *, P＜0.01).Illustrate that compound 4 has effect preferably aspect insulin resistant and the lipopenicillinase improving.
2. the chronic treatment curative effect of 4 couples of diabetes db/db of compound mouse
Diabetes db/db mouse after compound 4 treatments, its postprandial blood sugar (db/db-con vs db/db-compound 4,27.8 ± 1.8mM vs 17.1 ± 1.6mM) and hungry blood sugar (db/db-con vs db/db-compound 4,29.5 ± 1.4mM vs 19.6 ± 1.6mM) presents extremely significantly downtrending (* * * than the solvent control group, P＜0.001) (Fig. 5 A and 5B), and can obviously improve tolerance and the insulin sensitivity of diabetes db/db mouse to glucose.Shown in Figure 6, area all significantly descends (*, P＜0.05) insulin tolerance (ITT) curve display (Fig. 7, *, P＜0.05 than control group with dosage dihydroberberine (DHBBR) treatment group under the glucose tolerance curve of treatment group; *, P＜0.01; * *, P＜0.001) insulin sensitivity of administration group extremely significantly strengthens.
Behind compound 4 chronic treatments, triglyceride level TG content (db/db-con vs db/db-compound 4 in the blood plasma of db/db mouse basis, 1.32 it is (shown in Figure 8 that ± 0.1mmol/l vs 0.82 ± 0.07mmol/l) obviously descends, * *, and more obvious P＜0.001), than descending with dosage DHBBR treatment group.Illustrate that compound 4 has lipid-lowering effect preferably, and specific activity DHBBR is stronger.
Experiment conclusion:
Raise on the inductive insulin resistant obesity mice DIO model at high fat, compound 4 has obvious curative effects: improve sugar tolerance and insulin resistant, strengthen insulin sensitivity; Alleviate obesity and alleviate fatty liver.On diabetes db/db mouse model, compound 4 has tangible hypoglycemic effect, improves sugar tolerance, strengthens insulin sensitivity, and significantly improve the disorderly symptom of high fat of diabetic mice.
Claims (7)
1. 8 shown in following general formula (1), (2) or (3), 8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt:
Wherein, R
1, R
2Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
4Alkyl;
R
4, R
5Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
4, R
5Be connected to become-O-CH
2-O-;
Wherein, R
1, R
2Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be CN or COOR
6, R
6Be C
1-C
4Alkyl;
R
4, R
5Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
4, R
5Be connected to become-O-CH
2-O-;
Wherein, R
1, R
2Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
4Alkyl, C
1-C
4Acyloxy or aromatic base;
R
4, R
5Be H, OH, C independently of one another
1-C
4Alkoxyl group or C
1-C
4Acyloxy, or R
4, R
5Be connected to become-O-CH
2-O-.
2. as claimed in claim 18,8-two replaces-13, and 13a-dihydro berberine derivant or its physiologically acceptable salt is characterized in that,
In general formula (1):
R
1, R
2Be H or C independently of one another
1-C
2Alkoxyl group, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
3Alkyl;
R
4, R
5Be C independently of one another
1-C
2Alkoxyl group;
In general formula (2):
R
1, R
2Be H or C independently of one another
1-C
2Alkoxyl group, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be CN or COOR
6, R
6Be C
1-C
2Alkyl;
R
4, R
5Be C independently of one another
1-C
2Alkoxyl group;
In general formula (3):
R
1, R
2Be H or C independently of one another
1-C
2Alkoxyl group, or R
1, R
2Be connected to become-O-CH
2-O-;
R
3Be C
1-C
2Alkyl or phenyl;
R
4, R
5Be C independently of one another
1-C
2Alkoxyl group.
3. as claimed in claim 18,8-two replaces-13, and 13a-dihydro berberine derivant or its physiologically acceptable salt is characterized in that, and is described 8, and 8-two replaces-13, and the 13a-dihydro berberine derivant is selected from the compound shown below 1～10:
4. pharmaceutical composition that is used for the treatment of diabetes B, obesity, fatty liver or its complication, it is characterized in that, said composition comprise in the claim 1 to 3 for the treatment of effective dose each described 8,8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt.
5. each is described 8 in the claim 1 to 3, and 8-two replaces-13, and 13a-dihydro berberine derivant or its physiologically acceptable salt are used for the treatment of purposes in the medicine of diabetes B, obesity, fatty liver or its complication in preparation.
6. purposes according to claim 5 is characterized in that, and is described 8, and 8-two replaces-13, and the 13a-dihydro berberine derivant is selected from the compound shown below 1～10:
7. method for the treatment of diabetes B, obesity, fatty liver or its complication, this methods of treatment comprise to patient treat in the claim 1 to 3 of significant quantity each described 8,8-two replaces-13,13a-dihydro berberine derivant or its physiologically acceptable salt.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103127101A (en) * | 2011-11-22 | 2013-06-05 | 复旦大学 | Application of 8-diethyl malonate berberine in preparation of antitumor drug |
| CN103804374A (en) * | 2012-11-13 | 2014-05-21 | 上海交通大学医学院附属新华医院 | Application of berberine derivative in preparation of drug for treating atherosclerosis |
| CN107141284A (en) * | 2016-03-08 | 2017-09-08 | 中国医学科学院药物研究所 | Coptisine analog derivative, its preparation method, pharmaceutical composition and anticancer usage |
| CN112138007A (en) * | 2020-09-23 | 2020-12-29 | 广州中医药大学(广州中医药研究院) | Application of oxidized berberine in preparation of medicine for treating metabolic diseases and medicine composition containing oxidized berberine |
| CN114315823A (en) * | 2022-01-05 | 2022-04-12 | 西南交通大学 | Intermediate of berberine hydrochloride and analogue thereof and preparation method thereof |
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| CN101157692A (en) * | 2006-06-29 | 2008-04-09 | 华中科技大学同济医学院附属同济医院 | Berberinc derivatives, preparation method and medicinal composition and usage thereof |
| CN101153039B (en) * | 2006-09-30 | 2010-12-01 | 中国科学院上海药物研究所 | 13, 13a- dihydro berberine derivant and pharmaceutical composition |
| CN101323613B (en) * | 2008-06-16 | 2012-02-22 | 上海市徐汇区中心医院 | Berberine additive product, medicament containing the same and preparation thereof |
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| CN103127101A (en) * | 2011-11-22 | 2013-06-05 | 复旦大学 | Application of 8-diethyl malonate berberine in preparation of antitumor drug |
| CN103804374A (en) * | 2012-11-13 | 2014-05-21 | 上海交通大学医学院附属新华医院 | Application of berberine derivative in preparation of drug for treating atherosclerosis |
| CN107141284A (en) * | 2016-03-08 | 2017-09-08 | 中国医学科学院药物研究所 | Coptisine analog derivative, its preparation method, pharmaceutical composition and anticancer usage |
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| CN115590187A (en) * | 2021-10-08 | 2023-01-13 | 南京纽邦生物科技有限公司（Cn） | Methods and compositions for mimicking caloric restriction biological benefits by administering dihydroberberine |
| CN114315823A (en) * | 2022-01-05 | 2022-04-12 | 西南交通大学 | Intermediate of berberine hydrochloride and analogue thereof and preparation method thereof |
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