CN101704874A - Pentacyclic triterpene and melbine salt of derivative thereof, preparation method and medical application of pentacyclic triterpene - Google Patents
Pentacyclic triterpene and melbine salt of derivative thereof, preparation method and medical application of pentacyclic triterpene Download PDFInfo
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Abstract
The invention relates to field of natural medicine and medicinal chemistry, in particular to novel pentacyclic triterpene and melbine salt I of the derivative thereof. The salt compound can be used for preparing medicaments curing diabetes mellitus and complicating disease thereof, cerebral ischemia, angiocardiopathy, atherosclerosis, hepatitis, fatty liver and metabolic syndrome or tumour, descendens blood fat drugs and anti-obesity drugs. The invention also relates to the preparation method of the salt compound.
Description
Technical field
The present invention relates to natural drug and pharmaceutical chemistry field, be specifically related to the melbine salt of novel pentacyclic triterpene of a class and derivative thereof.Such salt compound can be used for preparing anti-diabetic and complication medicine, anti-cerebral ischemia drugs, anti-cardiovascular disease, blood lipid-lowering medicine, slimming medicine, Antiatherosclerosis medicine, Antihepatitis medicament, anti-fatty liveranti-fatty liver medicine, treatment metabolic syndrome medicine or antitumor drug.The invention still further relates to the preparation method of such salt compound.
Background technology
N1,N1-Dimethylbiguanide is the medicine of an oral administration diabetes B, and it is used for the treatment of diabetes B the history in more than 50 year, and it belongs to the biguanides antidiabetic drug, does not stimulate the beta Cell of islet excreting insulin.It is mainly used in the fat light-duty diabetic of non-insulin-depending type, and its general mechanism of action comprises: (1) increases the susceptibility of surrounding tissue to Regular Insulin; (2) suppress the liver starch heteroplasia, reduce the output of glycogen; (3) can suppress of the absorption of intestines parietal cell to glucose.At present, N1,N1-Dimethylbiguanide is extensive use of clinically with the form of its hydrochloride, adds that in addition it has much the price of advantage, more and more is subjected to the favor of doctor and patient.But also there are some side effects in N1,N1-Dimethylbiguanide, wherein intestines and stomach side reaction (diarrhoea, vomiting etc.) accounts for about 30%, and its reason to small part ascribes the high water-soluble of it to and the very poor absorptive character of intestines and stomach (only being absorbed at the duodenum position of small intestine).The absorption pattern of this medicine is subjected to the influence of its cationization trend, thereby tendency is adsorbed in electronegative small intestine endothelium.The absorption of N1,N1-Dimethylbiguanide has saturability, and very incomplete.Under common dosage and administering mode, Plasma Concentration reached stable state in 24-48 hour, and usually less than 1 mcg/ml.In the clinical experiment that contrast is arranged, even if under maximum dosage, the maximum plasma concentration of N1,N1-Dimethylbiguanide (Cmax) also is no more than 4 mcg/ml.Therefore, in order to reduce the gastrointestinal side effect of N1,N1-Dimethylbiguanide, there is following several scheme can supply to consider: 1) when taking N1,N1-Dimethylbiguanide, to take diarrhea medicine safely and effectively, as dioctahedral smectite; 2) the pharmaceutically acceptable fat-soluble salt of preparation N1,N1-Dimethylbiguanide to reduce the water-soluble of medicine, increases the gastrointestinal absorption of medicine, improves bioavailability of medicament, and then suppresses the gastrointestinal side effect of N1,N1-Dimethylbiguanide.
The distribution of pentacyclic triterpenoid in vegitabilia is very extensive, is the main effective constituent of many herbal medicine commonly used, has wide biological activity.Existing many is the clinical treatment that the medicine of activeconstituents is used for disease with the pentacyclic triterpene natural product directly, and the structure of modification that is guide's thing with natural pentacyclic triterpene compound also produced the medicine of clinical use.
Potenlini (1) is a most important effective constituent in the Radix Glycyrrhizae, has effects such as antiulcer agent, anti-inflammatory, antiviral, protecting liver and detoxication and raise immunity.Potenlini (naturally occurring Potenlini is mainly 18 β-Potenlini) can transform into its isomers, i.e. 18 alpha-liquorice acids (2) under the alkaline effect.18 β-Potenlini has similar physiologically active with 18 alpha-liquorice acids, and different is that 18 alpha-liquorice acids have better water-solubility and stability.The Potenlini preparation of having developed has 18 alpha-liquorice acids, two ammonium injection liquids, and commodity are called Glycyrrhizic acid,diammonium salt, and the monoammonium glycyrrhizinate injection liquid, and commodity are called potenlin, are used for the treatment of various acute, chronic hepatitis, bronchitis and tetter etc. clinically.What German scholar was nearest discovers, Potenlini has the activity of anti-preferably SARS correlated virus, its EC when high dosage
50Be 51～410mg/L, mechanism of action may be to induce nitrogen protoxide synthetic in the Vero cell, and then suppressed virus replication (Lancet, 2003,361 (9374): 2045-2046). in addition, thereby Potenlini also can produce restraining effect to virus by the generation of inducing the endogenous gamma-interferon. and Huang Wei etc. have reported that Potenlini has the activity of anti-human lung carcinoma cell invasion and attack and cell death inducing, and have shown human liver cancer cell differentiation reverse effect (Chinese lung cancer magazine, 2003,6:254).
The glucoside unit of Potenlini is 18 β-glycyrrhetinic acid (3), and it has anti-inflammatory, antiulcer agent, various active such as antitumor and anti-oxidant.The researchist of Russian Academy Of Sciences has reported that the derivative of some glycyrrhetinic acids has significant anti-hiv activity (BioorgKhim, 1996,22 (6): 451-457).Carbenoxolone (4) is a natural derivative of 18 β-glycyrrhetinic acid, and its disodium salt (Carbenoxolone) has been successfully used to clinical in the treatment gastric duodenal ulcer.Studies show that, 18 β-glycyrrhetinic acid and carbenoxolone all have 11beta-Hydroxysteroid dehydrogenase I type (11 β-HSD1) and the 11beta-Hydroxysteroid dehydrogenase II type (non-selective restraining effect (Endocrinology of 11 β-HSD2), 1989,125:1046-1053).Report carbenoxolone such as Andrews have insulin-sensitizing effect to the diabetes B patient, and can suppress liver glucose generation (J Clinical Endocrinology ﹠amp; Metabolism, 2003,88 (1): 285-291).It should be noted that, Sandeep etc. have reported that recently carbenoxolone also has the memory function of improving healthy elderly and diabetes B patient as 11beta-Hydroxysteroid dehydrogenase I type inhibitor, a thereby potential new way (the Proc Nat Acad Sci USA that has indicated the hypermnesis function, 2004,101 (17): 6734-6739).
Oleanolic Acid (5) is the pentacyclic triterpene compound very widely that distributes in vegitabilia, mainly is present in the herbal medicine such as Glossy Privet Fruit, beet, Aralia wood, pawpaw.At present, the Oleanolic Acid preparation is mainly used in assisting therapy acute, chronic hepatitis clinically.Except traditional hepatoprotective effect, pentacyclic triterpenoids such as Oleanolic Acid are proved to be has certain inhibition activity to protein-tyrosine-phosphatase 1B (PTP1B), and protein-tyrosine-phosphatase 1B inhibitor is considered to a class hypoglycemic drug very likely.Oleanolic Acid and related compound (as ursolic acid etc.) are at hypertension (Phytomedicine, 2003,10 (2-3): 115-121), also there is activity cardiac stimulant and anti-heart disorder aspect, its mechanism of action may partly be by acting on beta receptor (Phytomedicine, 2004,11 (2-3): 121-129).In addition, Oleanolic Acid also has certain anti-hiv activity (J Nat Prod, 1998,61 (9): 1090-1095) and to the propagation of tumor cell in vitro also inhibited (Planta Medica, 2000,66 (5): 485-486).
Ursolic acid (6) is present in the natural phant more widely, have calmness, anti-inflammatory, antibiotic, protect multiple biological activitys such as liver, lowering blood glucose.In recent years, find that ursolic acid has anti-tumor activity.Kim etc. have studied the inhibition proliferation activity of ursolic acid to kinds of tumor cells system, and the result shows that ursolic acid has tangible cytotoxicity (PlantaMedica, 2000,66 (5): 485-486) to the tumour cell of being tested.In addition, ursolic acid and derivative thereof have anti-hiv activity.The scientific research personnel of university of North Carolina designs and has synthesized a series of ursolic acid derivatives, and it has been carried out anti-hiv activity research, the result shows that ursolic acid and derivative thereof have certain anti-hiv activity (J Nat Prod, 2000,63 (12): 1619-1622).
But, pentacyclic triterpenoid water-soluble generally relatively poor, the bioavailability of its preparation is low, has limited its application clinically greatly.And high water-soluble of the Metformin of clinical use and partly caused its more serious intestines and stomach side reaction (diarrhoea, vomiting etc.) in the very poor absorptive character of intestines and stomach.
Summary of the invention
The present invention discloses the novel pentacyclic triterpene with pharmaceutical use shown in the formula I and the melbine salt of derivative thereof first, its preparation method and medicinal use, be included in preparation anti-diabetic and complication medicine thereof, anti-cerebral ischemia drugs, anti-cardiovascular disease, blood lipid-lowering medicine, slimming medicine, Antiatherosclerosis medicine, Antihepatitis medicament, the anti-fatty liveranti-fatty liver medicine, the purposes of treatment metabolic syndrome medicine and antitumor drug aspect, the melbine salt of pentacyclic triterpene and derivative thereof both can improve the water-soluble of pentacyclic triterpenoid, can reduce the serious gastrointestinal side effect of N1,N1-Dimethylbiguanide again.
The present invention relates to the compound shown in the formula I
In formula I, the pentacyclic triterpene or derivatives thereof exists as the anionic form of salt, and the carboxyl negative ion is provided, and N1,N1-Dimethylbiguanide exists as the cationic form of salt, and the ammonium positive ion is provided, and both are with the ionic linkage combination.
Wherein, R
1Represent hydrogen, OR
11, NHR
11, N (R
12)
2, SO
2NH
2, NHOR
11, NH
2NHR
11R
2Independent hydrogen, the OR of representing
11, NHR
11, N (R
12)
2, SO
2NH
2, NHOR
11, NH
2NHR
11Perhaps R
1With R
2Represent O or NOR together
11R
11Represent hydrogen or R
12, R
12CO; R
12Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of 1～10 carbon; X represents H, F, Cl, Br, I, CN, NO
2, NH
2, CF
3, SH, OH, OCH
3, OC
2H
5, COOH, COOCH
3, COOC
2H
5, 1～10 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl;
R
3Represent straight or branched carboxylic acid, the R of hydrogen, a 1-18 carbon
13CO, D-Glucopyranose aldehydic acid base, D-Glucopyranose aldehydic acid base-D-Glucopyranose aldehydic acid base; R
13CO represents the straight or branched carboxylic acid of 1-18 carbon;
R
4Represent hydrogen or methyl; R
5Represent hydrogen, methyl or carboxyl, and work as R
4When representing hydrogen, R
5Only represent methylidene or carboxyl; Work as R
4During represent methylidene, R
5Only represent hydrogen;
R
6Represent hydrogen or hydroxyl;
R
7Represent CH
3, CH
2OR
14, COOR
15, CONHR
14, CON (R
15)
2, NHR
14R
14Represent hydrogen or R
15CO; R
15Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of 1～10 carbon; X represents H, F, Cl, Br, I, CN, NO
2, NH
2, CF
3, SH, OH, OCH
3, OC
2H
5, COOH, COOCH
3, COOC
2H
5, 1～10 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl, naphthyl;
R
8Represent hydrogen, OR
16, NHR
16, N (R
17)
2, SO
2NH
2, NHOR
16, NH
2NHR
17R
9Represent hydrogen, OR
16, NHR
16, N (R
17)
2, SO
2NH
2, NHOR
16, NH
2NHR
17Perhaps R
8With R
9Represent O together;
R
10Represent 18 α-hydrogen or 18 β-hydrogen;
N represents the number of N1,N1-Dimethylbiguanide, n=1/2,1 or 2.
Shown in the above-mentioned formula I in the compound pentacyclic triterpene or derivatives thereof of preferred compound partly comprise:
18 β-Potenlini; 18 alpha-liquorice acids; glycyrrhetinic acid; 11-deoxidation glycyrrhetinic acid; Crategolic acid (maslinic acid); Oleanolic Acid; ursolic acid; asiatic acid; corosolic acid; Betulinic acid; mould is around acid (morolic acid); δ-Oleanolic Acid; 3-O-succinyl glycyrrhetinic acid (carbenoxolone); 3-O-succinyl Oleanolic Acid; 3-O-succinyl ursolic acid; 3-O-succinyl Betulinic acid; glycyrrhetinic acid-3-O-beta d glucopyranosiduronic acid glycosides; Oleanolic Acid-3-O-beta d glucopyranosiduronic acid glycosides; ursolic acid-3-O-beta d glucopyranosiduronic acid glycosides; Betulinic acid-3-O-beta d glucopyranosiduronic acid glycosides; 3, the two succinyl trochols of 28-O-; 3-O-succinyl Oleanolic Acid-28-benzyl ester or 3-O-succinyl ursolic acid-28-benzyl ester.
More preferred compound shown in the formula I comprises:
3-O-succinyl glycyrrhetinic acid half melbine salt;
3-O-succinyl glycyrrhetinic acid list melbine salt;
18 β-Potenlini list melbine salt;
The two melbine salts of 18 β-Potenlini;
18a-Potenlini list melbine salt;
The two melbine salts of 18a-Potenlini;
Glycyrrhetinic acid half melbine salt;
Glycyrrhetinic acid list melbine salt;
Oleanolic Acid half melbine salt;
Oleanolic Acid list melbine salt;
Ursolic acid half melbine salt;
Ursolic acid list melbine salt;
Betulinic acid half melbine salt;
Betulinic acid list melbine salt;
Crategolic acid half melbine salt;
Crategolic acid list melbine salt;
Corosolic acid half melbine salt;
Corosolic acid list melbine salt;
Asiatic acid half melbine salt;
Asiatic acid list melbine salt;
Madecassic acid half melbine salt;
Madecassic acid list melbine salt;
3-O-succinyl Oleanolic Acid half melbine salt;
3-O-succinyl Oleanolic Acid list melbine salt;
3-O-succinyl ursolic acid half melbine salt;
3-O-succinyl ursolic acid list melbine salt;
3-O-succinyl Betulinic acid half melbine salt;
3-O-succinyl Betulinic acid list melbine salt;
Oleanolic Acid-3-O-beta d glucopyranosiduronic acid glycosides half melbine salt;
Oleanolic Acid-3-O-beta d glucopyranosiduronic acid glycosides list melbine salt.
Compound of the present invention can prepare with following method:
A, the pentacyclic triterpene or derivatives thereof of compound shown in general formula I part is carried out to reactant salt with the N1,N1-Dimethylbiguanide free alkali in solvent, temperature of reaction is 0 ℃ to 150 ℃, and preferred temperature is 20 ℃ to 100 ℃.The solvent that is adopted can be methyl alcohol, ethanol, acetone, Virahol, the trimethyl carbinol, propyl carbinol, ether, isopropyl ether, n-butyl ether, methyl tertiary butyl ether, water, dimethyl formamide, diethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, methylene dichloride, 1, the mixed solvent that 2-ethylene dichloride, normal butane, hexanaphthene, benzene, toluene or above-mentioned solvent are optional preferentially adopts methyl alcohol, ethanol or acetone as solvent.
B, with step a gained solution cooling crystallization, obtain the pentacyclic triterpene melbine salt shown in the formula I.
The present invention also comprises pharmaceutical preparation, and said preparation comprises as the formula I compound of promoting agent or its pharmaceutically acceptable carrier.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, is meant one or more inert, atoxic solid or liquid filler material, thinner, auxiliary agent etc., and their not reverse and active compounds or patient have an effect.
The formulation of the present composition can be a formulation commonly used on the pharmaceuticies such as tablet, capsule, pill, suppository, soft capsule, oral liquid, suspensoid, injection liquid.
Tablet for oral use and capsule contain traditional vehicle such as weighting material, thinner, lubricant, dispersion agent and tackiness agent.
The various formulations of pharmaceutical composition of the present invention can be prepared according to the method for knowing in the pharmaceutical field.
The dosage of above promoting agent will be different because of prescription.
Usually, proved favourable amount, for reaching required result, the total amount of the formula I compound of every kilogram of administration in per 24 hours is about 0.01-800mg, and preferred total amount is 0.1-100mg/kg.If necessary, with the form administration of single dose several times.
Yet, if necessary, also can depart from above-mentioned consumption, promptly this depends on experimenter's to be treated type and body weight, individual behavior to medicine, the character of disease and type and the administration time and the interval of seriousness, preparation and administration.
Be part pharmacology test and result below:
Target compound is to the influence of glucose induced hyperglycemia mice blood sugar:
Method 1:
Get 120 of regular grade Kunming mouses, male and female half and half, body weight 18-22g, adaptability was fed 2 days. mouse is divided into 12 groups at random, every group 10. segment bounds I compound is mixed with the 5mg/ml suspension with 0.5%CMC-Na solution, N1,N1-Dimethylbiguanide is mixed with the 10mg/ml suspension. gastric infusion (0.2ml/10g) behind the mouse fasting 12h, the administration group is irritated stomach fraction I compound 100mg/kg, the positive drug group is irritated stomach N1,N1-Dimethylbiguanide 200mg/kg. negative control group and model group and is irritated behind the stomach isometric(al) 0.5%CMC-Na. gastric infusion 60min that each treated animal gavages glucose solution (10% glucose solution by 2g/kg except that normal group, 0.2ml/10g), the normal group animal gavages water. and gavage glucose 30min posterior orbit and get blood, measure blood sugar by Reagent kit of glucose. data are represented with mean ± standard deviation, adopt SSPS11.0 software to carry out statistical analysis. test result (table 1) shows, the formula I compound that is tried causes to glucose that the mouse hyperglycemia model has significantly or extremely remarkable hypoglycemic activity.
Table 1, segment bounds I compound are to the influence of glucose induced hyperglycemia mice blood sugar
| ??Group | ??Dose??(mg/kg) | ??Blood?glucose??(mmol/L) |
| ??Control | ??- | ??4.89±0.68 |
| ??Model | ??- | ??7.57±0.95## |
| N1,N1-Dimethylbiguanide | ??200 | ??4.32±0.83 ** |
| 3-O-succinyl glycyrrhetinic acid list melbine salt | ??100 | ??6.36±1.27 |
| 18 β-Potenlini list melbine salt | ??100 | ??6.14±0.86 ** |
| Glycyrrhetinic acid half melbine salt | ??100 | ??6.85±1.98 |
| 3-O-succinyl Oleanolic Acid half melbine salt | ??100 | ??6.52±0.99 * |
##P＜0.01，vs?control；
*P＜0.05，
**P＜0.01?vs?Model.Data?reter?to?mean±SD，n＝9-10.
Method 2:
Mouse is divided into 4 groups at random according to body weight, 10 every group.Hungry 24 hours, the administration group was irritated stomach fraction I compound 100mg/kg,, the positive drug group is irritated stomach N1,N1-Dimethylbiguanide 200mg/kg.Medicine 0.5%CMC-Na suspendible, administration volume 0.4ml/20g.Negative control group and model group are irritated stomach isometric(al) 0.5%CMC-Na.Administration group, positive drug group and model group are irritated stomach glucose 2g/kg (0.1ml/10g) behind the 1h, and control group is irritated stomach equivalent distilled water.0.5h after get blood and survey blood sugar, adopt determination of glucose oxidase vein blood-sugar content in strict accordance with the test kit explanation.Test result (table 2) shows, the formula I compound that is tried causes to glucose that the mouse hyperglycemia model has significantly or extremely remarkable hypoglycemic activity.
Table 2, segment bounds I compound are to the influence of glucose induced hyperglycemia mice blood sugar
| ??Group | ??Dose??(mg/kg) | ??Blood?glucose??(mmol/L) |
| ??Control | ??- | ??5.97±0.89 |
| ??Model | ??- | ??9.12±1.18# |
| N1,N1-Dimethylbiguanide | ??200 | ??7.09±1.24 * |
| 3-O-succinyl glycyrrhetinic acid half melbine salt | ??100 | ??5.78±0.65 ** |
| 3-O-succinyl glycyrrhetinic acid list melbine salt | ??100 | ??6.62±0.81 ** |
| 18 β-Potenlini list melbine salt | ??100 | ??7.25±1.62 |
#p＜0.05?vs.Control；
**p＜0.01，
*p＜0.05?vs.Model
Above pharmacology data shows that segment bounds I compound of the present invention has than the better blood sugar reducing function of N1,N1-Dimethylbiguanide, therefore can be used for preparing anti-diabetic and complication medicine thereof.
Embodiment
Specify content of the present invention below by embodiment.In the present invention, the example of the following stated is in order better to set forth the present invention, is not to be used for limiting the scope of the invention.
Embodiment 1
3-O-succinyl glycyrrhetinic acid half melbine salt
With 113mg (0.88mmol, 1eq) N1,N1-Dimethylbiguanide is dissolved in the 15ml methyl alcohol, adds 500mg (0.88mmol) 3-O-succinyl glycyrrhetinic acid again, stirring at room to the dissolving.The 3h after-filtration is removed insoluble impurity, puts into the refrigerator cooling crystallization then, suction filtration, and oven dry, getting the white solid product is 3-O-succinyl glycyrrhetinic acid half melbine salt.M.p.256-258℃。
1H?NMR(DMSO-d
6，300MHz)δ0.75(s，3H)，0.82(s，6H)，1.04(s，3H)，1.06(s，6H)，1.36(s，3H)，2.34-2.47(m，4H)，2.92(s，3H)，4.40-4.45(m，1H)，5.41(s，1H)；Anal.Calcd?forC
72H
111O
14N
5·0.5H
2O：C?67.57，H?8.82，N?5.47，Found：C?67.38，H?8.78，N?5.92.
Embodiment 2
3-O-succinyl glycyrrhetinic acid list melbine salt
With 227mg (1.76mmol; 2eq) N1,N1-Dimethylbiguanide is dissolved in the 26ml methyl alcohol; slowly add 500mg (0.88mmol, 1eq) 3-O-succinyl glycyrrhetinic acid, stirring at room 1h then; be warming up to 60 ℃ of reactants dissolved; filter filtrate cooling crystallization, suction filtration; oven dry, getting the white solid product is 3-O-succinyl glycyrrhetinic acid list melbine salt.M.p.232-234℃。
1H?NMR(DMSO-d
6，300MHz)δ0.74(s，3H)，0.82(s，6H)，1.02(s，3H)，1.04(s，3H)，1.06(s，3H)，1.36(s，3H)，2.26-2.39(m，4H)，2.92(s，6H)，4.38-4.44(m，1H)，5.42(s，1H)。
Embodiment 3
18 β-Potenlini list melbine salt
(2.44mmol, 2eq) N1,N1-Dimethylbiguanide is dissolved in the 25ml methyl alcohol, slowly adds 1.02g (1.22mmol, 1eq) 18 β-Potenlini, stirring at room 1h then with 314.76mg.Be warming up to 70 ℃, reactant still can not dissolve fully, and adding methyl alcohol to total amount is 40ml, reactants dissolved.Behind the 2h, stopped reaction, with its cooling crystallization, suction filtration, oven dry, getting the white solid product is 18 β-Potenlini list melbine salt.M.P.205-206℃。
1H?NMR(DMSO-d
6+D
2O，300MHz)δ0.66(s，3H)，0.70(s，3H)，0.89(s，3H)，0.97(s，6H)，1.05(s，3H)，1.27(s，3H)，2.89(s，6H)，4.30and?4.33(d，J＝6.4Hz，each?1H)，4.50and?4.53(d，J＝7.5Hz，each?1H)，5.38(s，1H)。
Embodiment 4
Glycyrrhetinic acid half melbine salt
With 280mg (2.17mmol, 1eq) N1,N1-Dimethylbiguanide is dissolved in the 14ml methyl alcohol, slowly adds 1.02g (2.17mmol, 1eq then, 98%) glycyrrhetinic acid, behind the stirring at room 2h, stopped reaction filters, cooling crystallization, suction filtration, oven dry, getting the white solid product is glycyrrhetinic acid half melbine salt.M.P.289-291℃。
1H?NMR(DMSO-d
6，300MHz)δ0.68(s，3H)，0.75(s，3H)，0.90(s，3H)，1.02(s，3H)，1.03(s，3H)，1.09(s，3H)，1.34(s，3H)，2.98-3.03(m，1H)，3.16(s，3H)，5.40(s，1H)。
Embodiment 5
3-O-succinyl Oleanolic Acid half melbine salt
With 464mg (3.60mmol, 2eq) N1,N1-Dimethylbiguanide is dissolved in the 10ml ethanol, slowly adds 3-O-succinyl Oleanolic Acid then, 67 ℃ the reaction 2h after; stopped reaction filters cooling crystallization; suction filtration, oven dry, getting the white solid product is 3-O-succinyl Oleanolic Acid half melbine salt.M.P.232-234℃。
1H?NMR(DMSO-d
6，300MHz)δ0.72(s，3H)，0.81(s，6H)，0.88(s，6H)，0.89(s，3H)，1.11(s，3H)，2.46(m，4H)，2.93(s，3H)，4.41(m，1H)，5.16(s，1H)，6.70(s，2H)，7.17(s，1H)。
Claims (10)
1. the melbine salt of pentacyclic triterpene shown in the general formula I and derivative thereof:
In formula I, the pentacyclic triterpene or derivatives thereof exists as the anionic form of salt, and the carboxyl negative ion is provided, and N1,N1-Dimethylbiguanide exists as the cationic form of salt, and the ammonium positive ion is provided, and both are with the ionic linkage combination.
Wherein, R
1Represent hydrogen, OR
11, NHR
11, N (R
12)
2, SO
2NH
2, NHOR
11, NH
2NHR
11R
2Independent hydrogen, the OR of representing
11, NHR
11, N (R
12)
2, SO
2NH
2, NHOR
11, NH
2NHR
11Perhaps R
1With R
2Represent O or NOR together
11R
11Represent hydrogen or R
12, R
12CO; R
12Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of 1～10 carbon; X represents H, F, Cl, Br, I, CN, NO
2, NH
2, CF
3, SH, OH, OCH
3, OC
2H
5, COOH, COOCH
3, COOC
2H
5, 1～10 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl;
R
3Represent straight or branched carboxylic acid, the R of hydrogen, a 1-18 carbon
13CO, D-Glucopyranose aldehydic acid base, D-Glucopyranose aldehydic acid base-D-Glucopyranose aldehydic acid base; R
13CO represents the straight or branched carboxylic acid of 1-18 carbon;
R
4Represent hydrogen or methyl; R
5Represent hydrogen, methyl or carboxyl, and work as R
4When representing hydrogen, R
5Only represent methylidene or carboxyl; Work as R
4During represent methylidene, R
5Only represent hydrogen;
R
6Represent hydrogen or hydroxyl;
R
7Represent CH
3, CH
2OR
14, COOR
15, CONHR
14, CON (R
15)
2, NHR
14R
14Represent hydrogen or R
15CO; R
15Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl, the naphthyl non-replacement or that X replaces of 1～10 carbon; X represents H, F, Cl, Br, I, CN, NO
2, NH
2, CF
3, SH, OH, OCH
3, OC
2H
5, COOH, COOCH
3, COOC
2H
5, 1～10 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl, naphthyl;
R
8Represent hydrogen, OR
16, NHR
16, N (R
17)
2, SO
2NH
2, NHOR
16, NH
2NHR
17R
9Represent hydrogen, OR
16, NHR
16, N (R
17)
2, SO
2NH
2, NHOR
16, NH
2NHR
17Perhaps R
8With R
9Represent O together;
R
10Represent 18 α-hydrogen or 18 β-hydrogen;
N represents the number of N1,N1-Dimethylbiguanide, n=1/2,1 or 2.
2. the compound of claim 1; it is characterized in that: the pentacyclic triterpene or derivatives thereof among the formula I partly comprises 18 β-Potenlini; 18 alpha-liquorice acids; glycyrrhetinic acid; 11-deoxidation glycyrrhetinic acid; Crategolic acid (maslinic acid); Oleanolic Acid; ursolic acid; asiatic acid; Madecassic acid; corosolic acid; Betulinic acid; mould is around acid (morolic acid); δ-Oleanolic Acid; 3-O-succinyl glycyrrhetinic acid (carbenoxolone); 3-O-succinyl Oleanolic Acid; 3-O-succinyl ursolic acid; 3-O-succinyl Betulinic acid; glycyrrhetinic acid-3-O-beta d glucopyranosiduronic acid glycosides; Oleanolic Acid-3-O-beta d glucopyranosiduronic acid glycosides; ursolic acid-3-O-beta d glucopyranosiduronic acid glycosides; Betulinic acid-3-O-beta d glucopyranosiduronic acid glycosides; 3, the two succinyl trochols of 28-O-; 3-O-succinyl Oleanolic Acid-28-benzyl ester or 3-O-succinyl ursolic acid-28-benzyl ester.
3. the compound of claim 1, it is characterized in that: the preferred compound shown in the formula I comprises following pentacyclic triterpene melbine salt:
3-O-succinyl glycyrrhetinic acid half melbine salt;
3-O-succinyl glycyrrhetinic acid list melbine salt;
18 β-Potenlini list melbine salt;
The two melbine salts of 18 β-Potenlini;
18a-Potenlini list melbine salt;
The two melbine salts of 18a-Potenlini;
Glycyrrhetinic acid half melbine salt;
Glycyrrhetinic acid list melbine salt;
Oleanolic Acid half melbine salt;
Oleanolic Acid list melbine salt;
Ursolic acid half melbine salt;
Ursolic acid list melbine salt;
Betulinic acid half melbine salt;
Betulinic acid list melbine salt;
Crategolic acid half melbine salt;
Crategolic acid list melbine salt;
Corosolic acid half melbine salt;
Corosolic acid list melbine salt;
Asiatic acid half melbine salt;
Asiatic acid list melbine salt;
Madecassic acid half melbine salt;
Madecassic acid list melbine salt;
3-O-succinyl Oleanolic Acid half melbine salt;
3-O-succinyl Oleanolic Acid list melbine salt;
3-O-succinyl ursolic acid half melbine salt;
3-O-succinyl ursolic acid list melbine salt;
3-O-succinyl Betulinic acid half melbine salt;
3-O-succinyl Betulinic acid list melbine salt;
Oleanolic Acid-3-O-beta d glucopyranosiduronic acid glycosides half melbine salt;
Oleanolic Acid-3-O-beta d glucopyranosiduronic acid glycosides list melbine salt.
4. the preparation method of the compound of claim 1 may further comprise the steps:
A. the pentacyclic triterpene or derivatives thereof part with compound shown in the general formula I is carried out to reactant salt with N1,N1-Dimethylbiguanide in solvent.
B. the solution with step a gained carries out crystallization, obtains corresponding pentacyclic triterpene melbine salt.
5. the preparation method of claim 4, it is characterized in that: the solvent that salt-forming reaction is adopted can be methyl alcohol, ethanol, acetone, Virahol, the trimethyl carbinol, propyl carbinol, ether, isopropyl ether, n-butyl ether, methyl tertiary butyl ether, water, dimethyl formamide, diethylformamide, methyl-sulphoxide, tetrahydrofuran (THF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetonitrile, methylene dichloride, 1, the mixed solvent that 2-ethylene dichloride, normal butane, hexanaphthene, benzene, toluene or above-mentioned solvent are optional preferentially adopts methyl alcohol, ethanol or acetone as solvent.The temperature of salt-forming reaction is 0 ℃ to 150 ℃, and preferred temperature is 20 ℃ to 100 ℃.
6. a pharmaceutical composition wherein contains the formula I compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.
7. the compound of claim 1 is used for preventing and treat the purposes of the medicine of diabetes and complication, ischemic cardio cerebrovascular diseases, hyperlipidemia, obesity, atherosclerosis, hepatitis, fatty liver, metabolic syndrome or tumour in preparation.
8. the purposes of claim 7, it is characterized in that: diabetes are 1 type or diabetes B, and its complication comprises: diabetic nephropathy, diabetic foot, diabetic neuropathy or diabetes complicated cardiovascular and cerebrovascular diseases.
9. the purposes of claim 7, it is characterized in that: ischemic cardio cerebrovascular diseases is myocardial infarction, stenocardia, irregular pulse, coronary heart disease, cerebral ischemia, apoplexy, cerebral infarction or ischemia nerve degenerative diseases.
10. the purposes of claim 7 is characterized in that: the compound of claim 1 can be used for prevention and treatment hepatitis and fatty liver.
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