CN101337984A - Bearberry type pentacyclic triterpenes amino acid derivates, method for preparing same and pharmaceutical use thereof - Google Patents
Bearberry type pentacyclic triterpenes amino acid derivates, method for preparing same and pharmaceutical use thereof Download PDFInfo
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Abstract
The invention relates to the field of natural drug and medicinal chemistry, in particular to ursane-type pentacyclic triterpenoid amino acid derivatives (I), and the preparation method and the medicinal application thereof. The compounds have effect on inhibiting glycogen phosphorylase, and can be used for preparing drugs for resisting diabetes, cerebral ischemia, cardiovascular diseases, hyperlipemia, obesity, atherosclerosis and tumor. The invention also relates to the preparation method of the compounds and drug preparations containing the compounds.
Description
Technical field
The present invention relates to natural drug and pharmaceutical chemistry field, be specifically related to the novel black bearberry alkane type pentacyclic triterpene derivative of a class.This compounds 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, treatment metabolic syndrome medicine or antitumor drug.The drug regimen that the invention still further relates to the synthetic method of this compounds and contain them.
Background technology
Black bearberry alkane type pentacyclic triterpene compound is widely distributed in vegitabilia, corosolic acid (1) and asiatic acid (2) are wherein representational compounds, have multiple pharmacologically actives such as anti-hepatitis, antitumor, antiviral, hypoglycemic and reducing blood-fat, and toxicity is low, side effect is little, has important exploitation value and application prospects.
Aspect hypoglycemic, bibliographical information, corosolic acid be by the transhipment of excited glucose, promotes absorption and the utilization of cell to glucose, thus realize its effect of lowering blood sugar (Chem.Pharm.Bull., 1993,41,2129-2131).Patent W02006054370 discloses corosolic acid and analogue asiatic acid thereof as a kind of glyconeogenesis inhibitor, not only can lowering blood glucose, can also bring high blood pressure down simultaneously, and blood fat reduces arteriosclerosis and fat probability of occurrence.Korea S scholar's research proof corosolic acid has certain inhibition activity to protein-tyrosine-phosphatase 1B (PTP1B), can be used for treating diabetes B (Planta Med.2006,72,261-263).Contriver's Chinese patent application (CN 1682740A) in advance discloses corosolic acid and asiatic acid and has had the effect that suppresses glycogen phosphorylase, thereby can be used for hypoglycemic, reducing blood-fat, ischemia resisting cardiovascular and cerebrovascular diseases and antitumor etc.At present, existing glycogen phosphorylase inhibitors enters the clinical study stage and is used for the treatment of diabetes and complication thereof, but still has the related drugs listing that do not go through.
The ischemia heart, brain injury are the important pathological factors that causes coronary heart disease, stenocardia, myocardial infarction, irregular pulse, cerebral infarction, apoplexy and ischemia nerve degenerative diseases.At present, the medicine that does not still have the damage of effectively preventing ischemia heart and brain clinically.Under normal circumstances, the heart, brain mainly rely on aerobic metabolism and come supplying energy.But, under severe ischemic (anoxic) situation, the anaerobic carbohydrate metabolism becomes important energy supply channel, at this moment, the glycogen phosphorylase height is active, and the degraded of glycogen aggravates, and produces a large amount of lactic acid through anaerobic glycolysis, cause lactic acidosis (lactic acidosis), and then cause the ischemia heart, brain injury.Therefore, suppress glycogen phosphorylase (under the insufficient situation of ischemic, anoxic and glucose supplies by part, the glycogen degraded energy supply of appropriateness is essential), can avoid because of glycogen excessive degradation and the lactic acidosis that anaerobic glycolysis caused subsequently, thereby be expected to become effective new way (Am.J.Physiol.Heart Circ.Physiol.2004 of the ischemia resisting heart, cerebrovascular disease, 286, H1177-H1184; Nat.Neurosci.2007,10,1377-1386).Especially significant is, glycogen phosphorylase becomes an important biochemical indicator that is used for diagnosis of myocardial ischemia clinically gradually.Cui Fugui is pointed out in patent documentation (CN 1582946), asiatic acid can obviously reduce the myocardial infarction district quality that the ligation coronary artery causes, the biochemical metabolism index LDH and the CK of reflecting myocardium infringement are obviously descended, and prompting can be used to centella asiatica glucoside to prepare anti-coronary heart disease, myocardial infarction and cerebral thrombosis, the cerebral infarction cardiovascular and cerebrovascular diseases of waiting indefinitely.
Aspect oncotherapy, bibliographical information, corosolic acid is to the ED of A549, SK-OV-3, SK-MEL-3, XF498 and five kinds of tumour cells of HCT15
50Between 3.9～5.5 μ g/mL (Planta Med., 2000,66,485-486).Asiatic acid can be induced the apoptosis (Cancer Lett., 2005,218,81) of human melanoma cell SK-MEL-2.
Black bearberry alkane type pentacyclic triterpene compound has the characteristics of many target spots, multipath performance drug effect in vivo as the main active ingredient of Chinese traditional Chinese medicine.Wherein corosolic acid and asiatic acid produce pharmacologically active widely by the coordinative role to a plurality of target spots just, therefore not only can be used for treating diabetes and complication thereof, ischemic cardio cerebrovascular diseases, also can be applicable to reducing blood-fat, fat-reducing, atherosclerosis, treatment metabolic syndrome and anti-tumor aspect.
But, the water-soluble extreme difference of corosolic acid and asiatic acid, the bioavailability of its preparation is low, has limited its application clinically greatly.It is water-soluble in order to improve, increase route of administration and improve medicine bioavailability in vivo, according to principle of pro-drug, corosolic acid and asiatic acid have been carried out structural modification, and introducing amino acid is chemical modification object, makes it become the water-soluble prodrug that improves greatly.
Summary of the invention
The present invention discloses novel black bearberry alkane type pentacyclic triterpene derivative, its preparation method and the medicinal use with pharmaceutical use shown in the formula (I) first, is included in the purposes of preparation anti-diabetic and complication medicine, anti-cerebral ischemia drugs, anti-cardiovascular disease, blood lipid-lowering medicine, slimming medicine, Antiatherosclerosis medicine, treatment metabolic syndrome medicine and antitumor drug aspect.Especially the compound shown in the formula (I) has glycogen phosphorylase inhibitory activity, therefore can be used for the treatment of and the unusual relevant disease of Glycogen Metabolism, these diseases comprise: diabetes (particularly diabetes B) and complication thereof, ischemic cardio cerebrovascular diseases (particularly myocardial infarction, stenocardia, irregular pulse, coronary heart disease, apoplexy, cerebral infarction or ischemia nerve degenerative diseases etc.), hyperinsulinemia, insulin resistant, metabolism syndrome, obesity, fasting hyperglycemia and tumour.
In addition, the present invention also provides the pharmaceutical preparation of compound shown in a kind of containing (I).
The present invention relates to the compound shown in the formula (I) and pharmacy acceptable salt or ester:
Wherein:
R
1Represent H or R
5CO;
R
2Represent H or R
5CO;
R
3Represent H, OH or R
5COO;
R
4Amino acid or amino acid ester (the D-type amino acid that comprises naturally occurring all amino acid and synthetic) that representative replaces;
R
5Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl or the naphthyl non-replacement or that X replaces of 1～20 carbon; X represents H, F, Cl, Br, I, CN, NO
2, NH
2, CF
3, SH, OH, OCH
3, OC
2H
5, COOH, 1～10 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl.
Preferred compound is characterised in that in the above-claimed cpd:
R
1Represent H or CH
3CO;
R
2Represent H or CH
3CO;
R
3Represent H, OH or CH
3COO;
R
4Amino acid or amino acid ester (the D-type amino acid that comprises naturally occurring all amino acid and synthetic) that representative replaces.
More preferred compound is:
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-glycine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-L-Ala;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Xie Ansuan;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Serine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-proline(Pro);
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-leucine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-methionine(Met);
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-tyrosine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserins;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-L-glutamic acid;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-glycine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-L-Ala;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-Xie Ansuan;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-Serine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-proline(Pro);
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-leucine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-methionine(Met);
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-tyrosine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserins;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-L-glutamic acid;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-glycine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-alanine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-valine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-serine methylester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-proline methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-leucine methyl esters;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine methyl esters;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-methyl methionine;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-L-Tyrosine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserin dimethyl esters;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-glutamic acid dimethyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides) glycine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-alanine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-valine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-serine methylester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-proline methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-leucine methyl esters;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine methyl esters;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-methyl methionine;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-L-Tyrosine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserin dimethyl esters;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-glutamic acid dimethyl ester.
Part derivative of the present invention can prepare with following method:
A. according to the hydroxy esterification method of routine,, obtain the corosolic acid or the asiatic acid derivative of hydroxyl protection with section's sieve institute rope acid or asiatic acid and various acyl chlorides, acid anhydrides or carboxylic acid reaction;
B. a product is dissolved in the organic solvent, adds sulfur oxychloride or oxalyl chloride, reacted 1-24 hour, temperature is 0 ℃ to 120 ℃.The solvent that is adopted can be a methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent preferentially adopts methylene dichloride, 1, and 2-ethylene dichloride or toluene are as solvent;
C. amino acid ester or amino acid ester hydrochloride are mixed in organic solvent with organic amine or mineral alkali, add the b product, reacted 1-48 hour, temperature is 0 ℃ and extremely refluxes, obtains the corosolic acid or the asiatic acid-28-amidoamino acid ester of hydroxyl protection.The organic amine that is adopted is triethylamine, pyridine or 4-Dimethylamino pyridine.The mineral alkali that is adopted is yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus.The solvent that is adopted can be a methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent preferentially adopts methylene dichloride, 1, and 2-ethylene dichloride or toluene are as solvent;
D. the c product is dissolved in the organic solvent, adds the alkaline solution reaction that is hydrolyzed, temperature be 0 ℃ to backflow, obtain corosolic acid or asiatic acid-28-amidoamino acid derivative.The solvent that is adopted can be methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent preferentially adopts methyl alcohol or tetrahydrofuran (THF) as solvent.The alkali that is adopted is sodium hydroxide, potassium hydroxide or lithium hydroxide.
The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I) compound or pharmaceutically acceptable salt thereof, ester or the pharmaceutically acceptable carrier as promoting agent.
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 formula (1) 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.
Description of drawings
Fig. 1 is the preparation process of expression part asiatic acid amino acid derivative of the present invention.
Fig. 2 is the preparation process of expression part corosolic acid amino acid derivative of the present invention.
In Fig. 1 and Fig. 2, R
5Such as in the above-mentioned formula (I) definition; NH
2CHR
7COOR
6Represent various amino acid esters, comprise the D-type amino acid of naturally occurring all amino acid or synthetic, wherein, R
6Represent alkyl or the benzyl of 1-5 C, R
7The different substituents of represented amino acid.
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.
Target compound is for the inhibition activity test of glycogen phosphorylase:
The preparation of reagent: the 1) preparation of colour developing liquid: weighing ammonium molybdate 5g, be dissolved among the 500ml 1M HCl, stir with agitator, to all dissolving the back, continue to be stirred to whole dissolvings, and use the masking foil lucifuge adding Victoria Green WPB 190mg; 2) preparation of damping fluid: 1. precision weighing Hepes 0.5958g is dissolved in 5ml H
2Among the O, transfer PH to 7.2, be mixed with the Hepes that final concentration is 0.5M with 10M NaOH; 2. precision weighing KCl 0.3728g is dissolved in 5ml H
2Among the O, be mixed with the KCl that final concentration is 1M; 3. precision weighing MgCl
20.0255g, be dissolved in 1ml H
2Among the O, be mixed with the MgCl that final concentration is 125mM
24. precision weighing EGTA 0.0476g is dissolved in 5ml H
2Among the O, transfer PH to 7.0, be mixed with the EGTA that final concentration is 25mM with 10M NaOH; 5. precision weighing G-1-P 0.0152g is dissolved in 10ml H
2Among the O, be mixed with the G-1-P that final concentration is 5mM; 6. precision weighing glycogen 10mg is dissolved in 1ml H
2Among the O, be mixed with the glycogen that final concentration is 10mg/ml; 3) preparation of positive drug caffeine solution: caffeine is dissolved in 10ml H
2The solution of O preparation 0.5,5,50 and 500 μ M; 4) preparation GPa solution: the GPa that gets 1 μ l joins in the 100 μ l reaction systems, and final concentration is 250ng/100 μ l; 5) preparation of compound solution to be tested: compound to be tested is dissolved in DMSO, and to be mixed with concentration be 10mM solution, gets an amount of compound solution and join in the reaction system to different final concentrations.
Measure the active amount effect curve of rabbit muscle glycogen Starch phosphorylase:, measure its amount effect curve by the OD value under 655nm behind the GPa adding colour developing liquid that reads different concns.Can select the amount of GPa by amount effect curve is 250ng.
Experimental procedure: 1) design PC (positive control), Blank (blank), positive drug (caffeine); 2) add reaction buffer52 μ l; 3) add test compounds to final concentration; 4) enzyme-added 1 μ l, final concentration is 250ng/100 μ l; 5) add colour developing liquid 150 μ l; 6) reacted 20 minutes under 20～25 degrees celsius; 7) colorimetric under wavelength 655nm condition; 8) reading and the calculating of inhibiting rate of data: inhibiting rate=[positive control-testing sample]/[positive control-blank].
Test result: listed the inhibition activity data of part derivative to rabbit muscle glycogen Starch phosphorylase in the table, the result shows, corosolic acid or asiatic acid-28-amidoamino acid derivative has in various degree inhibition activity to glycogen phosphorylase.
Corosolic acid or asiatic acid amino acid derivative are to the inhibition activity of rabbit muscle glycogen Starch phosphorylase
aIC
50Value is the mean value of three experiments;
bNI is illustrated under the 100 μ M concentration does not have activity.
Above pharmacology data shows, general formula of the present invention (I) compound has the restraining effect of glycogen phosphorylase, therefore can be used for preparing antidiabetic medicine, anti-cerebral ischemia drugs, anti-cardiovascular disease, blood lipid-lowering medicine, slimming medicine, Antiatherosclerosis medicine or antitumor drug.
Further specify enforcement of the present invention by the following examples
Embodiment 1
2a, 3 β, 23-triacetyl oxygen base asiatic acid synthetic
With asiatic acid (0.20g, 0.40mmol), (76mg 0.74mmol) adds in the pyridine (10ml) stirred overnight at room temperature to diacetyl oxide.After reaction solution dilutes with ethyl acetate; successively with water, 1N dilute hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing; organic phase drying, filtration, concentrated; rapid column chromatography (petrol ether/ethyl acetate: 10/1V/V); get 2a; 3 β, 23-O-triacetyl asiatic acid (170mg, 78%).M.p.93-95℃。
ESI-MSm/z：637[M+Na]
+.
1H-NMR(CDCl
3，300MHz)：0.78，0.85，0.88，0.94，1.07，1.11(each?3H，s)，1.98，2.02，2.08(each?3H，s)，2.19(1H，d，J＝11.3Hz)，3.58(1H，d，J＝11.8Hz)，3.85(1H，d，J＝11.8Hz)，5.07(1H，d，J＝10.3Hz)，5.12-5.17(1H，m)，5.25(1H，t).
Embodiment 2
Synthesizing of N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-glycine methyl ester
With 2a, 3 β, 23-triacetyl oxygen base asiatic acid (0.25g, 0.40mmol) be dissolved in refining exsiccant methylene dichloride (among the 20ml, ice bath drips oxalyl chloride (0.8ml) down, and stirring at room 24 hours removes methylene dichloride under reduced pressure, add refining exsiccant methylene dichloride (20 * 3) again, dissolving, steaming removes, and obtains 2a, 3 β, 23-triacetyl oxygen base Herba Centellae acyl chlorides.With glycine methyl ester hydrochloride (0.15g; 1.20mmol) and DMAP (0.03g; 0.22mmol) be dissolved in the exsiccant methylene dichloride; drip the dichloromethane solution of the triacetyl eliminate indigestion snow oxalyl chloride of above-mentioned prepared fresh; drip and finish; stirring at room 12 hours; reaction solution uses 1N aqueous hydrochloric acid, saturated common salt water washing successively; organic layer drying, filtration, concentrated; rapid column chromatography (petrol ether/ethyl acetate: 4/1V/V), get N-(2a, 3 β; 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-glycine methyl ester (244mg, 87%).M.p.175-178℃。
ESI-MS?m/z：686.4[M+H]
+.
1H-NMR(CDCl
3，300MHz)
0.73，0.87，0.89，0.96(each?3H，s)，1.10(6H，s)，1.98，2.02，2.08(each?3H，s)，3.58(1H，d，J＝11.8Hz)，3.76(3H，s)，3.81-3.88(2H，m)，4.05-4.13(1H，m)，5.12-5.21(2H，m)，5.43(1H，t)，6.85(1H，t).
Embodiment 3
Synthesizing of N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-alanine methyl ester
With reference to the method for embodiment 2, with 2a, 3 β, 23-triacetyl oxygen base asiatic acid and L-alanine methyl ester hydrochloride make N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-alanine methyl ester.M.p.220-222℃。
ESI-MS?m/z：700.5[M+H]
+.
1H-NMR(CDCl
3，300MHz)：0.70(3H，s)，0.88(6H，s)，0.96(3H，s)，1.09(9H，s)，1.98，2.02，2.08(each?3H，s)，3.57(1H，d，J＝11.8Hz)，3.75(3H，s)，3.84(1H，d，J＝11.8Hz)，4.45-4.49(1H，m)，5.07(1H，d，J＝10.3Hz)，5.12-5.17(1H，m)，5.40(1H，t)，6.57(1H，d，J＝5.9Hz).
Embodiment 4
Synthesizing of N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-valine methyl ester
With reference to the method for embodiment 2, with 2a, 3 β, 23-triacetyl oxygen base asiatic acid and L-valine methyl ester hydrochloride make N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-valine methyl ester.M.p.205-208℃。
ESI-MS?m/z：728.5[M+H]
+.
1H-NMR(CDCl
3，300MHz)：0.68(3H，s)，0.88-0.97(15H，m)，1.09(6H，s)，1.98，2.02，2.08(each3H，s)，3.57(1H，d，J＝11.8Hz)，3.70(3H，s)，3.84(1H，d，J＝11.8Hz)，4.42-4.46(1H，m)，5.07(1H，d，J＝10.3Hz)，5.11-5.19(1H，m)，5.38(1H，t)，6.36(1H，d，J＝7.4Hz).
Embodiment 5
Synthesizing of N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester
With reference to the method for embodiment 2, with 2a, 3 β, 23-triacetyl oxygen base asiatic acid and L-phenylalanine methyl ester hydrochloride make N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester.M.p.120-124℃。
ESI-MS?m/z：776.4[M+H]
+.
1H-NMR(CDCl
3，300MHz)
0.60，0.83，0.88，0.94，1.05，1.06(each?3H，s)，1.97，2.02，2.08(each3H，s)，3.00-3.17(2H，m)，3.56(1H，d，J＝11.7Hz)，3.68(3H，s)，3.84(1H，d，J＝12.0Hz)，4.71(1H，dd，J＝6.0，12.0Hz)，5.06(1H，d，J＝10.2Hz)，5.10-5.19(1H，m)，5.25(1H，t)，6.34(1H，d，J＝6.0Hz)，7.08-7.31(5H，m).
Embodiment 6
Synthesizing of N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-serine methylester
With reference to the method for embodiment 2, with 2a, 3 β, 23-triacetyl oxygen base asiatic acid and L-serine methyl ester hydrochloride make N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-serine methylester.M.p.217-219℃。
ESI-MS?m/z：716.5[M+H]
+.
1H-NMR(CDCl
3，300MHz)
0.70，0.88，0.88，0.97，1.09，1.10(each?3H，s)，1.98，2.02，2.08(each3H，s)，2.26(1H，d，J＝17.1Hz)，3.57(1H，d，J＝11.8Hz)，3.79(3H，s)，3.82-3.86(2H，m)，3.94-3.99(1H，m)，4.52-4.53(1H，m)，5.07(1H，d，J＝10.3Hz)，5.12-5.16(1H，m)，5.43(1H，t)，6.85(1H，d，J＝5.1Hz).
Embodiment 7
2a, 3 β-diacetoxy corosolic acid synthetic
With reference to the method for embodiment 1, make 2a with corosolic acid and diacetyl oxide, 3 β-diacetoxy asiatic acid.M.p.225-227℃。
ESI-MS?m/z：555.3[M-H]
-.
1H-NMR(CDCl
3，300MHz)：0.76，0.89，0.90(each?3H，s)，1.07(6H，s)，0.85(3H，d，J＝6.5Hz)，0.95(3H，d，J＝6.3Hz)，1.97(3H，s)，2.05(3H，s)，2.19(1H，d，J＝11.2Hz)，4.76(1H，d，J＝10.3Hz)，5.10(1H，m)，5.23(1H，t，J＝3.6Hz).
Embodiment 8
Synthesizing of N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-leucine methyl esters
With reference to the method for embodiment 2, with 2a, 3 β-diacetoxy corosolic acid and L-leucine methyl ester hydrochloride make N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-leucine methyl esters.M.p.133-135℃。
ESI-MS?m/z：684.4[M+H]
+.
1H?NMR(CDCl
3，300MHz)：0.68(3H，s)，0.86(3H，s)，0.89(6H，s)，0.91(3H，s)，0.93(3H，s)，0.95(3H，s)，1.05(3H，s)，1.08(3H，s)，1.97，2.04(each?3H，s)，3.69(3H，s)，4.55(1H，m)，4.74(1H，d，J＝10.3Hz)，5.04-5.12(1H，m)，5.36(1H，t)，6.33(1H，d，J＝7.08Hz).
Embodiment 9
Synthesizing of N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-methyl methionine
With reference to the method for embodiment 2, with 2a, 3 β-diacetoxy corosolic acid and L-hydrochloride methyl methionine make N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-methyl methionine.M.p.130-133℃。
ESI-MS?m/z：702.4[M+H]
+.
1H?NMR(CDCl
3，300MHz)：0.67(3H，s)，0.89(6H，d，J＝6.90Hz)，0.90(3H，s)，0.96(3H，s)，1.05(3H，s)，1.08(3H，s)，1.97，2.05(each?3H，s)，3.73(3H，s)，4.58(1H，dd，J＝5.91，11.82Hz)，4.74(1H，d，J＝10.34Hz)，5.04-5.12(1H，m)，5.40(1H，t)，6.60(1H，d，J＝6.22Hz).
Embodiment 10
Synthesizing of N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester
With reference to the method for embodiment 2, with 2a, 3 β-diacetoxy corosolic acid and L-phenylalanine methyl ester hydrochloride make N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester.M.p.128-132℃。
ESI-MS?m/z：718.3[M+H]
+.
1H?NMR(CDCl
3，300MHz)：0.60(3H，s)，0.82(3H，d，J＝6.29Hz)，0.89(6H，s)，0.94(3H，s)，1.02(3H，s)，1.05(3H，s)，1.96，2.04(each?3H，s)，3.05-3.12(2H，m)，3.67(3H，s)，4.70-4.75(2H，m)，5.03-5.12(1H，m)，5.24(1H，t)，6.35(1H，d，J＝6.18Hz)，7.08-7.11(2H，m)，7.25-7.28(3H，m).
Embodiment 11
Synthesizing of N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-L-Tyrosine methyl ester
With reference to the method for embodiment 2, with 2a, 3 β-diacetoxy corosolic acid and L-tyrosine methyl ester hydrochloride make N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-L-Tyrosine methyl ester.M.p.160-164℃。
ESI-MS?m/z：734.4[M+H]
+.
1H?NMR(CDCl
3，300MHz)：0.61(3H，s)，0.83(3H，d，J＝6.35Hz)，0.89(6H，s)，0.94(3H，s)，1.02(3H，s)，1.05(3H，s)，1.97，2.05(each?3H，s)，2.91-3.09(2H，m)，3.67(3H，s)，4.66-4.76(2H，m)，5.05-5.09(1H，m)，5.26(1H，t)，5.82(1H，br?s)，6.41(1H，d，J＝6.40Hz)，6.73(2H，dd，J＝8.41，63.74Hz)，6.95(2H，dd，J＝8.42，63.74Hz).
Embodiment 12
Synthesizing of N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-glycine
With N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-glycine methyl ester (152mg, 0.22mmol) be dissolved in the mixed solvent of methyl alcohol (3mL) and tetrahydrofuran (THF) (4.5mL), the adding aqueous sodium hydroxide solution (1.1ml, 4N), stirring at room 3 hours.Reaction solution dilutes with ethyl acetate, and with 1N dilute hydrochloric acid adjusting pH value, the mixture that obtains is successively with water, saturated common salt water washing, organic layer drying, filtration, concentrated, column chromatography (methylene chloride: 10/1 V/V), get N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-glycine (107mg, 89%).M.p.269℃(dec.)。
ESI-MS?m/z：544.3[M-H]
-.
1H-NMR(d
6-DMSO+D
2O，300MHz)：0.55，0.65，0.84，0.92，0.92，1.04(each?3H，s)，2.09(1H，d，J＝10.7Hz)，3.06(1H，d，J＝10.6Hz)，3.18(1H，d，J＝9.5Hz)，3.30(1H，d，J＝10.9Hz)，3.49-3.53(1H，m)，3.59(1H，d，J＝17.3Hz)，3.74(1H，d，J＝17.5Hz)，5.24(1H，t).
Embodiment 13
Synthesizing of N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-L-Ala
With reference to the method for embodiment 12, be that raw material makes N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-L-Ala with N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-alanine methyl ester.M.p.226-230℃。
ESI-MS?m/z：558.3[M-H]
-.
1H-NMR(d
6-DMSO+D
2O，300MHz)：0.51，0.62，0.80，0.88，0.88，1.00，1.19(each?3H，s)，2.04(1H，d，J＝10.5Hz)，3.02(1H，d，J＝10.5Hz)，3.13(1H，d，J＝9.1Hz)，3.26(1H，d，J＝10.7Hz)，3.48(1H，t)，4.06(1H，d，J＝6.3Hz)，5.20(1H，brs).
Embodiment 14
Synthesizing of N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Xie Ansuan
With reference to the method for embodiment 12, be that raw material makes N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Xie Ansuan with N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-valine methyl ester.M.p.214-218℃。
ESI-MS?m/z：588.3[M+H]
+.
1H-NMR(d
6-DMSO+D
2O，300MHz
0.54，0.63，0.83，0.86，0.87，0.91，0.91，1.04(each?3H，s)，2.09(1H，d，J＝10.5Hz)，3.03(1H，d，J＝10.5Hz)，3.16(1H，d，J＝9.3Hz)，3.29(2H，d，J＝10.5Hz)，4.00(1H，t)，5.20(1H，brs)，6.90(1H，d，J＝7.5Hz).
Embodiment 15
Synthesizing of N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine
With reference to the method for embodiment 12, be that raw material makes N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine with N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester.M.p.210-214℃。
ESI-MS?m/z：636.3[M+H]
+.
1H-NMR(d
6-DMSO+D
2O，300MHz)
0.52，0.76，0.78，0.83，0.87，0.94(each?3H，s)，2.88-2.91(1H，m)，2.92-2.96(2H，m)，3.13(1H，d，J＝9.3Hz)，3.27(1H，d，J＝10.2Hz)，4.16(1H，brs)，5.01(1H，t)，7.20(5H，s).
Embodiment 16
Synthesizing of N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Serine
With reference to the method for embodiment 12, be that raw material makes N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Serine with N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-serine methylester.M.p.224-227℃。
ESI-MS?m/z：574.2[M-H]
-.
1H-NMR(d
6-DMSO+D
2O，300MHz)：0.50，0.60，0.79，0.86，0.87，1.00(each?3H，s)，2.99(1H，d，J＝10.6Hz)，3.11(1H，d，J＝9.3Hz)，3.24(1H，d，J＝11.0Hz)，3.45-3.54(2H，m)，4.10-4.11(1H，m)，5.21(1H，br?s)，6.96(1H，d，J＝6.1Hz).
Embodiment 17
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-is leucic synthetic
With reference to the method for embodiment 12, be that raw material makes N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-leucine with N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-leucine methyl esters.M.p.156-160℃。
ESI-MS?m/z：584.4[M-H]
-.
1H-NMR(d
6-DMSO+D
2O，300MHz)：0.53，0.64，0.75，0.77，0.82，0.84，0.85，0.860.97(each?3H，s)，2.06(1H，d，J＝16.14Hz)，2.72(1H，d)，3.39-3.40(1H，m)，4.07-4.15(1H，m)，5.14(1H，t)，7.12(1H，d，J＝7.08Hz).
Embodiment 18
Synthesizing of N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine
With reference to the method for embodiment 12, be that raw material makes N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine with N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester.M.p.180℃(dec.)。
ESI-MS?m/z：642.6[M-H]
-.
1H-NMR(CD
3OD，300MHz)：0.69(3H，s)，0.80(3H，s)，0.85(3H，d，J＝6.46Hz)，0.94(3H，d，J＝6.23Hz)，0.97(3H，s)，1.00(3H，s)，1.09(3H，s)，2.90(1H，d，J＝9.60Hz)，3.07-3.28(2H，m)，3.56-3.61(1H，m)，4.23(1H，dd，J＝4.51，5.61Hz)，5.34(1H，t)，7.13-7.18(5H，m).
Embodiment 19
Synthesizing of N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-tyrosine
With reference to the method for embodiment 12, be that raw material makes N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-tyrosine with N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-L-Tyrosine methyl ester.M.p.182℃(dec.)。
ESI-MS?m/z：634.4[M-H]
-.
1H-NMR(CD
3OD，300MHz)：0.57(3H，s)，0.79(3H，s)，0.85(3H，d，J＝6.32Hz)，0.94(3H，s)，0.97(3H，s)，0.99(3H，s)，1.07(3H，s)，2.87(1H，d，J＝9.57Hz)，2.93-2.97(1H，m)，3.07-3.14(1H，m)，3.53-3.64(1H，m)，4.30(1H，brs)，5.27(1H，t)，6.64(2H，d，J＝7.61Hz)，6.99(2H，d，J＝8.27Hz).
Claims (10)
1. following general formula (I) compound and pharmacy acceptable salt or ester:
R
1Represent H or R
5CO;
R
2Represent H or R
5CO;
R
3Represent H, OH or R
5COO;
R
4Amino acid or amino acid ester (the D-type amino acid that comprises naturally occurring all amino acid and synthetic) that representative replaces;
R
5Represent straight or branched alkane, alkene, alkynes, phenyl, benzyl or the naphthyl non-replacement or that X replaces of 1～20 carbon; X represents H, F, Cl, Br, I, CN, N0
2, NH
2, CF
3, SH, OH, OCH
3, OC
2H
5, COOH, 1～10 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl.
2. the compound of claim 1 and pharmacy acceptable salt thereof or ester is characterized in that:
R
1Represent H or CH
3CO;
R
2Represent H or CH
3CO;
R
3Represent H, OH or CH
3COO;
R
4Amino acid or amino acid ester (the D-type amino acid that comprises naturally occurring all amino acid and synthetic) that representative replaces.
3. the compound of claim 1, wherein compound can be following arbitrary compound and medicinal salt or ester thereof:
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-glycine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-L-Ala;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Xie Ansuan;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Serine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-proline(Pro);
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-leucine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-methionine(Met);
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-tyrosine;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserins;
N-(2a, 3 β, 23-trihydroxy-black bearberry alkane-12-alkene-28-acid amides)-L-L-glutamic acid;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-glycine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-L-Ala;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-Xie Ansuan;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-Serine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-proline(Pro);
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-leucine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-methionine(Met);
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-tyrosine;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserins;
N-(2a, 3 beta-dihydroxyl black bearberry alkane-12-alkene-28-acid amides)-L-L-glutamic acid;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-glycine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-alanine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-valine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-serine methylester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-proline methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-leucine methyl esters;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine methyl esters;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-methyl methionine;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-L-Tyrosine methyl ester;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserin dimethyl esters;
N-(2a, 3 β, 23-triacetyl oxygen base black bearberry alkane-12-alkene-28-acid amides)-L-glutamic acid dimethyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides) glycine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-alanine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-valine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-phenylalanine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-serine methylester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-proline methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-leucine methyl esters;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-Isoleucine methyl esters;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-methyl methionine;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-L-Tyrosine methyl ester;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-days east propylhomoserin dimethyl esters;
N-(2a, 3 β-diacetoxy black bearberry alkane-12-alkene-28-acid amides)-L-glutamic acid dimethyl ester.
4. the preparation method of claim 1,2,3 compound comprises:
A. according to the hydroxy esterification method of routine,, obtain the corosolic acid or the asiatic acid derivative of hydroxyl protection with section's sieve institute rope acid or asiatic acid and various acyl chlorides, acid anhydrides or carboxylic acid reaction;
B. a product is dissolved in the organic solvent, adds sulfur oxychloride or oxalyl chloride, reacted 1-24 hour, temperature is 0 ℃ to 120 ℃.The solvent that is adopted can be a methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent preferentially adopts methylene dichloride, 1, and 2-ethylene dichloride or toluene are as solvent;
C. amino acid ester or amino acid ester hydrochloride are mixed in organic solvent with organic amine or mineral alkali, add the b product, reacted 1-48 hour, temperature is 0 ℃ and extremely refluxes, obtains the corosolic acid or the asiatic acid-28-amidoamino acid ester of hydroxyl protection.The organic amine that is adopted is triethylamine, pyridine or 4-Dimethylamino pyridine.The mineral alkali that is adopted is yellow soda ash, sodium bicarbonate, salt of wormwood or saleratus.The solvent that is adopted can be a methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, tetrahydrofuran (THF), t-butyl methyl ether or above-mentioned solvent preferentially adopts methylene dichloride, 1, and 2-ethylene dichloride or toluene are as solvent;
D. the c product is dissolved in the organic solvent, adds the alkaline solution reaction that is hydrolyzed, temperature be 0 ℃ to backflow, obtain corosolic acid or asiatic acid-28-amidoamino acid derivative.The solvent that is adopted can be methyl alcohol, tetrahydrofuran (THF), methylene dichloride, 1, and the mixed solvent of 2-ethylene dichloride, chloroform, toluene, normal hexane, hexanaphthene, t-butyl methyl ether or above-mentioned solvent preferentially adopts methyl alcohol or tetrahydrofuran (THF) as solvent.The alkali that is adopted is sodium hydroxide, potassium hydroxide or lithium hydroxide.
5. a pharmaceutical composition wherein contains formula (I) compound and the pharmaceutically acceptable carrier for the treatment of significant quantity.
6. the compound of claim 1 to 3, it is characterized in that: these compounds are novel glycogen phosphorylase inhibitors.
7. the compound of claim 1 to 3 is used for preventing and treat the purposes of the medicine of diabetes and complication, ischemic cardio cerebrovascular diseases, hyperlipidemia, obesity, atherosclerosis, metabolism syndrome or tumour in preparation.
8. the purposes of claim 7, it is characterized in that: diabetes are diabetes Bs, 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 to 3 can be used for prevention and treatment hyperlipidemia and atherosclerosis.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN102389437A (en) * | 2011-06-24 | 2012-03-28 | 中国人民解放军第二军医大学 | Application of Centella triterpenes in preparing products for improving cerebral apoplexy sequelae |
| WO2016086453A1 (en) * | 2014-12-04 | 2016-06-09 | 中国药科大学 | Pentacyclic triterpenoid cholesterol ester transfer protein inhibitor, pharmaceutical composition and medical use thereof |
| CN105017374A (en) * | 2015-07-20 | 2015-11-04 | 山西大学 | Oleanonic acid lactone derivative and its preparation method and use |
| CN110105561A (en) * | 2016-06-22 | 2019-08-09 | 中国药科大学 | A kind of tanshinone IIA high-molecular compound and its preparation and application |
| CN109517022B (en) * | 2017-09-18 | 2022-09-13 | 中国科学院上海药物研究所 | Pentacyclic triterpenoid and preparation method, pharmaceutical composition and application thereof |
| CN109517022A (en) * | 2017-09-18 | 2019-03-26 | 中国科学院上海药物研究所 | Pentacyclic triterpenoid and preparation method thereof, pharmaceutical composition and purposes |
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| EP3686212A4 (en) * | 2017-09-18 | 2021-06-09 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences | Pentacyclic triterpene compound and preparation method therefor, and pharmaceutical composition and use thereof |
| CN109232708A (en) * | 2018-10-24 | 2019-01-18 | 江西农业大学 | Water-soluble hawthorn acid derivative and its preparation method and application |
| CN109517025A (en) * | 2019-01-10 | 2019-03-26 | 广西师范大学 | 28- (L-phenylalanine)-pentacyclic triterpene derivative and its synthetic method and application |
| CN109517025B (en) * | 2019-01-10 | 2021-08-03 | 广西师范大学 | 28- (L-phenylalanine) -pentacyclic triterpene derivative and synthesis method and application thereof |
| CN109517026B (en) * | 2019-01-10 | 2021-08-31 | 广西师范大学 | L-phenylalanine modified maslinic acid and synthetic method and application thereof |
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| CN109517026A (en) * | 2019-01-10 | 2019-03-26 | 广西师范大学 | The hawthorn acid and its synthetic method of L-phenylalanine modification and application |
| CN109503697A (en) * | 2019-01-10 | 2019-03-22 | 广西师范大学 | 3- (L-phenylalanine)-pentacyclic triterpene derivative and its synthetic method and application |
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