CN104138384A - Applications of five-ring triterpenoid compounds as oxidized squalene cyclase inhibitors - Google Patents

Applications of five-ring triterpenoid compounds as oxidized squalene cyclase inhibitors Download PDF

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CN104138384A
CN104138384A CN201310163520.XA CN201310163520A CN104138384A CN 104138384 A CN104138384 A CN 104138384A CN 201310163520 A CN201310163520 A CN 201310163520A CN 104138384 A CN104138384 A CN 104138384A
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alkene
beta
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alkane
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孙宏斌
陈冬寅
柳军
邓洁
徐畅
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China Pharmaceutical University
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Abstract

The invention relates to the field of medicines, and particularly relates to applications of five-ring triterpenoid compounds shown as general formulas (I), (II) or (III) or pharmaceutical acceptable salts or esters thereof as oxidized squalene cyclase inhibitors, especially applications in the field of preparation of anti-hypercholesterolemia medicines, anti-hyperlipidemia medicines, medicines for treating heart and cerebral vessels and antitumor medicines, and other fields. The R1 to R6 are defined in the specification.

Description

Pentacyclic triterpenoid is as the purposes of squalene oxide cyclase inhibitor
Technical field
The present invention relates to drug world, be specifically related to a series of pentacyclic triterpenoids as the purposes of squalene oxide cyclase inhibitor, particularly in the application of preparing the aspects such as antihypercholesterolemic thing, lipidemia medicine, medicament against cardiovascular disease, antitumor drug, antifungal medicine, medicine for antiparasitic infection, anti-cholelithiasis and antidiabetic medicine.
Background technology
Many epidemiological studies show that hypercholesterolemia is atheromatosis, as one of three of myocardial infarction, angina pectoris and cerebral infarction kinds of Major Risk Factors.Therefore,, for prevention or the relevant cardiovascular and cerebrovascular disease for the treatment of atherosclerosis, it is very important suitably controlling Blood Cholesterol level.For reducing the medicine of Blood Cholesterol level, mainly contain clinically at present: can catch and suppress the medicine of cholesterol absorption, as colestyramine and colestipol; Suppress cholesterol at the medicine of intestinal absorption, as ezetimibe; The medicine that suppresses Biosynthesis of cholesterol, as statins.
Since first statins-lovastatin in 1987 goes through to be applied to clinical treatment hypercholesterolemia, statins is constantly proved sickness rate and the case fatality rate that can significantly reduce all kinds atherosclerosis (particularly coronary heart disease and apoplexy).Due to its outstanding effectiveness and reliability, statins has become one of the medicine the most widely of clinical practice since the dawn of human civilization.Yet statins, as hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, has not only suppressed the synthetic of endogenous cholesterol, and has suppressed the synthetic of other important living matter, as ubiquinone, dolichol and haemachrome A etc.Therefore, there are a considerable amount of patients and can not tolerate treatment because there is comparatively serious hepatic injury, myalgia, myopathy or even fatefulue rhabdomyolysis.In addition, for some special populations, as subtype familial hypercholesterolemia (HoFH) patient of isozygotying, existing Drug therapy still extremely difficulty make LDL-C level up to standard.
Squalene oxide cyclase (OSC) is another key enzyme in Biosynthesis of cholesterol process, is also the pharmaceutically-active unique target that reduces cholesterol.OSC can catalysis (S)-2, and 3-epoxy Squalene is converted into lanosterol, and lanosterol is converted into the material-cholesterol with important biomolecule function under the catalytic action of other enzyme.In recent years, take OSC gets more and more people's extensive concerning as the novel anticholesteremic agent of drone design.The activity that suppresses other enzyme in Biosynthesis of cholesterol approach by suppressing the specific activity of OSC reduces cholesterol syntheticly has an obvious advantage: on the one hand, after OSC is suppressed, (S)-2,3-epoxy Squalene is converted into 2,3-22,23-dual oxide Squalene, and then be metabolised to oxygen sterone, after oxygen sterone and other ligand binding, in the presence of liver X receptor, can strengthen again the relevant expression that regulates lipid metabolism gene in cell; On the other hand, can avoid the untoward reaction of using other kind of Inhibitors to bring, such as: Statins HMG-CoA reductase inhibitor suppresses the synthetic of the living matters such as ubiquinone, dolichol and haemachrome A.For example, the OSC inhibitor Ro488071 of Roche Holding Ag exploitation does not reduce the level side effect of statins (thereby can avoid) of experimental animal coenzyme Q10, and there is no to improve the activity (Pharmacol.Ther.127,19-40.) of the upstream enzymes such as HMG-CoA reductase compensatoryly.
Clinically, OSC inhibitor can suppress the synthetic of cholesterol effectively, thereby controls cholesterol levels in blood plasma, and then reduces atherosclerotic occurrence probability.In addition, the complication that OSC inhibitor also can be used for treatment or prevents cardiovascular injury to cause, as coronary heart disease, apoplexy, cerebral infarction, myocardial infarction and angina pectoris etc.OSC inhibitor also can be used as antifungal drug, because in fungus body, biosynthetic sterol is ergosterol, and mammalian biological synthetic be cholesterol, between two kinds of sterols, the process of biosynthesis lanosterol is common, can expect that OSC inhibitor also can suppress the biosynthesis of ergosterol.Also have report, OSC inhibitor suppresses active to the tumor cell tool of Various Tissues, mankind's glioblastoma cells particularly, this just illustrate the antitumor drug that OSC suppresses to be likely potential (J.Med.Chem.2012,55,4990-5002.).
At present, have been reported, OSC inhibitor comprises biphenyl derivatives (being disclosed in EP-464465), aminoalkoxy benzene derivative (being disclosed in EP-410359), piperidine derivative (J.Org.Chem.1992,57,2794-2803.), Decaline derivatives, Azadecalin derivant and 1,2-indane derivatives (being disclosed in WO/80/08450), condense furan derivative (being disclosed in WO/96/11201), azacycloparaffin derivatives (being disclosed in WO99/29669), the cyclohexyl derivatives (being disclosed in WO/2005/028427) that aminoalkylamide replaces.These OSC inhibitor are substrate analogue inhibitor, although can effectively suppress the biosynthesis of cholesterol, also can cause multiple side effect, comprising: the pathological changes of skin and epididymis tissue, cataractous formation and abnormal poison etc.For example, OSC inhibitor U18666A has toxicity to lens epithelial cells, may cause cataractous formation (Toxicol.Pathol.29,174-179).Therefore, safer in the urgent need to developing, effective New O SC inhibitor clinically.
Summary of the invention
The invention discloses a series of pentacyclic triterpene squalene oxide cyclases (OSC) inhibitor, this is the type of compounds that a class is different from existing OSC inhibitor.The invention also discloses these compounds as the purposes of OSC inhibitor, can be used for the treatment of and/or disease that prevention is relevant to squalene oxide cyclase, these diseases comprise hypercholesterolemia, hyperlipidemia, cardiovascular disease, mycosis, parasitic infection, cholelithiasis, tumor and/or excess proliferative disease and diabetes etc.Particularly they can be for the preparation of antihypercholesterolemic thing, lipidemia medicine, medicament against cardiovascular disease and antitumor drug etc.
Squalene oxide cyclase inhibitor provided by the invention comprise general formula (I), (II) and (III) shown in pentacyclic triterpenoid and pharmaceutically acceptable salt or ester:
R wherein 1, R 2, R 3, R 4and R 5represent H, O, OR 7, NHR 7, N (R 8) 2or NR 7r 8;
R 6represent CH 3, CH 2oR 7, COOR 7, CONHR 7, CON (R 8) 2, CONR 7r 8, CH 2nHR 7, CH 2n(R 8) 2, CH 2nR 7r 8, NHR 7, N (R 8) 2, NR 7r 8or CN;
R 7represent H, R 8, R 8cO or R 8sO 2
R 8represent straight or branched alkane that the non-substituted or X of 1～30 carbon replaces, alkene, alkynes, phenyl, benzyl or
Naphthyl;
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, 1～30 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl.Preferred general formula (I), (II) and compound (III), is characterized in that:
R 1, R 2and R 4represent H;
R 3represent OH;
R 5represent H or OH;
R 6represent CH 3, CH 2oR 7, COOR 7, CONHR 7, CON (R 8) 2, CONR 7r 8, CH 2nHR 7, CH 2n(R 8) 2, CH 2nR 7r 8, NHR 7, N (R 8) 2, NR 7r 8or CN;
R 7represent H, R 8, R 8cO or R 8sO 2;
R 8represent straight or branched alkane, alkene or the alkynes non-substituted or that X replaces of 1～30 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, 1～30 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl.
More preferred compound is: 3 beta-hydroxy oleanane-12-alkene-28-carboxylic acids, 3 beta-hydroxy Folium Vaccinii vitis-idaeae alkane-12-alkene-28-carboxylic acids, 3 beta-hydroxy lupinane-21 (29)-alkene-28-carboxylic acids, 3 β-acetoxyl group oleanane-12-alkene-28-carboxylic acid, 3 β-acetoxyl group Folium Vaccinii vitis-idaeae alkane-12-alkene-28-carboxylic acid, 3 β-acetoxyl group lupinane-21 (29)-alkene-28-carboxylic acid, 3 beta-hydroxies-12-alkene-28-methyl oleanane, 3 beta-hydroxies-12-alkene-28-methyl Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-methyl lupinane, 3 beta-hydroxies-12-alkene-28-amine methyl oleanane, 3 beta-hydroxies-12-alkene-28-amine methyl Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-amine methyl lupinane, 3 beta-hydroxies-12-alkene-28-itrile group oleanane, 3 beta-hydroxies-12-alkene-28-itrile group Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-itrile group lupinane, 3 beta-hydroxies-12-alkene-28-amido oleanane, 3 beta-hydroxies-12-alkene-28-amido Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-amido lupinane.
Above-mentioned pentacyclic triterpenoid and pharmaceutically acceptable salt thereof or ester have squalene oxide cyclase (OSC) and suppress active, or it in vivo can be through metabolic conversion for having the inhibiting reactive compound of OSC.
The preferred general formula (I) of part, (II) and compound structure (III) are as follows:
Part pentacyclic triterpenoid in the present invention is known compound, and remainder pentacyclic triterpene derivant is noval chemical compound, and these noval chemical compounds can be prepared by conventional method, as:
In above formula, R 1-5, R 7and R 8definition as previously mentioned.
The present invention also comprises pharmaceutical preparation, and said preparation comprises general formula (I), (II) and compound (III) and pharmaceutically acceptable salt or ester and the acceptable carrier as active component.
Above-mentioned pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, refer to one or more inertia, atoxic solid and liquid filler material, diluent, auxiliary agent etc., they are not reverse has an effect with reactive compound or patient.
The pharmaceutical dosage form the present invention relates to can be conventional dosage form on the pharmaceuticss such as tablet, capsule, granule, drop pill, suppository, oral liquid, suspensoid, injection.
Tablet for oral use and capsule contain traditional excipient as implant, diluent, lubricant, dispersant and binding agent.
Accompanying drawing explanation
Fig. 1 is liquid chromatography mass (LC-MS/MS) chromatogram of 1ug/ml standard mixed liquor, wherein 2, and the retention time of 3-oxidized keratin zamene is 3.316min, the retention time of lanosterol is 4.164min.
Fig. 2 is liquid chromatography mass (LC-MS/MS) chromatogram of the actual test of cell sample, wherein 2, and the retention time of 3-oxidized keratin zamene is 3.316min, the retention time of lanosterol is 4.164min.
The specific embodiment
In practical application of the present invention, for better statement pentacyclic triterpenoid and pharmaceutically acceptable salt thereof or ester have the inhibition activity of squalene oxide cyclase (OSC), we take oleanolic acid (OA) and suppress active as example explanation pentacyclic triterpenoid has squalene oxide cyclase (OSC), and have Lipid-lowering activities in high fat animal model test and clinical trial.Below by specific embodiment, content of the present invention is described.In the present invention, the embodiment of the following stated is in order better to set forth the present invention, is not for limiting the scope of the invention.
Embodiment 1
Use commercially available oleanolic acid tablet to reduce effect to hyperlipidemia patient's blood fat
Method: to 30 hyperlipemic patients, carry out the blood fat reducing clinical trial of commercially available oleanolic acid tablet to hyperlipidemia patient.Experimenter did not all use any blood lipid-lowering medicine or associated health product.Experimenter every day is oral oleanolic acid tablet after the meal, 3 times on the one, one time 4,20mg/ sheet, administration is 7 days weekly, successive administration 1 week.After last 1 administration 24 hours, overnight fasting, get blood, get blood appropriate, routine is prepared serum, observes blood lipids: serum total cholesterol (TC), triglyceride (TG), HDL-C (HDL-C) and low-density lipoprotein cholesterol (LDL-C).
Result: oleanolic acid tablet reduces effect in Table 1 to 3 hyperlipidemia patients' wherein blood fat.
Table 1. oleanolic acid tablet reduces effect to hyperlipidemia patient's blood fat
Conclusion: hyperlipidemia patient took oleanolic acid tablet after 1 week, and the blood lipids of observing patient all makes moderate progress, wherein TC level reduction by 3～10%, TG level reduction by 8～40%, HDL-C level remains unchanged substantially, and LDL-C level reduces by 5～20%.
Embodiment 2
Use the impact of commercially available oleanolic acid tablet on hyperlipidemia patient relative physiologic index
Method: to 30 hyperlipemic patients, carry out the blood fat reducing clinical trial of commercially available oleanolic acid tablet to hyperlipidemia patient.Experimenter did not all use any blood lipid-lowering medicine or associated health product.Experimenter every day is oral oleanolic acid tablet after the meal, 3 times on the one, one time 4,20mg/ sheet, administration is 7 days weekly, successive administration 1 week.After last 1 administration 24 hours, overnight fasting, get blood, get blood appropriate, routine is prepared serum, observes relative physiologic index: glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), glutamyl transpeptidase (GGT), creatine kinase (CK), carbamide (BUN), creatinine (Cr), uric acid (UA), C reactive protein (CRP) and super quick C reactive protein (HsCRP).
Result: oleanolic acid tablet on the impact of 3 hyperlipidemia patient relative physiologic indexes wherein in Table 2.
The impact of table 2. oleanolic acid tablet on hyperlipidemia patient relative physiologic index
Conclusion: hyperlipidemia patient took oleanolic acid tablet after 1 week, all not there is not directly affecting the variation of survival of patients in the relative physiologic index of observing patient.
Embodiment 3
Use oleanolic acid, 3-acetyloleanolic acid, ursolic acid and 3-acetyl ursolic acid to reduce effect to the blood fat of hyperlipidemia rat
Method: SD rat (200-220g, male) adaptability was fed after 1 week, be divided at random 2 groups: be respectively 6 Normal group and 36 model group of feeding with high lipid food of feeding with standard feed.Normal group does not apply intervention factor.(2% cholesterol of high lipid food for model group, 0.5% sodium cholate, 3% Adeps Sus domestica, 0.2% propylthiouracil, 94.3% basic powder feed) feed causes after hyperlipidemia model for 2 weeks, is divided at random solvent group (6) (feeding with solvent), Atorvastatin calcium group (6), oleanolic acid group (6), 3-acetyloleanolic acid group (6), ursolic acid group (6) and 3-acetyl ursolic acid group (6).Add that Normal group is 7 groups altogether.Wherein Atorvastatin calcium group is fed with Atorvastatin calcium 5mg/kg/d, oleanolic acid group is fed with oleanolic acid 30mg/kg/d, 3-acetyloleanolic acid group is fed with 3-acetyloleanolic acid 30mg/kg/d, ursolic acid group is fed with ursolic acid 30mg/kg/d, and 3-acetyl ursolic acid group is fed with 3-acetyl ursolic acid 30mg/kg/d.The solvent of all tested medicines is 0.5%CMC sodium solution.Oral administration 4 weeks, every day 1 time.The administration fasting day before yesterday the last time, collect blood last day, centrifuging and taking serum, measures Triglycerides in Serum (TG), T-CHOL (TC), HDL-C (HDL-C) and low-density lipoprotein cholesterol (LDL-C) level in strict accordance with test kit description.
Result: oleanolic acid, 3-acetyloleanolic acid, ursolic acid and 3-acetyl ursolic acid reduce effect in Table 3 to the blood fat of hyperlipidemia rat.
Table 3. oleanolic acid, 3-acetyloleanolic acid, ursolic acid and 3-acetyl ursolic acid reduce effect to the blood fat of hyperlipidemia rat
* P < 0.05, * * P < 0.01, and * * * P < 0.001 compares (t check) with Normal group;
#P < 0.05, ##P < 0.01, ###P < 0.001 compares (t check) with model group.
Conclusion: compare with independent use Atorvastatin calcium, use separately oleanolic acid, 3-acetyloleanolic acid, ursolic acid and 3-acetyl ursolic acid all to have the effect that reduces TC, TG and LDL-C, wherein use separately the lipid-lowering effect of 3-acetyloleanolic acid more obvious.
Embodiment 4
Detect the inhibitory action of oleanolic acid (OA) to squalene oxide cyclase (OSC)
Method: HL60 cell is as subject cell, and Ro 48-8071 is as positive drug, and oleanolic acid (OA) is as test-compound.In HL60 cell cultivation process, add the positive drug of variable concentrations, as positive group; The test-compound that adds variable concentrations, as tested group; And cultivate under normal condition, as a control group.By the cell breakage of different groups, and with organic solvent extraction, obtain extracting solution.Adopt liquid chromatography mass combined instrument (LC-MS/MS) to detect extracting solution, by the test collection of illustrative plates of analysis of control group, positive group and tested group, compare 2, the peak area ratio of 3-oxidized keratin zamene and lanosterol, the inhibitory action of judgement oleanolic acid (OA) to squalene oxide cyclase (OSC).
Specific experiment operation is as follows:
Matched group HL60 cell culture: 1, cultivate HL60 cell, with 5 * 10 6sum is inoculated in 24 orifice plates, and culture medium is changed to RPMI1640 (not containing serum) and spends the night; 2, second day, the centrifugal 5min of 1000g, collecting cell, then adds the same centrifugal condition of PBS to clean cell 2 times; 3, remove supernatant; 4, to put into refrigerator frozen, standby for cell precipitation.
Positive group HL60 cell culture: 1, cultivate HL60 cell, with 5 * 10 6sum is inoculated in 24 orifice plates, and culture medium is changed to RPMI1640 (not containing serum) and spends the night; 2, second day adds after variable concentrations (0.1uM, 1uM and 10uM) the irritation cell 24hr of positive compound (Ro 488071), the centrifugal 5min of 1000g, and collecting cell, then adds the same centrifugal condition of PBS to clean cell 2 times; 3, remove supernatant; 4, to put into refrigerator frozen, standby for cell precipitation.
Tested group of HL60 cell culture: 1, cultivate HL60 cell, with 5 * 10 6sum is inoculated in 24 orifice plates, and culture medium is changed to RPMI1640 (not containing serum) and spends the night; 2, second day adds after variable concentrations (0.1uM, 1uM and 10uM) the irritation cell 24hr of test-compound (OA), the centrifugal 5min of 1000g, and collecting cell, then adds the same centrifugal condition of PBS to clean cell 2 times; 3, remove supernatant; 4, to put into refrigerator frozen, standby for cell precipitation.
Cell sample pre-treatment: cell sample, after lyophilization, add 1000 μ l normal hexane, after 4 ℃ of supersound extraction 20min, 3000rpm vortex 15min, 4000rpm low-speed centrifugal 15min, gets supernatant 800 μ l, after the concentrated 30min of low-temperature centrifugation, with 150 μ l mobile phase (acetonitriles: water=95: 5, v/v) redissolve, low-temperature and high-speed is centrifugal, gets supernatant to sample introduction bottle.
LC-MS/MS analytical tool and testing conditions: Shimadzu triple quadrupole bar liquid chromatography mass combined instrument LCMS-8040, chromatographic column: Agilent ZORBAX SB-C18 (2.1mm * 50mm, 1.8 μ m); Mobile phase: acetonitrile: water=95: 5 (v/v), isocratic elution; Flow velocity: 0.3ml/min; Sample size: 3ul; Mass spectrum condition: atmospheric pressure chemical ionizing MRM (APCI +) Interface:250 ℃ DL: 150 ℃, Nebulizing gas:4L/min, Drying gas:5L/min, Heat block:200 ℃; Monitoring 2,3-epoxy Squalene [M+H] +: 427.45 → 427.25 (quantitatively), 427.45 → 409.40 (qualitative); Monitoring lanosterol [M+H-H 2o] +: 409.40 → 109.00 (quantitatively), 409.40 → 95.05 (qualitative).
The cell extract of LC-MS/MS analytical tool analyzing and testing matched group, positive group and tested group, and result tested in record.
Result: oleanolic acid (OA) the results are shown in Table 4 to the inhibiting LC-MS/MS analyzing and testing of squalene oxide cyclase (OSC); Liquid chromatography mass (LC-MS/MS) chromatogram of 1ug/ml standard mixed liquor (2,3-epoxy Squalene and lanosterol) is shown in accompanying drawing 1; Liquid chromatography mass (LC-MS/MS) chromatogram of the actual test of cell sample is shown in accompanying drawing 2.
The inhibiting LC-MS/MS analyzing and testing result of table 4. oleanolic acid (OA) to squalene oxide cyclase (OSC)
Conclusion: oleanolic acid (OA) is inhibited to squalene oxide cyclase (OSC), and to the inhibition degree of OSC, the concentration with OA increases.

Claims (9)

  1. General formula (I), (II) or (III) shown in pentacyclic triterpenoid or its pharmaceutically acceptable salt or ester for the preparation of the purposes of squalene oxide cyclase inhibitor:
    R wherein 1, R 2, R 3, R 4and R 5represent H, O, OR 7, NHR 7, N (R 8) 2or NR 7r 8;
    R 6represent CH 3, CH 2oR 7, COOR 7, CONHR 7, CON (R 8) 2, CONR 7r 8, CH 2nHR 7, CH 2n(R 8) 2, CH 2nR 7r 8, NHR 7, N (R 8) 2, NR 7r 8or CN;
    R 7represent H, R 8, R 8cO or R 8sO 2;
    R 8represent straight or branched alkane, alkene, alkynes, phenyl, benzyl or the naphthyl non-substituted or that X replaces of 1～30 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, 1～30 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl.
  2. 2. according to the purposes of claim 1, wherein, general formula (I), (II) or compound (III) or its pharmaceutically acceptable salt or ester are characterised in that:
    R 1, R 2and R 4represent H;
    R 3represent OH;
    R 5represent H or OH;
    R 6represent CH 3, CH 2oR 7, COOR 7, CONHR 7, CON (R 8) 2, CONR 7r 8, CH 2nHR 7, CH 2n(R 8) 2, CH 2nR 7r 8, NHR 7, N (R 8) 2, NR 7r 8or CN;
    R 7represent H, R 8, R 8cO or R 8sO 2;
    R 8represent straight or branched alkane, alkene or the alkynes non-substituted or that X replaces of 1～30 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, 1～30 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl.
  3. 3. according to the purposes of claim 2, wherein, general formula (I), (II) compound or (III) can be following arbitrary compound or its pharmaceutically acceptable salt or ester: 3 beta-hydroxy oleanane-12-alkene-28-carboxylic acids, 3 beta-hydroxy Folium Vaccinii vitis-idaeae alkane-12-alkene-28-carboxylic acids, 3 beta-hydroxy lupinane-21 (29)-alkene-28-carboxylic acids, 3 β-acetoxyl group oleanane-12-alkene-28-carboxylic acid, 3 β-acetoxyl group Folium Vaccinii vitis-idaeae alkane-12-alkene-28-carboxylic acid, 3 β-acetoxyl group lupinane-21 (29)-alkene-28-carboxylic acid, 3 beta-hydroxies-12-alkene-28-methyl oleanane, 3 beta-hydroxies-12-alkene-28-methyl Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-methyl lupinane, 3 beta-hydroxies-12-alkene-28-amine methyl oleanane, 3 beta-hydroxies-12-alkene-28-amine methyl Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-amine methyl lupinane, 3 beta-hydroxies-12-alkene-28-itrile group oleanane, 3 beta-hydroxies-12-alkene-28-itrile group Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-itrile group lupinane, 3 beta-hydroxies-12-alkene-28-amido oleanane, 3 beta-hydroxies-12-alkene-28-amido Folium Vaccinii vitis-idaeae alkane, 3 beta-hydroxy-21 (29)-alkene-28-amido lupinane.
  4. 4. the purposes of claims 1 to 3, wherein, general formula (I), (II) or (III) compound or its pharmaceutically acceptable salt or ester and medically acceptable excipient or carrier mixing, make pharmaceutical composition, its form can be tablet, capsule, granule, drop pill or injection.
  5. 5. the purposes of claim 1, wherein squalene oxide cyclase inhibitor is treatment or prevention hypercholesterolemia, hyperlipidemia, cardiovascular and cerebrovascular disease, mycosis, parasitic infection, cholelithiasis, tumor and/or excess proliferative disease, and the medicine for the treatment of or prevent diabetes.
  6. 6. the purposes of claim 5, wherein squalene oxide cyclase inhibitor is antihypercholesterolemic thing, lipidemia medicine, medicament against cardiovascular disease and antitumor drug.
  7. 7. claim 5 or 6 purposes, wherein cardiovascular and cerebrovascular disease comprises myocardial infarction, angina pectoris, arrhythmia, coronary heart disease, apoplexy, cerebral infarction or ischemic neurodegenerative diseases.
  8. General formula (I), (II) or (III) shown in pentacyclic triterpenoid or its pharmaceutically acceptable salt or ester, wherein,
    R 1, R 2and R 4represent H;
    R 3represent OH;
    R 5represent H;
    R 6represent CH 2nHR 7, CH 2n(R 8) 2or CH 2nR 7r 8;
    R 7represent H, R 8, R 8cO or R 8sO 2;
    R 8represent straight or branched alkane, alkene or the alkynes non-substituted or that X replaces of 1～30 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, 1～30 carbon straight or branched alkane, alkene, alkynes, phenyl, benzyl or naphthyl.
  9. 9. the compound in claim 8, is selected from following compounds or its pharmaceutically acceptable salt or ester:
CN201310163520.XA 2013-05-07 2013-05-07 Applications of five-ring triterpenoid compounds as oxidized squalene cyclase inhibitors Pending CN104138384A (en)

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CN112526018A (en) * 2020-11-24 2021-03-19 嘉兴迈维代谢生物科技有限公司 Method for detecting pentacyclic triterpenoid substance by adopting LC-MS APCI source
CN113234053A (en) * 2021-05-30 2021-08-10 吉林农业大学 Split-ring lupane derivative and application thereof in preparation of ASK1 inhibitor
CN114277024A (en) * 2020-09-27 2022-04-05 中国科学院分子植物科学卓越创新中心 Novel triterpene synthase and application thereof
CN115247167A (en) * 2021-08-31 2022-10-28 东北林业大学 Oat oxidation squalene cyclase AsHS1 and coding gene and application thereof

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