CN104873525A - 11 beta-hydroxysteroid dehydrogenase inhibitor and its pharmaceutical composition and use - Google Patents
11 beta-hydroxysteroid dehydrogenase inhibitor and its pharmaceutical composition and use Download PDFInfo
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Abstract
The invention provides a novel use of a ganoderic acid component with a structure shown in the general formula I as a 11 beta-HSD inhibitor. The ganoderic acid component as a 11 beta-hydroxysteroid dehydrogenase inhibitor with a novel structure has a certain selective inhibition effect on 11 beta-HSD1 and can be used for preparation of drugs for adjusting lipid metabolism and treating diabetes, adiposis and cardiovascular diseases.
Description
Technical field
The invention belongs to medical art, be specifically related to that there is the inhibiting Ganoderma lucidum triterpenes components of 11beta-Hydroxysteroid dehydrogenase, and pharmaceutical composition and new medical use.
Background technology
Glucocorticoid all plays an important role in sugar, protein, fat, water-electrolyte metabolism and stress.Glucocorticoid too much or lack and all can bring exception to body.11beta-Hydroxysteroid dehydrogenase (11 β-HSD) is the metabolic enzyme of glucocorticoid, redox reaction between the ketone group of its catalysis glucocorticoid C11 position and hydroxyl, bioactive hydrocortisone (cortisol) is transformed mutually with the dehydrocorticosterone (cortisone) of non-activity, thus regulates the level of glucocorticoid in local organization organ.It has two kinds of isozymes, is respectively 11 β-HSD1 types and 11 β-HSD2 types.11 β-HSD1 wide expression in liver, fat, placenta tissue and cerebral tissue, its overexpression in fatty tissue, can cause impaired glucose tolerance and islets of langerhans opposing aggravation, free fatty and triglyceride increases and blood pressure increases.11 β-HSD2 are mainly present in kidney, Placenta Hominis, and for the fetus grown provides reply from the barrier of the glucocorticoid of parent, it is also regarded as the novel targets of Therapeutic cancer, inflammation regulation and control.Research shows, the pathological process that it is the metabolism syndrome of main manifestations with type 2 diabetes mellitus, obesity, insulin resistant, hypertension, hyperlipidemia etc. that 11 β-HSD participate in, simultaneously also closely related with the disease such as cancer and cognitive disorder, thus 11 β-HSD inhibitor have good DEVELOPMENT PROSPECT.Current 11 β-HSD inhibitor mainly contain enoxolone and carbenoxolone (Carbenoxolone), clinical being mainly used in treats chronic peptic ulcer, the latter can also reduce fasting glucose, reduce triglyceride and free cholesterol level, improve the cognitive competence of healthy geriatric male and type 2 diabetes mellitus patient, but side effect and untoward reaction more, incidence rate is high.
Ganoderma lucidum has long medicinal history in China, begins to be loaded in Shennong's Herbal, has the effects such as invigorating the spleen and replenishing QI, strengthening by means of tonics, strengthening the body resistance, is classified as rare medicinal herbs.Containing the abundant composition such as polysaccharide, sterol, triterpenic acid in Ganoderma plant, wherein ganoderan is subject to extensive concern due to its significant immunoregulation effect, and about the research of Triterpene acids relatively less.In recent years along with people's deepening continuously to the basic research of Ganoderma plant material, plant Triterpene acids from being wherein isolated to more than 150, its biological activity also receives publicity gradually.Pharmacological research shows, Ganoderma triterpenoids has the effects such as antitumor, AntiHIV1 RT activity, antiinflammatory, hepatoprotective and Improving memory power.Patent about Ganoderma mostly is the compound recipe component containing Ganoderma medical material, and the patent of triterpenic acid purposes is less, and concentrates on antitumor and anti-virus aspect.Patent 200510026378.X discloses Ganoderic acid T GA-T Ganoderic acid T. and the application of Ganoderic acid Me GA-Me (+)-Ganoderic acid Me in tumor growth or antiblastic; Patent CN201110291616.5 discloses the application of the medicine that Lanost-8-en-26-oic acid,3,7,12-trihydroxy-11,15,23-trioxo-,(3BETA,7BETA,12BETA)-relies on as immunostimulant and superantigen in oncotherapy; Patent JP2002383433 discloses Ganodenic acid F and derivant thereof the purposes as angiogenesis inhibitor; Patent 201110162657.4 discloses the application of Ganodenic acid Y in preparation treatment or prevention enterovirns type 71 infection medicine.At present there are no the relevant report being applied to 11beta-Hydroxysteroid dehydrogenase inhibitor about Ganoderma triterpenoids acrylic component, the present invention is the new discovery to its medical usage.
Summary of the invention
The invention provides a kind of purposes that there is the inhibiting Ganoderma triterpenoids acrylic component of 11beta-Hydroxysteroid dehydrogenase and be applied to treatment relevant disease.
The object of this invention is to provide there is general formula I compound and pharmaceutically acceptable salt thereof as 11beta-Hydroxysteroid dehydrogenase inhibitor.
In the compound with general formula I:
R
1for=O ,-OH ,-OAc;
R
2for=O ,-OH ,-OAc ,-OCH
3,-H;
R
3for-OH ,-OAc ,-H;
R
4for-OH ,-OAc ,-H;
R
5for
R
6for-CH
3
At above-mentioned R
1~ R
6in, substituent group can be the combination of any one or several group in above-mentioned group,
At above-mentioned R
5in, R ' is-COOH ,-CH
2oH ,-COOCH
3,-CHO ,-CH
3.
Following table lists representational preferred compound structure:
The compound with general formula I is normally separated from the material of natural origin, particularly Ganoderma plant.The raw grade of such as Wang Fang extracts Ganoderma lucidum (Leyss. Ex Fr.) Karst. 4Kg solution, after gained extractum thin up, successively with petroleum ether and dichloromethane extraction with 70% alcohol heating reflux.Extractum 53.8g is obtained after dichloromethane extraction liquid is concentrated, carry out silica gel column chromatography, with petroleum ether-ethyl acetate (9:1 ~ 1:9) gradient elution, component 4 is again through silica gel column chromatography, a noval chemical compound Ganodenic acid DM (ganoderic acid DM) 20mg [Acta Pharmaceutica Sinica is obtained through recrystallization, 1997,32 (6): 447-450].Byung-Sun Min etc. is separated the methanolic extract 30g of Ganoderma lucidum (Leyss. Ex Fr.) Karst. spore powder.After carrying out defat with normal hexane, be scattered in water, extract with chloroform, obtain 23.2g extractum.Through silica gel column chromatography, with normal hexane-acetone system (3:2,1:1,2:3) carry out eluting with chloroform-methanol system (4:1), obtained component A, through silicagel column mesolow preparation (normal hexane-acetone, 4:1), obtains compound Ganoderma lucidum (Leyss. Ex Fr.) Karst. alcohol A (lucidumol A) 15mg [Chem.Pharm.Bull., 1998,46 (10): 1607-1612].
Or use naturally occurring and/or commercially available compound for raw material, by organic synthesis or the biological method transformed, in conjunction with purification procedures, prepare the compound of general formula I.Japanese scholars finds in lanostane compounds is on the impact of mice Biosynthesis of cholesterol activity test, and the α hydroxyl of this compounds 7 oxos and 15 may be very important functional group.Take ganoderic acid C as raw material; obtained 3 methyl ester derivations, are obtained by reacting the product of 7 oxidations, 11 de-carbonyl reductions, again through oxidative decarboxylation under Wolff-Kishner condition; catalytic reduction and hydroxyl go protection to obtain compound VI, are the analog of a 7-oxo-DHL.[Chem.Pharm.Bull,1989,37(2):531-533]。
The pharmaceutically acceptable salt of general formula I compound of the present invention, comprises organic salt and inorganic salt.Organic salt is the salt that acidic-group in described compound molecule and meglumine, arginine, lysine, histidine generate, and inorganic salt is acidic-group in described compound molecule and lithium, sodium, potassium, magnesium, NH
4 +the salt that plasma generates.
The structural compounds that present invention also offers containing general formula I is the pharmaceutical composition of active component, uses the structural compounds of general formula provided by the invention or its pharmaceutically acceptable salt and the acceptable pharmaceutic adjuvant of pharmaceutics, can pharmaceutical compositions.The acceptable pharmaceutic adjuvant of pharmaceutics comprises diluent, lubricant, binding agent, disintegrating agent, stabilizing agent, solvent etc.
Diluent of the present invention includes but not limited to starch, microcrystalline Cellulose, sucrose, dextrin, lactose, Icing Sugar, glucose, low molecular dextran, Kaolin, sodium chloride, mannitol etc.; Described lubricant includes but not limited to magnesium stearate, stearic acid, boric acid, sodium chloride, enuatrol, DL-LEUCINE, sodium laurylsulfate, Macrogol 4000-6000, the husky mother in pool Lip river etc.; Described binding agent includes but not limited to water, ethanol, starch slurry, syrup, gelatin, methylcellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose, sodium alginate, ghatti gum, polyvinylpyrrolidone etc.; Described disintegrating agent includes but not limited to starch, carboxymethyl starch sodium, effervescent mixture and sodium bicarbonate and citric acid, tartaric acid, low-substituted hydroxypropyl cellulose etc.; Described stabilizing agent includes but not limited to that polysaccharide is as acacin, agar, alginic acid, guar gum, tragacanth, acrylate resins, cellulose ether and carboxymethyl crusta ester etc.; Described solvent includes but not limited to the saline solution etc. of Ringers solution, water, phosphate buffer, balance.
Different and different according to preparation of the portfolio ratio of active ingredient and adjuvant composition, the dosage of active ingredient or compositions can at 1mg/kg-200mg/kg, according to suitable being adjusted of object various dose for the treatment of.The difference that described compositions needs according to treatment, can make various different preparation, comprise various solid orally ingestible, liquid oral medicine, injection, membrane, aerosol etc.The acceptable oral agents solid preparation of pharmaceutics has: conventional tablet, dispersible tablet, slow controlled release, enteric coatel tablets, granule, capsule, drop pill, powder etc., and oral liquid has oral liquid, Emulsion; Injection has: little liquid drugs injection, transfusion, freeze-dried powder etc.Each preparation can be prepared from according to the technique of routine.
Inhibit activities test shows, the compound with I structure has obvious 11 β-HSD inhibitory action, as 11beta-Hydroxysteroid dehydrogenase inhibitor, the associated conditions such as diabetes, metabolism syndrome, obesity, glucose intolerance, insulin resistant, hyperglycemia, hyperlipidemia, hypertension and relevant cardiovascular disease, nephropathy, osteoporosis, cognitive dysfunction, anxiety neurosis, depression, disease of immune system can be used for the treatment of.
The invention provides the novelty teabag of Ganoderma triterpenoids acrylic component as 11 β-HSD inhibitor.As 11 β-HSD inhibitor of a class new construction type, it has certain selective inhibitory to 11 β-HSD1, is expected to develop the medicine becoming and regulate lipid metabolism, diabetes, obesity, cardiovascular etc. sick.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, to help the present invention of those skilled in the art's comprehend, but not in this, as limitation of the present invention.
embodiment 1
11 β-HSD inhibit activities tests
1. experiment material
Reagent: Ganoderma triterpenoids acid, make by oneself by this seminar, purity is greater than 95%; Cortisone, hydrocortisone, prednisolone acetate and nicotinamide-adenine dinucleotide phosphate (NADPH) are purchased from lark prestige Reagent Company; HPLC methanol is chromatographically pure, and all the other reagent are AG domestic reagent.
Animal: Wistar rat, body weight 240 ~ 300g, by Tianjin Inst. of Materia Medica animal housing propagating and breeding.
Instrument: 515 type efficient liquid-phase chromatographic pumps (Waters company), 717plus automatic sampler (Waters company), 2487 type UV-detector (Waters company).
2. experimental technique:
2.1 inhibition of enzyme activity experiments
The preparation of hepatomicrosome and 11 β-HSD1 activity analysiss: get rat some, after heparinization with etherization, get liver and add 0.25mol/L sucrose solution homogenate (ice bath); Homogenate respectively at 1300, the centrifugal 30min of 11000r/min, supernatant is in the centrifugal 60min of 35000r/min, precipitation plate is with TMS buffer (Tris6.05g, magnesium chloride 0.609g, sucrose 68.4g, adds water to 500ml, pH7.5) wash down in right amount and carry out protein quantification, with above-mentioned buffer dilution microsome to 2mg/ml ,-85 DEG C of preservations.
Every part of reactant mixture comprises microparticle suspension 80 μ L, cortisone methanol solution 20 μ L (144 μMs), NADPH solution 50 μ L, Krebs-Henseleit buffer of 5mmol/L, the given the test agent of 0.2mM, cumulative volume 0.5mL.Cultivate 60min 37 DEG C of water-baths, negative control group does not add sample, tests simultaneously.In reactant mixture, the conversion ratio of cortisone is measured by HPLC.
The active suppression test enzyme of 11 β-HSD2 takes from renal cortex of rats, and replace cortisone with hydrocortisone methanol solution in reactant mixture, all the other operations are the same.
The HPLC of 2.2 steroid hormones analyzes
In microsomal enzyme reactant mixture, cortisone, hydrocortisone assay adopt HPLC method.
HPLC chromatographic condition
Be interior mark with prednisolone acetate, the efficient liquid phase C of chromatographic column: Hypersil-C18
18chromatographic column (Dalian Yi Lite, 4.6 × 150mm, 5 μm), mobile phase: methanol-water (5:5), flow velocity 1.0mLmin
-1, column temperature: 25 DEG C, ultraviolet detection wavelength 240nm.Cortisone, hydrocortisone and interior target retention time are respectively 6.8min, 8.9min and 14.1min with this understanding.
3. experimental result
By to the conversion ratio of cortisone and hydrocortisone in conjunction with the result of negative control group, calculate different compound to 11 β-HSD1 and 11 β-HSD2 suppression ratio (n=2),
embodiment 2
Pulverize dry ganoderma lucidum sporocarp 6kg, extract 3 times with 70% alcohol heating reflux, each 2h, merge extractive liquid, is evaporated to without alcohol taste, and with a small amount of aqueous dispersion, add 3 times amount acetone and stir, leave standstill, filter, filtrate reduced in volume obtains fluid extract 120g.Turn molten with methanol, 60-100 order silica gel mixed sample, carry out silica gel column chromatography (1200g), with methylene chloride-methanol system (100:0 ~ 3:1) gradient elution, every 500ml is a collection eluent, and TLC combining data detection same composition, obtains 21 components.
Component 5 is through semi-preparative HPLC (chromatographic column: Vision HT C
18, 5 μm, 20*200mm; Mobile phase: acetonitrile-water=52:48, containing 0.1% formic acid; Flow velocity 16mLmin
-1; Determined wavelength: 250nm) separation and purification, obtain clever red aldehyde B (lucialdehyde B) 27.3mg.
Component 6 is through half preparative HPLC (chromatographic column: Vision HT C18,5 μm, 20 × 200mm; Mobile phase: acetonitrile-water=55:45, containing 0.1% formic acid; Flow velocity: 16.0mLmin
-1; Determined wavelength: 250nm) refining, obtain compound spirit red aldehyde C (lucialdehyde C) 22.7mg.
The red aldehyde B of spirit is white powder: (methanol).EI-MSm/z:452 [M]
+, molecular formula is C
30h
44o
3.
1H-NMR(400MHz,CDCl
3)δ:0.68(3H,s,H-18),0.94(3H,s,H-30),0.97(3H,d,J＝5.8Hz,H-21),1.08(3H,s,H-28),1.11(3H,s,H-29),1.33(3H,s,H-19),1.74(3H,s,H-27),6.48(1H,m,H-24),9.40(1H,s,H-26).
13C-NMR(100MHz,CDCl
3)δ:35.4(C-1),34.3(C-2),214.6(C-3),47.2(C-4),50.4(C-5),37.1(C-6),198.0(C-7),139.8(C-8),162.6(C-9),39.4(C-10),23.8(C-11),30.1(C-12),45.0(C-13),47.8(C-14),28.7(C-15),31.8(C-16),49.0(C-17),15.9(C-18),17.9(C-19),36.2(C-20),18.6(C-21),34.7(C-22),26.0(C-23),155.2(C-24),139.2(C-25),195.3(C-26),9.2(C-27),25.4(C-28),21.4(C-29),24.9(C-30)。
The red aldehyde C of spirit is white powder: (methanol).EI-MS:m/z:454 [M]
+, molecular formula is C
30h
46o
3.
1h-NMR (400MHz, CDCl
3) δ: 0.66 (3H, s, H-18), 0.88 (3H, s, H-29), 0.92 (3H, s, H-30), 0.97 (3H, d, J=5.8Hz, H-21), 1.00 (3H, s, H-28), 1.16 (3H, s, H-19), 1.74 (3H, s, H-27), 3.27 (1H, dd, H-3), 6.48 (1H, m, H-24), 9.40 (1H, s, H-26).
13c-NMR (100MHz, CDCl
3) δ: 34.8 (C-1), 38.8 (C-2), 78.0 (C-3), 39.8 (C-4), 50.7 (C-5), 36.7 (C-6), 199.0 (C-7), 138.9 (C-8), 164.7 (C-9), 38.9 (C-10), 23.6 (C-11), 30.2 (C-12), 45.0 (C-13), 49.0 (C-14), 27.5 (C-15), 32.0 (C-16), 49.9 (C-17), 15.3 (C-18), 18.4 (C-19), 36.3 (C-20), 18.6 (C-21), 34.8 (C-22), 26.0 (C-23), 155.3 (C-24), 139.2 (C-25), 195.3 (C-26), 9.2 (C-27), 27.5 (C-28), 15.8 (C-29), 25.0 (C-30).
embodiment 3
Get No. 5 compound 10g, add 30g lactose-microcrystalline Cellulose (4:1), magnesium stearate 1%, use 70% alcohol granulation, tabletting, obtain 1000 tablets of tablets.Specification 10mg/ sheet.
embodiment 4
Get No. 1 compound 10g, mannitol 50g, add 1000ml water for injection and dissolve, supply water for injection to 2000ml, with proper amount of active carbon removing thermal source, 0.2 μm of microporous filter membrane filters, fill, lyophilization, obtained 2000 freeze-dried powders.Specification: 30mg/ props up, every compound that only contains is no less than 4.9mg.For muscle or intravenous injection.
embodiment 5
Get No. 2 compound 10g, add dextrin 10g, lactose 30g 60% alcohol granulation, drying, encapsulated, obtained 1000 capsules.Specification 50mg/ grain, every is no less than 9.8mg containing compound.
embodiment 6
Get 50g Macrogol 4000, water-bath melting, add No. 6 compound 5g, stir, pour in insulating tube, regulating thermostatic device, medicinal liquid is instilled in cooled liquid paraffin at 80 ~ 90 DEG C, after dripping off, pill is poured on filter paper and blots paraffin oil, make 1000 drop pills.Specification 5mg/ grain.
embodiment 7
Polyvinylpyrrolidone 15g is dissolved in appropriate distilled water, separately gets polyvinyl alcohol 1g and sodium carboxymethyl cellulose 6g and is placed in appropriate distilled water respectively and dissolves in 75 DEG C of water-baths, and all mix homogeneously obtains glue until completely dissolved; Stir 2g azone, 10g glycerol and 2g zinc oxide to obtain suspension, joined in suspension while hot by glue and be prepared into substrate; Get 10g compound 4 to be dissolved in appropriate dehydrated alcohol, then add in substrate, under 45 DEG C of conditions, stir 15min; Get non-woven fabrics, catablasm base material even spread on it, is put into drying baker in 30 DEG C of dried overnight; Getting polyethylene film is affixed on mastic as lid lining, die-cut, obtains cataplasma.
Claims (4)
1. have the compound of general formula I and pharmaceutically acceptable salt thereof for the preparation of the purposes of 11beta-Hydroxysteroid dehydrogenase inhibitor medicaments compositions, it is characterized in that, the structural formula of general formula I is:
Wherein:
R
1for=O ,-OH ,-OAc;
R
2for=O ,-OH ,-OAc ,-OCH
3,-H;
R
3for-OH ,-OAc ,-H;
R
4for-OH ,-OAc ,-H;
R
5for
R
6for
At above-mentioned R
1~ R
6in, substituent group can be the combination of any one or several group in above-mentioned group,
At above-mentioned R
5in, R ' is-COOH ,-CH
2oH ,-COOCH
3,-CHO ,-CH
3,
Wherein, pharmaceutically acceptable salt comprises organic salt or inorganic salt.
2. purposes according to claim 1, it is characterized in that, the pharmaceutically acceptable salt of the structural compounds of general formula I comprises organic salt and inorganic salt, organic salt is the salt that acidic-group in described compound molecule and meglumine, arginine, lysine, histidine generate, and inorganic salt is acidic-group in described compound molecule and lithium, sodium, potassium, magnesium, NH
4 +ionogenic salt.
3. purposes according to claim 1, is characterized in that, the structural compounds of general formula I or its pharmaceutically acceptable salt and the acceptable pharmaceutic adjuvant of pharmaceutics, comprise diluent, lubricant, binding agent, disintegrating agent, stabilizing agent, solvent.
4. purposes according to claim 1, it is characterized in that, described inhibitor includes but not limited to the application in the medicine of diabetes, metabolism syndrome, obesity, glucose intolerance, insulin resistant, hyperglycemia, hyperlipidemia, hypertension and relevant cardiovascular disease, nephropathy, osteoporosis, cognitive dysfunction, anxiety neurosis, depression, disease of immune system in treatment.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023143400A1 (en) * | 2022-01-28 | 2023-08-03 | 珂阑(上海)医药科技有限公司 | Steroid compound, preparation method therefor and use thereof |
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| CN1322130A (en) * | 1998-08-07 | 2001-11-14 | 恩多研究公司 | Inhibitors of type 3 3a -hydrosteroid dehydrogenase |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1322130A (en) * | 1998-08-07 | 2001-11-14 | 恩多研究公司 | Inhibitors of type 3 3a -hydrosteroid dehydrogenase |
Non-Patent Citations (2)
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| 叶鹏飞等: "灵芝主要成分及其药理作用的研究进展综述", 《食药用菌》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023143400A1 (en) * | 2022-01-28 | 2023-08-03 | 珂阑(上海)医药科技有限公司 | Steroid compound, preparation method therefor and use thereof |
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Application publication date: 20150902 |