CN101502507A - Egonol type benzofuran and novel use in pharmacy of glycosides thereof - Google Patents

Egonol type benzofuran and novel use in pharmacy of glycosides thereof Download PDF

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CN101502507A
CN101502507A CNA2009100056307A CN200910005630A CN101502507A CN 101502507 A CN101502507 A CN 101502507A CN A2009100056307 A CNA2009100056307 A CN A2009100056307A CN 200910005630 A CN200910005630 A CN 200910005630A CN 101502507 A CN101502507 A CN 101502507A
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egonol
glycosides
benzofuran
dioxy methylene
och
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晏菊芳
李麒麟
颜永红
孙建
王晓琴
陈欣
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CHENGDU DIAO JIUHONG PHARMACEUTICAL FACTORY
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CHENGDU DIAO JIUHONG PHARMACEUTICAL FACTORY
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Abstract

The invention discloses the application of egonol-type benzofuran and glycosides thereof in the preparation of an ACAT (Acyl-CoA:Cholesterol Acyltransferase) inhibitor, provides the application of egonol-type benzofuran as shown in general formula I and glycosides thereof in the preparation of the ACAT inhibitor, and further provides the drug combination of the ACAT inhibitor, which contains egonol-type benzofuran and glycosides thereof with the active component being shown in the general formula I. The egonol-type benzofuran and the glycosides thereof can be prepared into various forms of drug, such as tablets, capsules and the like, because of the significant effect of the ACAT inhibitor thereof. The invention is suitable for preventing and treating diseases, such as angina, myocardial infarction, cerebral infarction, Alzheimer's disease, acute coronary syndromes (ACS), percutaneous transluminal coronary angioplasty (PTCA) or post-stenting coronary restenosis; and the invention, as a therapeutic agent for regulating the sebaceous gland function and inhibiting the excessive production of sebum, is also suitable for curing diseases, such as oily skin, acne, seborrhea, acne-like lesion caused by corticosteroid and the like.

Description

The new pharmaceutical use of Egonol type benzofuran and glycosides thereof
Technical field
The present invention relates to a kind of new purposes of general formula compound, specifically, the present invention relates to Egonol type benzofuran and glycosides thereof and prevent and/or treat angina pectoris, myocardial infarction, cerebral infarction, apoplexy, Alzheimer, acute coronary syndrome, PTCA or support is placed the back coronary restenosis in preparation, and the purposes in the medicine of the diseases such as acne sample infringement that cause of oily skin, acne, seborrhea, corticosteroid.
Background technology
Cholesteryl ester can produce the atheroma pathological changes large-area the accumulating of blood vessel, forms lipid-rich spot, and the destruction of lipid-rich spot can form thrombosis, produce the obstruction of coronary artery lumen, thereby causes diseases such as acute coronary syndrome, angina pectoris, myocardial infarction.The speckle that atheromatosis is deformed into forms at carotid artery and cerebral blood vessel then can cause cerebral infarction or apoplexy, so these diseases and atherosclerosis, hyperlipemia are closely related.
Acyl-CoA: cholesterol acyltransferase (Acyl-CoA:Cholesterol Acyltransferase; ACAT) being the enzyme that interior unique catalysis free cholesterol of cell and fatty acid generate cholesteryl ester, is one of key enzyme of cholesterol and esters metabolic balance thereof.The ACAT inhibitor that suppresses this enzymatic activity can be to all wielding influence in the physiological process such as cholesterol absorption, transhipment, distribution and metabolism, thus blood fat reducing, and can stop atherosclerotic early lesion.In addition, existing document as: US 6133326, CN1863521A, report ACAT inhibitor can suppress the sebaceous gland sebum and generate, it can be used as and regulate the sebaceous gland function, suppresses the therapeutic agent that sebum excessively generates, and is used for the treatment of the diseases such as acne sample infringement that oily skin, acne, seborrhea, corticosteroid cause.
Egonol type benzofuran and glycosides thereof are present in (as a watt mountain Benzoinum, high post spring Benzoinum etc.) in some natural plants, and can separate acquisition from these natural plants.There is research report Egonol type benzofuran constituents to have antibiotic and anti-tumor activity (Pauletti PM, Araujo AR et al.Phytochemistry 2000; 597-601; Tsai IL, Hsieh CF, Duh CY.Phytochemistry 1998; 48:1371-1375; Tsai IL, Hsieh CF, Duh CY, Chen IS.Phytochemistry 1996; 43:1261-1263; Cui B, Chai H et al.Tetrahedron 1997; 53:17625-17632); Patent CN1830435, CN1830976, CN1830980, WO2006094456 etc. disclose the application of Egonol type benzofuran constituents in prevention or treatment premature ovarian failure, climacteric syndrome, osteoporosis and adolescence ovarian hypofunction, polycystic ovary syndrome, infertility and the disease that causes because of estrogen deficiency or relative deficiency.Do not see as yet that up to now relevant Egonol type benzofuran and glycosides thereof are used for the document record or the research report of above-mentioned disease as the ACAT inhibitor.
Summary of the invention
Technical scheme of the present invention provides a kind of Egonol type benzofuran and glycosides prepares acyl-CoA in preparation: the purposes in the chole-sterol acyltransferase inhibitor class medicine.
The invention provides Egonol type benzofuran and the glycosides thereof that general formula is I and prepare acyl-CoA: the purposes in the chole-sterol acyltransferase inhibitor class medicine in preparation.
Wherein: R 1For-H ,-OH ,-OCH 3R 2For-H ,-COCH 3,-CO (CH 2) 2CH 3, β-D-glucosyl group, gentiobiose base, gentianose base, R 3-R 7For-H ,-OH ,-OCH 3And other oxygen-containing substituents groups.
Described medicine is to prevent and/or treat angina pectoris, myocardial infarction, cerebral infarction, apoplexy, Alzheimer, acute coronary syndrome, percutaneous transluminal coronary angioplasty or support is placed the back coronary restenosis, and the medicine of the diseases such as acne sample infringement that cause of oily skin, acne, seborrhea, corticosteroid.
Preferably, work as R 1Be-OCH 3, R 2Be-H R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be 5-(3-hydroxyl) propyl group-7-methoxyl group-2-(3,4-dioxy methylene phenyl) benzofuran (be egonol, that is egonol, be designated hereinafter simply as compd A).
Figure A200910005630D00052
5-(3-hydroxyl) propyl group-7-methoxyl group-2-(3,4-dioxy methylene phenyl) benzofuran
Work as R 1Be-H R 2Be-H R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be 5-(3-hydroxyl) propyl group-2-(3,4-dioxy methylene phenyl) benzofuran (the de-methoxy egonol is designated hereinafter simply as compd B).
Figure A200910005630D00053
5-(3-hydroxyl) propyl group-2-(3,4-dioxy methylene phenyl) benzofuran (being the de-methoxy egonol)
Work as R 1For-OH, R 2For-H, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be 5-(3-hydroxyl) propyl group-7-hydroxyl-2-(3,4-dioxy methylene phenyl) benzofuran (the demethyl egonol is designated hereinafter simply as Compound C).
Figure A200910005630D00061
5-(3-hydroxyl) propyl group-7-hydroxyl-2-(3,4-dioxy methylene phenyl) benzofuran (being the demethyl egonol)
Work as R 1For-OCH 3, R 2For-COCH 3, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol acetas (being designated hereinafter simply as Compound D).
Figure A200910005630D00062
The egonol acetas
Work as R 1For-H, R 2For-COCH 3, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be de-methoxy egonol acetas (being designated hereinafter simply as compd E).
Figure A200910005630D00063
De-methoxy egonol acetas
Work as R 1For-OCH 3, R 2For-CO (CH 2) 2CH 3, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol butyrate (being designated hereinafter simply as compound F 17-hydroxy-corticosterone).
Figure A200910005630D00064
The egonol butyrate
Work as R 1For-OCH 3, R 2Be β-D-glucosyl group, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol-glucoside (being designated hereinafter simply as chemical compound G).
Figure A200910005630D00065
Egonol-glucoside
Work as R 1For-OCH 3, R 2Be gentiobiose base, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol-gentiobiose glycosides (being designated hereinafter simply as compound H).
Figure A200910005630D00071
Egonol-gentiobiose glycosides
Work as R 1For-OCH 3, R 2Be gentianose base, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol-gentianose glycosides (being designated hereinafter simply as Compound I).
Egonol-gentianose glycosides
Work as R 1For-H, R 2Be gentiobiose base, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be de-methoxy egonol-gentiobiose glycosides (being designated hereinafter simply as chemical compound J).
Figure A200910005630D00073
De-methoxy egonol-gentiobiose glycosides
Compd A, B, C, D, E, F, G, H, I, J see table 1:
Table 1. compd A, B, C, D, E, F, G, H, I, J
Figure A200910005630D00074
The present invention also provides a kind of ACAT of having to suppress active pharmaceutical composition, and any one or a few that contains above-mentioned general formula I Egonol type benzofuran and glycosides thereof is active component, adds that acceptable accessories or carrier form.The dosage form of described pharmaceutical composition is peroral dosage form or injection.
The clinical amount ranges of wherein said Egonol type benzofuran and glycosides thereof is 1 μ g～500 μ g/kg/ day/people.
General formula is Egonol type benzofuran and glycosides and the above-mentioned preferred compd A of I, B, C, D, E, F, G, H, I, J, can be from natural plants watt mountain Benzoinum [Styrax perkinsiae], high post spring Benzoinum [S.macranthus Perk.], Chuxiong Benzoinum [S.limprichtii Lingelsh et Borza], Styrax tonkinensis [S.tonkinensis (Pierre) Craib et Hartw.], Zhejiang Benzoinum [S.zhejiangensis S.M.Hwang et L.L.Yu], fragrance Benzoinum [S.odoratissimus Champ.], China's Benzoinum [S.chinehsis Hu et S.Y.Liang], the southern regions of the Yunnan Province Benzoinum [S.benzoinoidesGraib], sumatra benzoin [S.benzoin Dryand], Flos Lonicerae Benzoinum [S.argentifolius H.L.Li], Herba Tephrosiae purpureae snowball [S.calvescens Perk], good gift leaf snowball [S.casearifolius Craib], yellow fruit Benzoinum [S.chrysocarpus H.L.Li], Sai Shanmei [S.confusus Hemsl], hanging bead flower [S.dasyanthus Perk], Styrax faberi Perk. [S.faberi Perk], Flos Caryophylli snowball [S.grandiflorus Griff], crow bell [S.hemsleyanus Diels], Tibet snowball [S.hookeri C.B.Clarke], snowball [S.japonicus Sieb.et Zucc], big seed snowball [S.macrospermus C.Y.Wu], Folium paulowniae snowball [S.mallotifolius C.Y.Wu], pink blossom snowball [S.roseus Dunn], wrinkle leaf snowball [S.rugosusKurz], tingia snowball [S.serrulatus Roxb], bolt leaf Benzoinum [S.suberifolius Hook.etArn], lobule Benzoinum [S.wilsonii Rehd], S.ferrugineus, S.officinalis separates acquisition in any one or a few among the S.obassia Sieb.et Zucc etc.; Also can obtain by chemical method is synthetic.Concrete chemical extraction separation method can carry out [Akgul YY, Anil H.Phytochemistry2003 by literature method; 63:939-943; Anil H.Phytochemistry 1980; 19:2784-2786; Takanashi M, Takizawa Y.Phytochemistry 1988; 27:1224-1226; Li QL, Li BG, Qi HY, Gao XPand Zhang GL.Four New Benzofurans from Seeds of Styrax perkinsiae.PlantaMedica, 2005; 71 (9): 847-851].Therefore provide multiple possible effective substance source for the actual therapeutic process, can use any one or any several mixture that contain above-mentioned Egonol type benzofuran and glycosides thereof, or use plant effective site or the crude extract that contains this compounds in a large number.
General formula is any one or any several mixture of the Egonol type benzofuran of I and glycosides thereof, add acceptable accessories or carrier, can prepare becomes multiple oral formulations or injection type, promptly can be made into multiple dosage forms such as tablet, capsule, granule, pill, oral liquid, injection.On preparation method, can Egonol type benzofuran and these active component of glycosides thereof and starch, lactose, glucose, sucrose, dextrin, cellulose family, agar, magnesium stearate, Talcum, acacia gum, gelatin, water, plant wet goods is mixed, preparation becomes suitable dosage form.The use effective dose of Egonol type benzofuran and glycosides thereof is extremely low, reach Gamma Magnitude, according to patient's age, body weight and decide, usually calculate by the adult, its clinical amount ranges is 1 μ g～500 μ g/kg/ day/people, preferred clinical consumption is 10 μ g～100 μ g/kg/ day/people, and clinical practice is very effective and convenient.
Egonol type benzofuran and glycosides thereof are formed Chinese medicine, Western medicine or Chinese and Western compound preparation jointly with other chemicals and/or other Chinese medicine extract, and make multiple dosage forms such as tablet, capsule, granule, pill, oral liquid, injection according to conventional method.
Because Egonol type benzofuran and glycosides thereof have good ACAT inhibitory action, can be made into multiple dosage forms such as tablet, capsule, be applicable to angina pectoris, myocardial infarction, cerebral infarction, apoplexy, Alzheimer, acute coronary syndrome, PTCA (percutaneous transluminal coronary angioplasty) or support placement back coronary restenosis, and the treatment of diseases such as acne sample infringement that cause of oily skin, acne, seborrhea, corticosteroid, have advantages such as evident in efficacy, that using dosage is small, and is cheap, easy to use.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
Embodiment 1: extraction separation and the structural confirmation of Egonol type benzofuran and glycosides A, B, C, D, E, F, G, H, I, J
Extraction with separate: get the fruit 2.2kg (dry weight) of a watt mountain Benzoinum (Styrax perkinsiae picks up from the Yongde County, Yunnan), pulverize the back with 80-90% industrial alcohol 25L lixiviate at room temperature 3 times, each 7 days.Lixiviating solution gets total extractum 550g behind vacuum concentration, it is suspended in the 5L hot water, respectively extracts 5 times with petroleum ether, chloroform and n-butyl alcohol successively, each 5L solvent, concentrated extract gets extractum respectively: petroleum ether part 16g, chloroform part 200g, n-butyl alcohol part 120g.The external activity screening is carried out in sampling, and chloroform and n-butyl alcohol part show that all having the estrogen of promotion generates active.Chloroform is partly gone up silica gel column chromatography, use petroleum ether: acetone=10:1 successively, 5:1, the 0:1 eluting is divided into three sections Fr.1-3 with it.Fr.1 (30g) goes up silicagel column, and use petroleum ether: acetone=10:1 eluting obtains compound F 17-hydroxy-corticosterone (60mg), D (30mg) and E (20mg).Fr.2 (150g) goes up silicagel column, and use petroleum ether: acetone=5:1 eluting obtains compd A (95g), B (5g).Fr.3 (15g) goes up silicagel column, uses CHCl 3: the MeOH=50:1 eluting obtains Compound C (45mg).With getting 55g extractum after the desaccharide of D101 macroporous resin, last silica gel column chromatography is used CHCl to the n-butyl alcohol part successively earlier 3: MeOH=20:1,10:1,5:1, the 0:1 eluting obtains chemical compound G (4.2g), H (33g) and I (2.8g).
With above-mentioned same method, from high post spring Benzoinum (Styrax macranthus Perk.) fruit, also separate having obtained compd A, B, G, H, also obtain chemical compound J simultaneously.
Structural confirmation: in the above-claimed cpd, the carbon of compd A, B, D, E, G, H, I spectrum and consistent (Akgul YY, the Anil H.Phytochemistry 2003 of hydrogen spectrum data with the literature research report; 63:939-943; Takanashi M, Takizawa Y, Mitsuhashi T.Chem Lett 1974; 869-871; Takanashi M, Takizawa Y.Phytochemistry 1988; 27:1224-1226; Anil H.Phytochemistry 1980; 19:2784-2786), promptly compd A is 5-(3-hydroxyl) propyl group-7-methoxyl group-2-(3,4-dioxy methylene phenyl) benzofuran, i.e. egonol, that is egonol; Compd B is 5-(3-hydroxyl) propyl group-2-(3,4-dioxy methylene phenyl) benzofuran, i.e. de-methoxy egonol; Compound D is the egonol acetas; Compd E is a de-methoxy egonol acetas; Chemical compound G is egonol-glucoside; Compound H is egonol-gentiobiose glycosides; Compound I is egonol-gentianose glycosides.Compound C, F, J are noval chemical compound, and its feature is described below:
Compound C is characterised in that:
CF: white amorphous powder; Mp196-199 ℃;
Infrared spectrum: main key band is positioned at 3456,2946,2919,1600,1504,1482,1459,1236,1042,928cm -1
Ultraviolet spectra (MeOH): λ Max(log ε)=204 (4.69), 302 (4.47), 317 (4.54) nm;
Mass spectrum (HRESIMS): m/z=335.0886[M+Na] +(calcd.:335.0890);
Proton nmr spectra (600MHz, DMSO-d 6): δ 6.83 (1H, s, H-3), 7.45 (1H, d, J=1.6Hz, H-4), 6.57 (1H, d, J=1.6Hz, H-6), 9.88 (1H, s, H-7-OH), 7.17 (1H, d, J=1.6Hz, H-2 '), 7.05 (1H, d, J=8.0Hz, H-5 '), 7.42 (1H, dd, J=8.0,1.6Hz, H-6 '), 2.60 (2H, t, J=7.4Hz, H-1 "), 1.72 (2H, m, H-2 "), 3.42 (2H, m, H-3 "); 4.46 (1H, t, J=5.0Hz, H-3 " OH), 6.10 (2H, s, H-(O-CH2-O-));
Carbon-13 nmr spectra (150MHz, DMSO-d 6): δ 32.2 (C-2 "), 35.2 (C-1 "), 60.6 (C-3 "), 101.9 (O-CH 2-O-), 105.4 (C-2 '), 111.0 (C-5 '), 119.1 (C-6 '), 124.8 (C-1 '), (148.2 C-4 '), 148.4 (C-3 '), 101.5 (C-3), 109.3 (C-6), 111.6 (C-4), 131.1 (C-9), 138.4 (C-5), 141.8 (C-8); 142.3 (C-7), 155.3 (C-2).
High resolution mass spectrum quasi-molecular ion peak m/z=335.0886[M+Na from Compound C] +Extrapolating its molecular formula is C 18H 16O 5Ultraviolet spectra is at λ Max=204,302, maximum absorption band appears in the 317nm place, and is similar to the ultra-violet absorption spectrum of egonol, prompts for benzofuran derivatives.Compound C 1The H-NMR signal is similar to egonol also, just than egonol Duo a phenolic hydroxyl group signal δ 9.88 (1H, s, H-7-OH), and methyl signals less.The methylation reaction of Compound C (KOH-(CH 3) 2SO 4) obtained egonol, show that its phenolic hydroxyl group is in the C-7 position.Therefore Compound C is 5-(3-hydroxyl) propyl group-7-hydroxyl-2-(3,4-dioxy methylene phenyl) benzofuran, i.e. demethyl egonol, that is demethyl egonol.
Figure A200910005630D00101
Compound C
Compound F 17-hydroxy-corticosterone is characterised in that:
CF: light yellow solid; Mp76-79 ℃;
Infrared spectrum: main key band is positioned at 2959,1729,1599,1504,1477,1449,1236,1186,1042,930cm -1
Ultraviolet spectra (MeOH): λ Max(log ε)=220 (3.97), 300 (3.86), 315 (4.01) nm;
Mass spectrum (HRESIMS): m/z=419.1459[M+Na] +(calcd.:419.1465);
Proton nmr spectra (600MHz, CDCl 3): δ 6.74 (1H, s, H-3), 7.28 (1H, d, J=1.2Hz, H-4), 6.55 (1H, d, J=1.2Hz, H-6), 6.90 (1H, d, J=1.6Hz, H-2 '), 6.82 (1H, d, J=8.2Hz, H-5 '), 7.35 (1H, dd, J=8.2,1.6Hz, H-6 '), 2.70 (2H, t, J=7.4Hz, H-1 "), 1.95 (2H, m, H-2 "), 4.07 (2H, t, J=6.5Hz, H-3 "), 5.96 (2H, s, H-(O-CH 2-O-)), 3.98 (3H, s, H-7-OMe), 2.26 (2H, t, J=7.8Hz, H-2 " '), 1.62 (2H, m, H-3 " '), 0.92 (3H, t, J=8.5Hz, H-4 " ');
Carbon-13 nmr spectra (150MHz, CDCl 3): δ 13.9 (C-4 " '), 18.7 (C-3 " '), 36.5 (C-2 " '), 31.0 (C-2 "), 32.7 (C-1 "), 63.8 (C-3 "), 56.4 (OMe-7), 101.5 (O-CH 2-O-), 105.8 (C-2 '), 108.8 (C-5 '), 119.4 (C-6 '), 124.9 (C-1 '), (148.2 C-4 '), 148.3 (C-3 '), 100.6 (C-3), 107.6 (C-6), 112.6 (C-4), 131.3 (C-9), 137.2 (C-5), 142.7 (C-8); 145.0 (C-7), 156.3 (C-2), 174.0 (C-1 " ').
The ultraviolet spectra of compound F 17-hydroxy-corticosterone is at λ Max=220,300, maximum absorption band appears in the 315nm place, and is similar to the ultra-violet absorption spectrum of egonol, prompts for benzofuran derivatives.The major part of compound F 17-hydroxy-corticosterone 1H, 13The C-NMR signal is similar to egonol, just has more than egonol 1H-NMR signal δ 0.92 (3H, J=8.2Hz, H-4 " '), 2.26 (2H, t, J=7.8Hz, H-2 " '), 1.62 (2H, m, H-3 " ') and corresponding 13C-NMR signal δ 13.9 (C-4 " '), 36.5 (C-2 " '), 18.7 (C-3 " '), 174.0 (C-1 " ') (according to HMQC), show that compound F 17-hydroxy-corticosterone has more a butanoic acid ester group than egonol.Compound F 17-hydroxy-corticosterone basic hydrolysis (10%KOH alcoholic solution) obtains egonol, and therefore, the structure of this chemical compound is 5-(3-butyryl oxygen propyl group)-7-methoxyl group-2-(3,4-dioxy methylene phenyl) benzofuran, i.e. egonol butyrate.High resolution mass spectrum quasi-molecular ion peak m/z=419.1459[M+Na] +Extrapolating its molecular formula is C 23H 24O 6, further proved conclusively the correctness of this structure.
Figure A200910005630D00111
Compound F 17-hydroxy-corticosterone
Chemical compound J is characterised in that:
CF: white amorphous powder; Mp110-113 ℃;
Infrared spectrum: main key band is positioned at 3427,2924,1620,1503,1474,1363,1256,1232,1074,1038,929,810cm -1
Ultraviolet spectra (MeOH): λ Max(log ε)=216 (4.52), 302 (4.47), 317 (4.10), 331 (3.72) nm;
Mass spectrum (HRESIMS): m/z=620.0546[M+Na] +(calcd.:620.0539);
Proton nmr spectra (600MHz, DMSO-d 6): δ 7.41 (1H, d, J=8.4Hz, H-7), 7.38 (1H, dd, J=7.9,1.8Hz, H-6 '), 7.39 (1H, d, J=1.6Hz, H-4), 7.17 (1H, s, H-2 '), 7.01 (1H, d, J=8.0Hz, H-5 '), 6.99 (1H, s, H-3), 6.77 (1H, s, H-6), 6.07[2H, s, H-(O-CH 2-O-)], 3.45 (2H, t, J=6.4Hz, H-3 "), 2.71 (2H, t, J=7.6Hz, H-1 "), 1.86 (2H, m, H-2 "), 5.04 (1H, d, J=5.0Hz, glc-H-1 '), 4.90 (1H, d, J=4.8Hz, glc-H-1 ");
Carbon-13 nmr spectra (150MHz, DMSO-d 6): δ 155.6 (C-2), 101.5 (C-3), 112.6 (C-4), 138.3 (C-5), 108.3 (C-6), 120.2 (C-7), 142.1 (C-8), 130.9 (C-9), 124.5 (C-1 '), (105.4 C-2 '), (148.4 C-3 '), 148.2 (C-4 '), 109.3 (C-5 '), (119.2 C-6 '), 101.9[C-(O-CH 2-O-)], 32.3 (C-1 "); 31.9 (C-2 "), 68.3 (C-3 "), 103.3 (glc-1 '), (73.9 glc-2 '), 77.3 (glc-3 '), 70.5 (glc-4 '), (76.2 glc-5 '), (68.8 glc-6 '), 103.8 (glc-1 "), 74.0 (glc-2 "), 77.4 (glc-3 "); 70.5 (glc-4 "), 77.3 (glc-5 "), 61.6 (glc-6 ");
The relative optical value of chemical compound J is
Figure A200910005630D0012100531QIETU
:-27.6 ° (c0.1, MeOH); Molecular ion peak m/z621[M+H among the ESI-MS] +And 619[M-H] -Pointing out its molecular weight is 620, fragment peak m/z459[M+H-162] +, m/z297[M+H-162-162] +There are 2 hexose unit in the prompting molecule.Similar characteristic absorption (λ to egonol appears in the UV spectrum Max=218,302,318nm), pointing out it is olive alcohols glycosides.This chemical compound only detects glucose and de-methoxy egonol behind the thin layer acid hydrolysis.δ in the NMR spectrum C103.3,103.8 and δ H5.04 (1H, d, J=5.0Hz), 4.90 (1H, d, J=4.8Hz) glucosyl groups of 2 beta comfigurations of demonstration chemical compound J existence.Chemical compound J's 13The comparison of C NMR data and compd B (de-methoxy egonol) has more 12 carbon signals of two glucosyl groups, remainder chemical shift basically identical.Directly with glucosyl group that the de-methoxy egonol links to each other in C-6 to low field displacement δ 7.2 (61.6 → 68.8), C-5 shows that to high field displacement δ 1.0 (77.2 → 76.2) bind mode of two glycosyls is 1 → 6, is the gentiobiose glycosides.Therefore chemical compound J is accredited as de-methoxy egonol gentiobiose glycosides.
Chemical compound J
The preparation of embodiment 2 tablets
Tablet is formed: compd A 300mg
HPMC LV100 28.7g
Lactose 70g
Magnesium stearate 1g
(making 1000 altogether)
Get compd A, HPMC, lactose, mixing is a binding agent system wet granular with 75% ethanol, cross 22 mesh sieves, 50 ℃ of dry 3h, 22 mesh sieve granulate add magnesium stearate mixing tabletting, every heavy 100mg, be used for atherosclerosis or hyperlipidemia patient, oral, twice of every day, each 1, be a course of treatment January.
The preparation of embodiment 3 capsules
Capsule is formed: compd B 300mg
Starch 98.8g
Magnesium stearate 1g
(making 1000 altogether)
Get compd B, starch, magnesium stearate, mixing, dress gum cover.Every dress 100mg is used for atherosclerosis or hyperlipidemia patient, and oral, every day twice, each 1, be a course of treatment January.
The preparation of embodiment 4 injection
Injection is formed: Compound I 200mg
Tween 80 10mL
Sodium chloride 8g
(making 1000ml altogether)
Get Compound C, add 10%Na 2CO 3Transfer pH to 7.0-7.5, cold preservation filters, and adds tween 80, and NaCl adds the injection water to 1000mL, G 3Sintered filter funnel (glass) filters, packing, and embedding, 100 ℃ of circulation steam sterilization 30min are promptly.
Embodiment 5 compound tablet or capsular preparation
Get Compound D, each 150mg of E, F adds corresponding adjuvant, makes 1000 of tablet or capsules, every the dress 200mg, be used for atherosclerosis or hyperlipidemia patient, oral, once a day, each 1 or 1, be a course of treatment January.
Below prove beneficial effect of the present invention by pharmacodynamics test.
Test example 1 Egonol type benzofuran and glycosides A, B, C, D, E, F, G, H, I, J are to the inhibition activity of ACAT
According to (the Identification of ACAT1-andACAT2-specific inhibitorsusing a novel of method like the mankind such as Rudel, cell-based fluorescence assay, Journal of Lipid Research, Volume45,2004), use the fluorescopy method on a kind of cellular level to come the inhibition activity of authenticating compound to ACAT.
NBD-cholesterol is a kind of novel fluorogenic substrate, and NBD gives cholesterol does not but influence cholesterol with fluorescent characteristic absorption and internal metabolism function.NBD-cholesterol also has a kind of very important characteristic: the fluorescence intensity of NBD-cholesterol depends on its residing environment, NBD-cholesterol sends fluorescence hardly or sends extremely weak fluorescence when being in a kind of polar environment, and NBD-cholesterol just can send very strong fluorescence when being in a kind of nonpolar environment.NBD-cholesterol itself is a kind of polar molecule, but enter in the cell when it is absorbed, under the catalysis of ACAT, generate corresponding cholesteryl ester, just become nonpolar molecule by a kind of polar molecule, and be gathered into the fat granule, form a kind of nonpolar environment.This just provides a kind of ACAT of detection active very easy method.Cholesterol is synthetic mainly to carry out in liver with metabolism.This experimental selection HepG 2Screen cell as supplying, and detected HepG by methods such as RT-PCR 2The expression of cell ACAT.
ACAT suppresses the concrete scheme of determination of activity: inoculation HepG 2Cell is in 96 orifice plates, 20,000/hole, 37 ℃ of overnight incubation, culture medium is abandoned in suction, every hole adds the fresh low sugar DMEM culture medium of 160 μ L earlier, add 20 μ L PBS in blank and the negative control hole, (each sample is done 10 holes, and starter hole concentration is 30 μ g/ml, dilutes successively by 3 times of dilution factors for compd A～J sample that added respectively by prospect hole to prepare in advance and positive control medicine SANDOZ58-035 (Sigma company provides) 20 μ L, make 10 Concentraton gradient), cultivated 1 hour for 37 ℃, blank group adds 20 μ L PBS again, and all the other each holes add the substrate NBD-cholesterol 20 μ L that prepare in advance, final concentration is 2 μ g/ml, 37 ℃ of overnight incubation, PBS washes 3 times, uses WALLAC Victor 2Measure fluorescent value, excitation wavelength is 485nm, and emission wavelength is 535nm, calculates suppression ratio, suppression ratio=(feminine gender-sample)/(feminine gender-blank) * 100% according to fluorescent value.According to suppression ratio, the 4Parameter Logistic Model that uses in the Xlfit software calculates IC 50Value.The result is as shown in table 1:
Table 1 Egonol type benzofuran and glycosides thereof are to the inhibitory action of ACAT
Chemical compound IC 50(μg/mL)
A 7.82
B 9.34
C 10.04
D 16.79
E 25.12
F 13.59
G 9.05
H 8.44
I 3.21
J 12.42
SANDOZ58-035 8.72
As can be seen from Table 1, compd A～J and SANDOZ58-035 all show inhibitory action to ACAT, and wherein the inhibitory action of Compound I is the strongest, its IC 50Value is lower than the IC of SANDOZ58-035 50Value, the effect of compd A, B, G, H and SANDOZ58-035 are roughly suitable.Above result shows that Egonol type benzofuran of the present invention and glycosides thereof have the ACAT inhibitory action, can be used as a kind of new selection of preparation ACAT inhibitor medicaments.

Claims (8)

1, general formula is the Egonol type benzofuran of I and glycosides thereof at the preparation acyl-CoA: the purposes in the chole-sterol acyltransferase inhibitor class medicine.
Figure A200910005630C00021
Wherein: R 1For-H ,-OH ,-OCH 3R 2For-H ,-COCH 3,-CO (CH 2) 2CH 3, β-D-glucosyl group, gentiobiose base, gentianose base, R 3-R 7For-H ,-OH ,-OCH 3Or other oxygen-containing substituents groups.
2, purposes according to claim 1 is characterized in that: described medicine be the treatment or prevention of arterial is atherosis, the medicine of hyperlipemia.
3, purposes according to claim 1 is characterized in that: described medicine is that treatment or prevention angina pectoris, myocardial infarction, cerebral infarction, Alzheimer, acute coronary syndrome, PTCA or support are placed the medicine of back coronary restenosis.
4, purposes according to claim 1 is characterized in that: described medicine is the medicine that is used to regulate the sebaceous gland function, suppresses the excessive generation of sebum.
5, according to each described purposes of claim 1-4, it is characterized in that: described general formula is the chemical compound of I:
R 1Be-OCH 3, R 2Be-H R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be-5-(3-hydroxyl) propyl group-7-methoxyl group-2-(3,4-dioxy methylene phenyl) benzofuran (be egonol, that is egonol);
R 1Be-H R 2Be-H R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be-5-(3-hydroxyl) propyl group-2-(3,4-dioxy methylene phenyl) benzofuran (that is de-methoxy egonol);
R 1For-OH, R 2For-H, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be-5-(3-hydroxyl) propyl group-7-hydroxyl-2-(3,4-dioxy methylene phenyl) benzofuran (that is demethyl egonol);
R 1For-OCH 3, R 2For-COCH 3, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be the egonol acetas;
R 1For-H, R 2For-COCH 3, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be de-methoxy egonol acetas;
R 1For-OCH 3, R 2For-CO (CH 2) 2CH 3, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be the egonol butyrate;
R 1For-OCH 3, R 2Be β-D-glucosyl group, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol-glucoside;
R 1Be OCH 3, R 2Be gentiobiose base, R 6-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol-gentiobiose glycosides;
R 1Be OCH 3, R 2Be gentianose base, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be egonol-gentianose glycosides;
R 1For-H, R 2Be gentiobiose base, R 4-R 5Be dioxy methylene, R 3, R 6, R 7Be-H, be de-methoxy egonol-gentiobiose glycosides.
6, a kind of have an inhibition acyl-CoA: the pharmaceutical composition of cholesterol acyltransferase effect is characterized in that: contain any one or a few of each described Egonol type benzofuran of active component such as claim 1-5 and glycosides thereof.
7, pharmaceutical composition according to claim 6 is characterized in that: be by any one or a few of Egonol type benzofuran and glycosides thereof for active component, add that acceptable accessories or carrier form.
8, according to claim 6 or 7 described pharmaceutical compositions, it is characterized in that: the dosage form of described pharmaceutical composition is: peroral dosage form or injection.
CNA2009100056307A 2008-02-04 2009-01-20 Egonol type benzofuran and novel use in pharmacy of glycosides thereof Pending CN101502507A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103333163A (en) * 2013-07-09 2013-10-02 广州中医药大学 Coumarone derivative, and preparation method and applications thereof
CN106674311A (en) * 2016-12-27 2017-05-17 西安交通大学 Benzofuran glycoside compounds as well as preparation method and application thereof
JP2017515898A (en) * 2014-05-08 2017-06-15 イミューンエクサイト， インコーポレイテッド Immunoregulatory β-1,6-D-glucan

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103333163A (en) * 2013-07-09 2013-10-02 广州中医药大学 Coumarone derivative, and preparation method and applications thereof
JP2017515898A (en) * 2014-05-08 2017-06-15 イミューンエクサイト， インコーポレイテッド Immunoregulatory β-1,6-D-glucan
CN106674311A (en) * 2016-12-27 2017-05-17 西安交通大学 Benzofuran glycoside compounds as well as preparation method and application thereof
CN106674311B (en) * 2016-12-27 2019-02-05 西安交通大学 A kind of benzofuran glycosides compound and its preparation method and application

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