CN101541780A - Fibrate carboxylate compound and preparation method and application thereof - Google Patents

Fibrate carboxylate compound and preparation method and application thereof Download PDF

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CN101541780A
CN101541780A CNA2008800003290A CN200880000329A CN101541780A CN 101541780 A CN101541780 A CN 101541780A CN A2008800003290 A CNA2008800003290 A CN A2008800003290A CN 200880000329 A CN200880000329 A CN 200880000329A CN 101541780 A CN101541780 A CN 101541780A
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hydroxybenzene
thioketones
amyl
alkene
bis
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CN101541780B (en
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广兵
黄振
唐云
岑国栋
付铁军
李伯刚
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CHENGDU DI'AO JIUHONG PHARMACEUTICAL FACTORY
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

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Abstract

The invention discloses (5- (p-hydroxyphenyl) -1, 2-dithienyl-4-ene-3-thioketone) fibrate carboxylate compounds shown as a general formula (I), a pharmaceutical composition containing any one of the compounds, and application of the compounds in preparation of medicines for treating fatty liver and hyperlipidemia.

Description

Fibrate carboxylate compounds, preparation methods and uses thereof
Fibrate carboxylate compounds and its production and use technical field
The present invention relates to formula（I shown in)（The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-) fibrate carboxylate compounds, preparation method and the usage belongs to field of medicaments.Background technology
Fatty liver is a kind of common liver pathological changes, refers to caused by a variety of causes fat accumulation in liver cell, when fat content exceedes the 5% of liver weight (weight in wet base), or when histologically exceeding liver parenchyma 30%, referred to as fatty liver.Fatty liver is divided into obesity fatty liver, alcoholic fatty liver, trophic disturbance fatty liver, Drug fatty liver, acute fatty liver of pregnancy, diabetes fatty liver etc. again.One is the characteristics of important, and fatty liver patient is often with dyslipidemia, and therefore, reduction blood fat is beneficial to prevent and treat hepatic steatosis.Have the medicine of ideal treatment also more rare currently for fatty liver patient.Clinically conventional hepatic has N- (2- mercapto radical propionyl groups)-glycine; Polyene Phosphatidylcholine; anethol trithione etc.; effect with certain preventing and treating hepatocellular injury; but for the steatosis offer limited effectiveness of liver cell, and the fatty liver patient for being directed to dyslipidemia has the danger for aggravating hepatic injury directly using lipid-lowering medicine on the contrary.Therefore, the treatment fatty liver new drug that can prevent hepatocellular injury can reduce the steatosis of liver cell again has important clinical demand.
Fibrate is current reduction serum total cholesterol（TC one of maximally effective medicine), it can also raise Serum High-Density Lipoprotein-Cholesterol (HDL-C) simultaneously, and its validity has clinically obtained extensive checking.But the side effect of fibrate also limits its application to a certain extent, in addition to the gastrointestinal reactions such as nausea, stomachache, abdominal distension, diarrhoea, more importantly, it may cause the infringement to liver, the abnormal patient of hepatic and renal function need to use fibrate lipid-lowering medicine with caution, therefore, there is very big limitation in its dyslipidemia treatment for being directly used in fatty liver patient., the amyl- 4- alkene -3- thioketones of sulphur ring of compound 5- (to Yue oxygen phenyl) -1,2- bis-, i.e. anethol trithione are found from crucifer earliest, are used as the clinical practice history of hepatic cholagogic medicine existing decades.Anethol trithione is played a role with prototype absorbed into serum, but also rare to the research report of its derivative and structure-activity relationship.Particularly influence of the change of benzene ring substituents to its drug effect, is still difficult to predict.The derivative correlative study of de- Yue anethol trithiones is connected with ester bond, WO2006125293 discloses a class（The amyl- 4- Xi -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）Aminosalicyclic esters of gallic acid anti-inflammatory compound.It there is no at present（The sulphur rings penta of 5- (p-hydroxybenzene) -1,2- bis- bucket alkene -3- thioketones）The pertinent literature report of fibrate carboxylate compounds, Also the relevant report without such use of a compound.The content of the invention
The technical scheme is that there is provided the new compound of a class, it is（The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）Fibrate carboxylate compounds.Present invention also offers the preparation method of such compound and purposes.
The present invention provides a class formula（I shown in)（The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）Fibrate carboxylate compounds.
( I )
Wherein：
R represents single or multiple substituent, selected from hydrogen, halogen, hydroxyl, CMAlkoxy, CMAlkyl, amino, sulfydryl, carboxyl, nitro, sulfonyl, halogen-substituted Yue acyl groups, halogen substituted cyclopropane base, halogen-substituted Yue amide groups substitution ethyl；
X is selected from O, S, NH, CH2;
N represents 0-4 integer.
Halogen elements are selected from F, CI, Br, I, preferably Cl.
Compound is selected from：
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）Chlorophibrinic Acid ester,
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- is [p- (to chlorobenzene formacyl）Benzene oxygen] -2- Yue bases propionic ester,
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）{ p- [2- is (to the stupid formamide of chlorine by 2-）Ethyl] stupid oxygen 2- Yue bases propionic ester,
(5- (p-hydroxybenzene) -1,2The amyl- 4- alkene -3- thioketones of _ bis- sulphur rings）2- [p- (2,2- dichloro cyclopropyl) benzene oxygen] -2 Methylpropionic acid ester,
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）5- (2,5- dimethyl phenoxy) -2,2- dimethyl-pentens acid esters,
The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）To Yue Bezalip Tabletses ester,
The amyl- 4- Xi -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）To Yue phenoxies isobutyrate, The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）Bezalip Tablets ester.
Further, it is preferable to which compound is certainly：
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）Chlorophibrinic Acid ester,
(the amyl- 4- Xis -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）2- is [p- (to chlorobenzene Yue acyl groups）Benzene oxygen] -2- Yue bases propionic ester,
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- [p- (2,2- dichloro cyclopropyl) benzene oxygen] -2- Yue bases propionic ester,
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）The Yue base valerates of 5- (2,5- bis- Yue bases phenyl) -2,2- bis-.
Present invention also offers prepare formula（I the method for compound in), i.e., be condensed into ester with the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis- by the special carboxylic acid compound of shellfish and obtain.
The invention discloses formula（I) application of the compound in treatment fatty liver, high blood cholesterol drug is prepared.The invention discloses a kind of Pharmaceutical composition, it includes such as formula（I the hydrate and pharmaceutical carrier of any compound shown in), its pharmaceutically acceptable salt, salt.
The compounds of this invention can be taken orally or parenteral administration.It can be tablet to be administered orally, glue Nang agent, coating agent etc.；Parenteral administration can be injection, suppository, transdermal absorption formulation etc..Released in addition, can also make Slow, controlled release preparation etc..
When carrying out SARS drug design, according to pharmaceutical chemical principle of hybridization, by two identical pharmacophoric groups, a molecule is connected into appropriate bridge chain, the medicine of formation, is referred to as with contraction medicine, and existing multiple successful examples of design have simultaneously been used in clinic.And by two different pharmacophoric groups, connect into a molecule, the medicine of formation, referred to as different contraction medicine.This splitting mode seems simple, but general pharmaceutical chemistry technical staff thinks, successful probability is relatively with relatively low for contraction medicine, and reason is many.Mainly two medicines are difficult to while playing optimum treatment dose effect, and the trickle different performances to drug effect in the site, bridged bond along with connection suffer from important influence, therefore pharmacodynamic results are more difficult to expect.It is generally believed that the possibility for surmounting active compound is little.For example, after camptothecin derivative and taxol are pieced together a series of noval chemical compounds by Ohtsu et al. by bridged bond, it is found that such compound anti-cancering activity is less than camptothecine.（Bioorg Med Chem, 2003, 11 : 1851-1857 )
The creativeness of the present invention is, the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis- and fibrate lipid-lowering drugs is combined into new（The amyl- 4- alkene -3- thioketones of sulphur ring of 5- (to the stupid base of hydroxyl) -1,2- bis-）Fibrate carboxylate compounds, and it is surprised to find that the analog derivative has the fatty liver therapeutic effect stronger compared with anethol trithione and fibrate, therefore, with important potential applicability in clinical practice. Embodiment
Present invention also offers the following embodiment, but these embodiments are not construed as limiting the invention.
The structure of compound is by nuclear magnetic resonance（) or mass spectrum NMR（MS) determine.NMR displacements（δ) provided with the unit of hundred a ten thousandths (ppm), mp. be with.The fusing point that C is provided, the non-correction up of temperature.It is to use BrukerAvance 600, fusing point test WRS-1 numeral melting point instruments that NMR, which is determined,.【Embodiment 1】The preparation of the compounds of this invention
(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）Synthesis：
Mix the amyl- 4- alkene -3- thioketones of sulphur ring of 5- (to Yue oxygen phenyl) -1,2- two（25g, 104 awake ol), DMAP
(2.5g, 20.4mmol), dry dichloromethane lOOOmL forms dark red solution in 2000 mL three-necked bottle.550mL lmol-L " are added dropwise at room temperature1 BBr3Dichloromethane solution, solution fades to orange red suspension.Finish, continue to react after about 24h terminating.Reaction solution is poured into 4000mL water in batches, is sufficiently stirred for lh, is stood, and filtering, filter cake is rinsed with a large amount of water, is dried, is obtained yellow orange solid crude product 22.3g, yield 95%. mp.l92 ~ 193 °C *H NMR(CDC13, 600MHZ):6ppm 9.36 (s, lH), 7.79 (d, 2H, J=9.0Hz), 7.50 (s, lH), 7.01 (d, 2H, J=9.0Hz).
ESI-MS: m/z 227(M+l)+
IR: 3179,1608,1587,1476,1288,1196,1182,1032,831,561.,
【Embodiment 2】
((the amyl- 4- alkene -3- of sulphur ring of 5- (p-hydroxybenzene)-l, 2- bis- dredge ketone) Chlorophibrinic Acid ester）Synthesis： Mix chlorine shellfish butyric acid（11.4g, 53.1mmol), DMAP (196mg, 1.6mmol), the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-（12g, 53.1mmol), ethyl acetate 1000ml is in 2L three-necked bottle.Lower addition DCC (16.4g, 79.7mmol) is stirred at room temperature, finishes, continues stirring reaction and is terminated after 5 hours.Reacting liquid filtering, filtrate saturated sodium bicarbonate, saturated aqueous common salt is washed 2-3 times successively.Organic layer is dried with anhydrous magnesium sulfate, and filtering, filtrate is concentrated into 200ml, adds 700ml alcohol crystals.Separate out solid and use ethyl acetate/ethyl alcohol recrystallization again, obtain sterling 13.2g, the % of yield 60.
mp.97 - 98 °C Ή NMR(CDC13 , 600MHz): 6ppm 7.68(d,2H,J=8.4Hz), 7.39 (s, lH), 7.25 (d, 2H, J=8.6Hz), 7.15 (d, 2H, J-8.4Hz), 6.89 (d, 2H, J=8.4Hz), 1.75 (s, 6H).
ESI-MS: m/z 445(M+Na) +
IR: 3422, 1761,1489, 1178,1122, 1024,818,672,538。
【Embodiment 3】
((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）{ p- [2- is (to chlorobenzene Yue acid amides by 2-）Ethyl] benzene oxygen } -2- Yue base propionic esters）Synthesis：
With Bezafibrate acid for raw material, synthetic method is similar to embodiment 2, the % of yield 88.
mp.l56 ~ 157°C 'H NMR(CDC13, 600MHz): 6ppm 7.66(d,2H,J=8.4Hz), 7.61(d,2H,J=8.4Hz), 7.38(s,lH),7.36(d,2H,J=8.4Hz), 7.14-7.16(m,4H),
6.92(d,2H,J=8.4Hz), 6.10(brs, 1 H),3.69(dt,2H, J=6.2, 7.0Hz), 2.89(t,2H,J=7.0Hz), 1.76(s,6H)。
ESI-MS: m/z 570(M+1) +
【Embodiment 4】
((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene)-l, 2- bis-）2- [p- (to chlorobenzene Yue acyl groups) benzene oxygen] -2- Yue base propionic esters）Synthesis：
Using fenofibrate as raw material, synthetic method is similar to embodiment 2, the % of yield 89.
mp.l34 ~ 135°C
1HNMR(CDC13, 600MHz): 5ppm7.79(d,2H,J=8.8Hz), 7.72(d,2H,J=8.6Hz), 7.67(d,2H,J=8.8Hz), 7.46(d,2H,J-8.6Hz), 7.38(s,lH), 7.14(d,2H,J=8.6Hz),
7.00 (d, 2H, J=8.8Hz), 1.84 (s, 6H).
ESI-MS: m/z 527(M+1) +
【Embodiment 5】
((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）To Yue Bezalip Tablets esters）Synthesis:
Mixing is to the stupid oxygen isobutyric acid of Yue bases（232mg, 1.2mmol), DMAP (3.7mg, 0.03mmol), the amyl- 4- alkene -3- thioketones of the stone gram rings of 5- (p-hydroxybenzene) -1,2- bis-（226mg, 1 mmol), ethyl acetate 50ml is in 250ml three-necked bottle.Lower addition DCC (309mg, 1.5mmol) is stirred at room temperature, finishes, continues stirring reaction and is terminated after 5 hours.Reacting liquid filtering, filtrate saturated sodium bicarbonate, saturated aqueous common salt is washed 2-3 times successively.Organic layer is dried with anhydrous magnesium sulfate, filtering, and column chromatography obtains Pure product 321mg, the % of yield 80 after concentration. mp.98 ~ 99°C
'H NMRCCDC , 600MHz): 6ppm 7.66(d,2H,J=8.9Hz), 7.38(s,lH),
7.17 (d, 2H, J=8.8Hz), 7.09 (d, 2H, J=8.3Hz), 6.86 (d, 2H, J=8.6Hz), 2.31 (s, 3H), 1.74 (s, 6H).
【Embodiment 6】
((the amyl- 4- Xis -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）To methoxybenzene oxygen isobutyrate) synthesis：
So that to the stupid oxygen isobutyric acid of Yue epoxides, as raw material, synthetic method is similar to embodiment 5, the % of yield 71. mp.98 ~ 99 "C
,HNMR(CDCl3,600MHz):6ppm7.68(d,2H,J-8.7Hz),7.40(s,lH),
7.20(d,2H,J=8.7Hz), 6.94(d,2H,J=8.9Hz), 6.82(d,2H,J=8.9Hz), 3.78(s,3H) 1.71(s,6H)。
【Embodiment 7】
((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene)-l, 2- bis-）Bezalip Tablets ester）Synthesis： Using Bezalip Tablets as raw material, synthetic method is similar to embodiment 5, the % of yield 65.
mp.90 ~ 91 °C
1HNMR(CDCl3,600MHz):5ppm7.66(d,2H,J=8.6Hz),7.38(s,lH),
7.30(t,2H,J=8.6Hz), 7.14(d,2H,J=8.6Hz), 7.05(t,lH,J=7.4Hz), 6.96(d,2H,J=7.8Hz);1.77 (s, 6H). 【Embodiment 8】
((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）The Yue base valerates of 5- (the Yue phenoxyls of 2,5- bis-) -2,2- two）Synthesis：
With the Yue bases valeric acids of 5- (2,5 two Yue phenoxyls) -2,2- bis- for raw material, synthetic method is similar to embodiment 5, obtains a grease, the % of yield 60.
^ NMRCCDC^, 600MHz): 5ppm7.64 ( d,2H,J=8.6Hz ) , 7.38(s,lH), 7.15(d,2H,J-8.6Hz), 7.00(d,lH,J=7.4Hz), 6.66(d,lH,J=7.4Hz), 6.62(s,lH), 3.99(t,2H,J=5.8Hz), 2.30(s,3H), 2.17(s,3H), 1.88(m,4H), 1.39(s,6H)。
【Embodiment 9】
((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene)-l, 2- bis-）2- [p- (2,2- dichloro cyclopropyl) benzene oxygen] -2- Yue base propionic esters）Synthesis
With 4- (2,2- dichloro cyclopropyl) Bezalip Tablets for raw material, synthetic method is similar to embodiment 5, the % of yield 65. mp.l01-102°C. ESI-MS: m/z 498(M+1) +
1HNMR(CDC13, 600MHz):5ppm7.64 (d, 2H, J=8.7Hz), 7.37 (s, lH), 7.17 (d, 2H, J=8.6Hz), 7.09 (d, 2H, J=10.8Hz), 6.92 (d, 2H, J=8.6Hz), 2.86 (lH, m), 1.96 (dd, 1H, J=7.3,7.5Hz), 1.80 (t, 1 H, J=7.7Hz), 1.77 (6H, s).
【Embodiment 10】Glue Nang is prepared and usage and dosage：
Compound in Example 2（The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-) Chlorophibrinic Acid ester（Cylinder claims BOA-1) 100g, microcrystalline cellulose 400g, after fully mixing, canned No. 1 glue Nang 2000.It is within three weeks a course for the treatment of with daily three of the fatty liver patient of dyslipidemia.
【Embodiment 11】Injection is prepared and usage and dosage：
Compound in embodiment 4（The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- [p- (to chlorobenzene formacyl) benzene oxygen] -2 Methylpropionic acid ester（（Abbreviation BOA-2) 250mg crush after, injection soybean oil 75g, medium chain fatty acid ester 25g, lecithin 12g, polyethylene glycol 50g, glycerine 20g, water for injection 1000ml, disperse on high speed homogenizer, sterilizing is made 25mg/100ml fat emulsion intravenous fluid parenteral solutions.With the daily consumption 100-300ml of fatty liver patient of dyslipidemia. Beneficial effects of the present invention are proved below by way of specific pharmacodynamics test.
1 test material and method
1. 1 trial drug
Test medicine：Numbering BOA-1 ((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）Chlorophibrinic Acid ester）, i.e. the compound of embodiment 2；BOA-2 ((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- [p- (to chlorobenzene Yue acyl groups) benzene oxygen] -2- Yue base propionic esters）, i.e. the compound of embodiment 4；Numbering BOA-3 ((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）The Yue base valerates of 5- (2,5- bis- Yue phenoxyls) -2,2- bis-）, i.e. the compound of embodiment 8；BOA-4 ((the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- [p- (2,2- dichloro cyclopropyl) benzene oxygen] -2- Yue base propionic esters）, i.e. the compound of embodiment 9.During experiment first with appropriate tween grind, then with 0.5% carboxylic Yue base sodium cellulosates（CMC) prepared by design concentration.
Control drug：1. the Polyene Phosphatidylcholine 2. Clofibrate 3. sulphur ring penta _ 4- alkene -3- thioketones of 5- (to Yue phenyls) -1,2- two（Numbering 3S), during experiment first with appropriate tween grind, then with 0.5% carboxylic Yue base sodium cellulosates（CMC) prepared by design concentration.
1. 2 experimental animals
Stomach stomach stomach stomach stomach emits stomach and emits stomach
Wistar rats, 180 ~ 220g of body weight, male, 180, every group of 20 rats, animal quality certification number：410117, by Henan Medical Univ., Experimental Animal Center is provided.
1. 3 reagents
Cholesterol（Chengdu Ke Long chemical reagents factory）, Tween-80 (Chengdu Ke Long chemical reagents factory）, carbon tetrachloride（Chengdu Ke Long chemical reagents factory）, sodium taurocholate (Shanghai Solarbio), Propylthiouracil Tablets（Shanghai Fosun Zhaohui Pharmaceutical Co., Ltd.）, 1,2-PD（Tianjin great Mao chemical reagent factories）, carboxylic Yue base sodium cellulosates（Shanghai San Pu Chemical Co., Ltd.s）, lard, Beijing Erguotou wine.
1. 4 packets and dosage are set
Table 1 is grouped and dosage is set
Administered volume is administered
Approach（ml/100g)
Blank group -- 0
Model group -0
BOA-1 27 0
BOA-2 27 0
BOA-3 27 0
BOA-4 27 0
Polyene Phosphatidylcholine 246.24 0
Clofibrate 27 0
3S 27_ 0
1. 5 data statistical approach
Metering experiment result with（X ± SD) represent, carry out variance point using SPSS-10.0 statistical softwares Analysis；Count Test result uses non-parametric test（Kruskal-Wallis methods are analyzed）.
1. 6 test methods and step
After rat adaptability is raised 3 days, every morning each group rat is respectively by the design dosage administration of table 1, and blank group gives corresponding CMC suspensions.
Afternoon, gavage gave high fat liquor to remaining each group rat respectively in addition to blank group（10% lard, 4% cholesterol, 0.6% sodium taurocholate and 0.3% propylthiouracil (PTU)）White wine lml/100g, continuous 18 days are given after lml/100g, lh again.
Separately in addition to blank group, 10% CC1 is injected intraperitoneally in remaining each group rat every other day4Vegetable seed oil solution, injection dosage is：0.08ml/100g, blank group is with isometric(al) physiological saline in same area.
In fasting 16 hours after the 18th day last dose（It can't help water）, animal weighed, and stock is moved
Centrifuge and separate serum, -30 °C of Cord bloods, the biochemical indicator in test serum.Separately win liver and weigh, after observation general appearance, every takes 2 pieces of left lobe of liver to be put in 10% neutral formalin solution, liver histopathology inspection to be made respectively（After fixation, HE dyeing and fat stains are made in FFPE, section respectively）.
2 result of the tests
2. the measure of 1 the 18th day each test group biochemical indicator of administration
Table 2 is administered the 18th day each test group Biochemical Indexes and compares the scholar 0.78 6.13 ± 2.51 of 67.4 ± 8.9AA of (± SD) group ALT AST TG CHOL blank groups, 74.4 ± 130 2.59 ± 0.54 Α Α model groups of why not legendary venomous insect of Α Α 0.88 ± 0.33 356.0 ± 273.9 185.7 ± 125.9 2.08
The legendary venomous insect Ginseng of 1. 31 ± 0. 65 Α of ± 127. 104. 9 ± 82. 6 Α * * of BOA- 1 208. 7 4. 16 ± 1. 14 start
The 7A* 98. 0 ± 27. 4 of BOA- 2 167. 5 ± 60. * * that stand tall and upright start the Α of ± 0. 78 legendary venomous insect Ginseng Ginseng of the 18' of Ginseng 1. 4. 25 ± 1. 17
The Α of 161.0 ± 100.3 legendary venomous insect * of BOA-3,140.0 ± 27.4 * * 1.38 ± 0.70 why not Ginseng 4.01 ± 1.30
BOA-4 280.5 ± 90.5 starts 108.3 ± 45.3 Α of 1.20 ± 0.81 legendary venomous insect Ginseng Ginseng of * * fists 3.99 ± 1.24 that stand tall and upright and starts the native Α of ± 253.6 175.0 ± 100.3 1.10 ± 0.45 Α of 1.21 Clofibrate 300.0 3.95 ± 1.26 of 136.5 ± 95.8A of Ginseng Polyene Phosphatidylcholines, 102.0 ± 81.2 legendary venomous insects 2.02 ± 0.56 5.38
Why not 160.9 ± 101.4 1.80 ± 0.46 5.21 ± 1.44 note of 3S 192.4 ± 180.1：Compare with model group, A A P<0.01, A P< 0.05;
Compare with Clofibrate group, * *< 0.01, * < 0.05
With 3S (anethol trithione groups）Compare,< 0.01, · < 0.05.
As seen from the above table, it is administered the 18th day, model group and Normal group compare, rat blood serum ALT (alanine aminotransferases）, AST (aspartic transaminases）, TG (triglycerides）, CHOL (cholesterol）Activity significantly increases.
Compared with model group, test medicine Β Ο Α -1, BOA-2 can significantly reduce ALT, AST active elevated-levels, and triglyceride, cholesterol can be reduced again；^ third constellations ALT can significantly drop in BOA-3, and triglyceride, cholesterol can be reduced again；BOA-4 can significantly reduce AST, and triglyceride, cholesterol can be reduced again. Compared with Clofibrate group, there was no significant difference for reduction effects of test medicine BOA-l, BOA-2, BOA-3, the BOA- 4 to TG, CHOL.Meanwhile, test medicine Β Ο Α -1, BOA-2, BOA-3, BOA- 4 can significantly reduce AST, and BOA- 2, BOA-3 can significantly reduce ALT, and Clofibrate significantly reduces effect to this equal nothing.
With 3S (anethol trithiones）Group is compared, and there was no significant difference for the reduction effect of test medicine BOA-l, BOA-2, BOA-3 to ALT, and test medicine BOA-l, BOA-2, BOA-4 can more significantly reduce AST;Meanwhile, test medicine BOA- 1, BOA-2, BOA-3, BOA-4 can significantly reduce TG, CHOL, and 3S groups significantly reduce effect to this equal nothing.
2. 2 liver histopathology Inspection and analysis：（HE is dyed, 100 X)
The rat liver middle period is taken, is fixed with 4% paraformaldehyde, normal wax embedded section, h and E is dyed, the change of optical microphotograph Microscopic observation liver pathomorphology, its histological change is scored with reference to table 3, and hepatic tissue pathology the results are shown in Table 4.
The hepatic tissue pathology of table 3 damages criterion
Histopathology changes rank scores value without degeneration of liver cells.Without ' -0
Swelling of liver cell, volume increase, iuntercellular still bounded
Hydropic degeneration minor injury+1
Limit, the light dye of endochylema.
(cell infiltration cell obvious tumefaction, iuntercellular boundary is unclear, endochylema
Sinus hepaticus dilatation and congestion）Moderate lesion ++ 2
Light dye.
Balloon sample becomes, and cell is expanded such as balloon, and endochylema becomes
Severe injury +++ 3
It is relatively transparent.
Represent normal.Without -0
Fat vacuole in liver cell is smaller, and is dispersed in.Minor injury+1
Fat vacuole in steatosis hepatocyte becomes big, wider range.Moderate lesion ++ 2
Fat vacuole is fused to big vacuole, and nucleus is pressed to
Severe injury +++ 3
Under after birth, shape is like fat cell.
Represent without necrosis.Without -0
There can be the liver cell being dispersed in spotty necrosis, lobuli hepatis
Necrosis, each necrosis region only involves single or several liver minor injuries+1
Non-viable non-apoptotic cell.
Broken strip necrosis, liver cell is in focal necrosis, is collapsed
Moderate lesion ++ 2
Solution
There is large stretch of dissolving focal necrosis.Severe injury +++ 3
There is no hyperplasia.Without -0
Fibrosed tissue, which increases, only has fibrocyte and a few fibres hyperblastosis, just
Minor injury+1
Raw normal lobuli hepatis structure is may be seen indistinctly.
There are obvious proliferation of fibrous tissue, normal lobuli hepatis knot
Moderate lesion ++ 2
Structure is not obvious, but not yet forms obvious pseudolobuli.
There are a large amount of hyperblastosises, cell is surrounded into fritter in small
Severe injury +++ 3
Island, hence it is evident that pseudolobuli is formed. The medicine of table 4 causes influence group dosage (mg/kg) the oedema steatosis cell infiltration necrosis blank group -0AA 0.07AA 0.87AA 0.8AA model groups 2.08 2.38 1.92 2.54 of Models of Fatty Liver rat liver pathology to complex method
BOA-1 27 1.51 A 1.8 1.21 A 1.90
BOA-2 27 1.53A 1.3A 1.72 1.83
BOA-3 27 0.90AA 1.7 1.24A 1.88
The A 1.5A 1.67 2.00 of 27 1.55A of BOA-4,1.9 1.60 1.76 Polyene Phosphatidylcholines 246.24 1.27
Clofibrate 27 1.82 2.10 1.83 2.35
The notes of 27 1.50A of 3S 1.90 1.60 2.00：Compare with model group, A A P<0.01, A P< 0.05
Statistical method：The non-parametric test analysis method that the softwares of SPSS 11.0 are provided is used in the significance test of group difference.
Model group is compared with blank control group, the denaturation and necrosis of liver cell is occurred in that, through non-parametric test, with significant difference（▲), show modeling success.
Compared with model group, Clofibrate is to the oedema of liver cell, steatosis, cell infiltration and necrosis there are no significant improvement result；3S can significantly improve liver cell oedema, but steatosis, cell infiltration and necrosis be acted on without significant improvement；Test medicine BOA-l, BOA-2, BOA-3, BOA-4 can significantly improve liver cell oedema；BOA-2 can significantly improve hepatic cell fattydegeneration；BOA-l, BOA-3 can significantly improve the infiltration of inflammatory cell.
2. 3 liver fat stains（Soudan III is dyed）.
After hepatic tissue is fixed through 10% Yue aldehyde solution, water freezes section（6 ~ 8 μ η ι of thickness), distilled water is slightly washed；Haematine dye core l ~ 2min, becomes after basket and washes；Developed a film quarter with 70% alcohol again；Entering the min of soudan III coloring agent 5 ~ 10, (sealing prevents reagent from volatilizing as far as possible in dyeing, and such as 56 °C of times of heating can shorten）；70% alcohol washes away unnecessary dye liquor；With glycerin gelatine mounting.As a result：Neutral fat is in orange red, and core is in blueness.The change of its liver fat stains is scored with reference to table 5, and liver fat stains the results are shown in Table 6.
The liver fat stains criterion of table 5
Histopathology changes rank scores value
Represent normal.Without -0
Chinese red fat drips in liver cell are smaller, and
Minor injury+1
It is dispersed in.
Chinese red fat drips in fat stains liver cell become big, model
Moderate lesion ++ 2
Enclose wider.
Fat is fused to big Chinese red adipose capsule, will be thin
Severe injury +++ 3
Karyon is pressed under after birth. The liver fat stains appraisal result of table 6
Group measures (mg/kg) fat stains scoring together
The 0AA of blank group one
Model group 1
BOA-1 27 1.81
BOA-2 27 1.53A
BOA-3 27 1.50A
BOA- 4 27 1.45 A
The A of Polyene Phosphatidylcholine 246.24 1.67
Clofibrate 27 2.2
3S 27 1.9
Note：Compare with model group, A A P< 0.01 , Α Ρ < 0.05
Result above shows：Model group is compared with blank control group, occurs in that hepatic cell fattydegeneration, is examined through nonparametric number, with significant difference（ A P<0.01), show to cause fatty liver model of rats by complex factors.
Compared with model group, with model group, there was no significant difference for the liver fat stains scoring of Clofibrate group and 3S groups；Test medicine BOA-2, BOA- 3, BOA-4 liver fat stains scoring are considerably better than model group；Test medicine BOA-1 trend of the liver cell fat stains scoring with reduction.
3 conclusions
Above-mentioned pharmacodynamics test proves, test medicine BOA-l, BOA-2, and BOA-3, BOA-4 are specific as follows also with other unexpected effects in the going out of the reduction blood fat with fibrate and anethol trithione and liver protecting therapy effect：
Test medicine BOA-l, BOA-2. BOA- 3, BOA-4 are the special carboxylic acid of shellfish and the conjugate for removing Yue anethol trithiones, and molecular weight is greatly increased with respect to Bei Te with anethol trithione, and dosage is 27mg/kg.By taking BOA-1 as an example, such as using chlorine shellfish butyric acid and go first anethol trithione for pharmacophoric group metering, noval chemical compound BOA-1 molecular weight after coupling increases by 1 times compared with Clofibrate and anethol trithione, therefore the chlorine shellfish butyric acid and 1/2 dosage of identical dosage only 1/2 dosage remove first anethol trithione.
Pass through above-mentioned result of the test：In biochemical indicator detection experiment, Clofibrate can significantly reduce TG, CHOL, but on ALT, AST without influence, 3S only significantly reduces ALT, and the compounds of this invention is significantly improved to four indexs；Liver histopathology Inspection and analysis, Clofibrate is invalid for liver cell oedema, steatosis, cell infiltration, necrosis, 3S is only effective to liver cell oedema, and the compounds of this invention has obvious effect to three kinds of indexs in addition to necrosis, especially BOA-3 has extremely significant improvement for liver cell oedema；Liver fat stains experiment shows that Clofibrate, 3S is invalid to hepatic cell fattydegeneration, and the compounds of this invention is significantly improved effect for hepatic cell fattydegeneration. Above-mentioned experiment shows, the compound of the present invention can not only significantly reduce TG, CHOL, ALT, AST, and for hepatic pathology damage, especially hepatic cell fattydegeneration tool is significantly improved, it can be seen that the compounds of this invention has good therapeutic effect to fatty liver, and when Clofibrate or anethol trithione with the compounds of this invention effective dose same dose is used alone, it is invalid to treatment hepatic cell fattydegeneration, hepatic pathology damage is not also obviously improved, only anethol trithione has certain improvement to liver oedema.Industrial applicability
The present invention（The amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）Fibrate carboxylate compounds, pass through specific pharmacophoric group split, effect for reducing fat and the function for protecting liver and reducing enzyme activity of anethol trithione class medicine not only with fibrate, and, the compounds of this invention has prominent therapeutic action to liver cell fat lesion, the curative effect is that not available for anethol trithione class and fibrate, therefore, the compounds of this invention has extremely good application prospect in terms of fatty liver is treated.
Meanwhile, general formula compound of the present invention has good effect for reducing blood fat, and can mitigate the side effects such as the hepar damnification of fibrate, the application prospect with good treatment hyperlipidaemic conditions.

Claims (9)

  1. Claims
    1st, formula（I shown in)（5- the sulphur rings penta of (p-hydroxybenzene) -1,2- two _4_ Xi -3- dredge ketone) fibrate carboxylate compounds：
    ( I )
    Wherein：
    R represents single or multiple substituent, selected from hydrogen, halogen, hydroxyl, d.4Alkoxy, CM alkyl, amino, sulfydryl, carboxyl, nitro, sulfonyl, halogen-substituted formoxyl, halogen substituted cyclopropane base, halogen-substituted Yue amide groups substitution ethyl；
    X is selected from 0, S, NH, CH2;
    N represents 0-4 integer.
    2nd, compound according to claim 1, it is characterised in that：Halogen is selected from F, CI, Br,
    I。
    3rd, compound according to claim 2, its feature is being：Halogen elements are selected from Cl.
    4th, compound according to claim 1, it is characterised in that described compound is selected from：(the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）Chlorophibrinic Acid ester,
    (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）2- is [p- (to chlorobenzene Yue acyl groups）Benzene oxygen] -2- Yue bases propionic ester,
    (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）{ p- [2- is (to chlorobenzene Yue acid amides by 2-）Ethyl] benzene oxygen } -2 Methylpropionic acid ester,
    (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- [p- (2,2- dichloros cyclopropyl) benzene oxygen] -2 Methylpropionic acid ester,
    (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）The Yue bases valerates of 5- (2,5 two Yue bases phenyl) -2,2- bis-,
    (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- two）To Yue Bezalip Tabletses ester, (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）To Yue phenoxies isobutyrate, (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）Bezalip Tablets ester.
    5th, compound according to claim 4, it is characterized in that, compound preferably is selected from：
    (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）Chlorophibrinic Acid ester,
    (the amyl- 4- Xis -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- is [p- (to chlorobenzene Yue acyl groups）Benzene oxygen] -2- Yue bases propionic ester,
    (the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis-）2- [p- (2,2- dichloro cyclopropyl) benzene oxygen] -2- Yue bases propionic ester,
    (5- (p-hydroxybenzene) -1,2_ bis- sulphur rings penta _4_ alkene _3_ thioketones）5-(2,5_ bis- Yue bases phenyl) _2,2- two Yue base valerates.
    6th, purposes of the compound described in any one of claim 1-5 in treatment fatty liver medicament is prepared.
    7th, purposes of the compound described in any one of claim 1-5 in treatment high blood cholesterol drug is prepared.
    8th, a kind of method of the compound prepared described in claim 1, it is characterised in that：
    The special carboxylic acid compound of shellfish is condensed into ester with the amyl- 4- alkene -3- thioketones of the sulphur rings of 5- (p-hydroxybenzene) -1,2- bis- and obtained.
    9th, it is a kind of to treat fatty liver or the pharmaceutical composition of high fat of blood, it be as the compound any one of the claim 1-5 of effective dose or its pharmaceutically acceptable salt, salt hydrate be active ingredient, add the medicament that is prepared from of pharmaceutical carrier.
    10th, pharmaceutical composition according to claim 9, it is characterised in that：Described medicament is oral formulations or non-intestinal drug delivery agent.
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