CN101541780B - Fibrate carboxylate compounds, preparation methods and uses thereof - Google Patents
Fibrate carboxylate compounds, preparation methods and uses thereof Download PDFInfo
- Publication number
- CN101541780B CN101541780B CN2008800003290A CN200880000329A CN101541780B CN 101541780 B CN101541780 B CN 101541780B CN 2008800003290 A CN2008800003290 A CN 2008800003290A CN 200880000329 A CN200880000329 A CN 200880000329A CN 101541780 B CN101541780 B CN 101541780B
- Authority
- CN
- China
- Prior art keywords
- thioketones
- alkene
- hydroxybenzene
- rings penta
- sulphur rings
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Gastroenterology & Hepatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The present invention discloses (5-(p-hydroxyphenyl)-1,2-dithiacyclopent-4-ene-3-thione) fibrate carboxylate compounds represented by general formula (I), pharmaceutical compositions containing anyone of aforementioned compounds, and the uses of aforementioned compounds in preparing medicaments which are used to treat fatty liver or hyperlipemia.
Description
Technical field
The present invention relates to (5-(p-hydroxybenzene)-1, the 2-two sulphur rings penta-4-alkene-3-thioketones) fibrate carboxylate compounds shown in the general formula (I), Preparation Method And The Use belongs to field of medicaments.
Background technology
Fatty liver is a kind of common liver pathological changes, is meant fat accumulation in the liver cell that a variety of causes causes, when lipid content surpasses 5% of liver weight (weight in wet base), or when on histology, surpassing liver parenchyma 30%, is called fatty liver.Fatty liver is divided into obese fatty liver, alcoholic fatty liver, nutritional trouble property fatty liver, medicine property fatty liver, acute fatty liver of pregnancy, diabetic fatty liver etc. again.An important characteristic is, fatty liver patient often follows hyperlipemia, and therefore, reduce fat is of value to prevents and treats the liver fat sex change.The medicine that the present fatty liver patient of being directed against has ideal treatment also compares rare.Hepatic commonly used clinically has N-(2-mercapto radical propionyl group)-glycocoll; Polyene Phosphatidylcholine; Trithioanethole etc.; Effect with certain control hepatocellular injury, but limited for hepatocellular steatosis curative effect, and directly use lipid lowerers to have the danger that increases the weight of liver injury on the contrary to the fatty liver patient of hyperlipemia.Therefore, can prevent that the treatment fatty liver new drug that hepatocellular injury can reduce hepatocellular steatosis again from having the important clinical demand.
Fibrate is one of the most effectively medicine that reduces at present serum total cholesterol (TC), its serum high-density LP-SUV (HDL-C) that can also raise simultaneously, and its validity has obtained extensive checking clinically.But the spinoff of fibrate has also limited its application to a certain extent; Except that gastrointestinal reactions such as nauseating, stomachache, abdominal distension, diarrhoea; The more important thing is that it possibly cause the infringement to liver, the unusual patient of hepatic and renal function needs the careful fibrate lipid-lowering medicine of using; Therefore, there is very big limitation in its hyperlipemia treatment that directly is used for the fatty liver patient.
Compound 5-(p-methoxyphenyl)-1,2-two sulphur rings penta-4-alkene-3-thioketones, promptly trithioanethole is found from cress the earliest, as the hepatic cholagogic medicine clinical application history of existing decades.Trithioanethole is absorbed into blood with prototype and plays a role, but also rare to the research report of its verivate and structure activity relationship.Particularly substituent variation still is difficult to prevision to the influence of its drug effect on the phenyl ring.With the verivate correlative study of ester bond connection piptonychia trithioanethole, WO2006125293 discloses one type of (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) aminosallcylic acid ester class anti-inflammatory compound.Still do not have the pertinent literature of (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) fibrate carboxylate compounds at present and report do not have the relevant report of such use of a compound yet.
Summary of the invention
Technical scheme of the present invention has provided one type of new compound, and it is (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) fibrate carboxylate compounds.The present invention also provides the preparation method and the purposes of this compounds.
The present invention provides (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) shown in one type of general formula (I) fibrate carboxylate compounds.
Wherein:
R represents list or multi-substituent, is selected from hydrogen, halogen, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkyl, amino, sulfydryl, carboxyl, nitro, alkylsulfonyl, halogen-substituted formyl radical, halogen substituted cyclopropane base, halogen-substituted formamido-replace ethyl;
X is selected from O, S, NH, CH
2
N represents the integer of 0-4.
Halogen is selected from F, Cl, Br, I, preferred Cl.
Compound is selected from:
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Chlorophibrinic Acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(to chlorobenzene formacyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-{ is right-[2-(to chlorobenzamide) ethyl] benzene oxygen }-the 2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(2,2-dichloro cyclopropyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 5-(2, the 5-dimethyl phenoxy)-2,2-dimethyl-penten acid esters,
5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) to toluene oxygen isobutyrate,
5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) to the methoxycarbonyl phenoxy isobutyrate,
5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) the Bezalip Tablets ester.Further, preferred compound is certainly:
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Chlorophibrinic Acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(to chlorobenzene formacyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(2,2-dichloro cyclopropyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 5-(2, the 5-3,5-dimethylphenyl)-2,2-dimethyl-penten acid esters.
The present invention also provides the method for preparing compound in the general formula (I), is about to special carboxylic acid compound of shellfish and 5-(p-hydroxybenzene)-1, and 2-two sulphur rings penta-4-alkene-3-thioketones is condensed into ester and gets.
The invention discloses the application of general formula (I) compound in preparation treatment fatty liver, high blood cholesterol drug.
The invention discloses a kind of medicinal compsns, it comprises arbitrary compound shown in general formula (I), its pharmaceutically hydrate and pharmaceutical carrier of acceptable salt, salt.
The compounds of this invention can be taken orally or parenteral administration.Oral administration can be a tablet, capsule, seed dressing agent etc.; Parenteral administration can be injection, suppository, transdermal absorption formulation etc.In addition, also can make slowly-releasing, controlled release preparation etc.
When carrying out SARS drug design, according to pharmaceutical chemical principle of hybridization,, connect into a molecule with suitable bridge chain with two identical pharmacophoric groups, the medicine of formation is called with the contraction medicine, and the example that existing a plurality of designs are successful has also used in clinical.And, connecting into a molecule with two different pharmacophoric groups, the medicine of formation is called different contraction medicine.This splitting mode seems simply, but general pharmaceutical chemistry technician thinks that probability of successful is on the low side with the contraction medicine, and reason is many-sided.Mainly be that two medicines are difficult to bring into play the optimum treatment dose effect simultaneously, the trickle difference of site, bridged bond of adding connection is to the performance of drug effect important influence all, so the drug effect result is more difficult expects.It is generally acknowledged that the possibility that surmounts former medicine is little.For example, people such as Ohtsu find that such compound anti-cancering activity is lower than NSC 94600 after camptothecin derivative and taxol are pieced together a series of new compounds through bridged bond.(BioorgMed?Chem,2003,11:1851-1857)
Creativeness of the present invention is; With 5-(p-hydroxybenzene)-1; 2-two sulphur rings penta-4-alkene-3-thioketones and fibrate lipid-lowering drugs are combined into new (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) fibrate carboxylate compounds, and are surprised to find this analog derivative and have than trithioanethole and the stronger fatty liver result of treatment of fibrate; Therefore, has the important clinical application prospect.
Embodiment
The present invention also provides the following embodiment, but these embodiment are not construed as limiting the invention.
The structure of compound is to confirm through nucleus magnetic resonance (NMR) or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit, and mp. is that temperature is correction up not with a ℃ fusing point that provides.It is with Bruker Avance 600 that NMR measures, and fusing point test is with WRS-1 numeral fusing point appearance.
The preparation of [embodiment 1] The compounds of this invention
Synthesizing of (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones):
Mix 5-(p-methoxyphenyl)-1, (25g, 104mmol), (2.5g, 20.4mmol), exsiccant methylene dichloride 1000mL forms dark red solution in the three-necked bottle of 2000mL to DMAP to 2-two sulphur rings penta-4-alkene-3-thioketones.Be added dropwise to 550mL 1molL under the room temperature
-1BBr
3Dichloromethane solution, solution fades to orange red suspension liquid.Finish, continue to stop behind the about 24h of reaction.Reaction solution in the impouring 4000mL water, fully stirs 1h in batches, leaves standstill, and filters, and filter cake washes with big water gaging, and drying must orange solid crude product 22.3g, yield 95%.mp.192~193℃
1H?NMR(CDCl
3,600MHz):δppm9.36(s,1H),7.79(d,2H,J=9.0Hz),7.50(s,1H),7.01(d,2H,J=9.0Hz)。
ESI-MS:m/z?227(M+1)
+
IR:3179,1608,1587,1476,1288,1196,1182,1032,831,561。
[embodiment 2]
Synthesizing of ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Chlorophibrinic Acid ester):
Mixing chlorine shellfish butyric acid (11.4g, 53.1mmol), DMAP (196mg, 1.6mmol), 5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-(12g, 53.1mmol), ETHYLE ACETATE 1000ml is in the three-necked bottle of 2L for the 3-thioketones.(16.4g 79.7mmol), finishes, and continues stirring reaction and stops after 5 hours to add DCC under the stirring at room.Reacting liquid filtering, filtrating is used saturated sodium bicarbonate, and saturated aqueous common salt washs 2-3 time successively.Organic layer is used anhydrous magnesium sulfate drying, filters, and filtrating is concentrated into 200ml, adds the 700ml alcohol crystal again.Separate out solid and use ETHYLE ACETATE/ethyl alcohol recrystallization again, obtain pure article 13.2g, yield 60%.
mp.97~98℃
1H?NMR(CDCl
3,600MHz):δppm?7.68(d,2H,J=8.4Hz),7.39(s,1H),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]
((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-{ is right-[2-(to chlorobenzamide) ethyl] benzene oxygen-the 2 Methylpropionic acid ester) synthetic:
With bezafibrate acid is raw material, and compound method is similar to embodiment 2, yield 88%.
mp.156~157℃
1H?NMR(CDCl
3,600MHz):δppm?7.66(d,2H,J=8.4Hz),7.61(d,2H,J=8.4Hz),7.38(s,1H),7.36(d,2H,J=8.4Hz),7.14-7.16(m,4H),6.92(d,2H,J=8.4Hz),6.10(brs,1H),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]
((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-'s [right-(to chlorobenzene formacyl) benzene oxygen]-2 Methylpropionic acid ester) is synthetic:
With fenofibrate acid is raw material, and compound method is similar to embodiment 2, yield 89%.
mp.134~135℃
1HNMR(CDCl
3,600MHz):δppm7.79(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,1H),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]
Synthesizing of ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) being to toluene oxygen isobutyrate):
Mixing to the methylenedioxy phenoxy isopropylformic acid (232mg, 1.2mmol), DMAP (3.7mg, 0.03mmol), 5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-(226mg, 1mmol), ETHYLE ACETATE 50ml is in the three-necked bottle of 250ml for the 3-thioketones.(309mg 1.5mmol), finishes, and continues stirring reaction and stops after 5 hours to add DCC under the stirring at room.Reacting liquid filtering, filtrating is used saturated sodium bicarbonate, and saturated aqueous common salt washs 2-3 time successively.Organic layer is used anhydrous magnesium sulfate drying, filters, and concentrates the back column chromatography and gets pure article 321mg, yield 80%.mp.98~99℃
1H?NMR(CDCl
3,600MHz):δppm?7.66(d,2H,J=8.9Hz),7.38(s,1H),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]
Synthesizing of ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) being to anisole oxygen isobutyrate):
To be raw material to the methoxyl group Bezalip Tablets, compound method is similar to embodiment 5, yield 71%.mp.98~99℃
1HNMR(CDCl
3,600MHz):δppm7.68(d,2H,J=8.7Hz),7.40(s,1H),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]
Synthesizing of ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Bezalip Tablets ester):
With the Bezalip Tablets is raw material, and compound method is similar to embodiment 5, yield 65%.mp.90~91℃
1HNMR(CDCl
3,600MHz):δppm7.66(d,2H,J=8.6Hz),7.38(s,1H),7.30(t,2H,J=8.6Hz),7.14(d,2H,J=8.6Hz),7.05(t,1H,J=7.4Hz),6.96(d,2H,J=7.8Hz),1.77(s,6H)。
[embodiment 8]
Synthesizing of ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 5-(2, the 5-dimethyl phenoxy)-2,2-dimethyl-penten acid esters):
With 5-(2,5 dimethyl phenoxy)-2,2-dimethyl-valeric acid is a raw material, and compound method is similar to embodiment 5, gets an oily matter, yield 60%.
1H?NMR(CDCl
3,600MHz):δppm7.64(d,2H,J=8.6Hz),7.38(s,1H),7.15(d,2H,J=8.6Hz),7.00(d,1H,J=7.4Hz),6.66(d,1H,J=7.4Hz),6.62(s,1H),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]
((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-'s [right-(2,2-dichloro cyclopropyl) benzene oxygen]-2 Methylpropionic acid ester) is synthetic:
With 4-(2,2-dichloro cyclopropyl) Bezalip Tablets is raw material, and compound method is similar to embodiment 5, yield 65%.mp.101-102℃。ESI-MS:m/z?498(M+1)
+
1HNMR(CDCl
3,600MHz):δppm7.64(d,2H,J=8.7Hz),7.37(s,1H),7.17(d,2H,J=8.6Hz),7.09(d,2H,J=10.8Hz),6.92(d,2H,J=8.6Hz),2.86(1H,m),1.96(dd,1H,J=7.3,7.5Hz),1.80(t,1H,J=7.7Hz),1.77(6H,s)。
Preparation of [embodiment 10] capsule and usage and dosage:
Get compound among the embodiment 2 (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Chlorophibrinic Acid ester (being called for short BOA-1) 100g, Microcrystalline Cellulose 400g, behind the abundant mixing, 2000 of canned No. 1 capsules.Follow three of fatty liver patient every days of hyperlipemia, three weeks were a course of treatment.
Preparation of [embodiment 11] injection and usage and dosage:
Compound among the embodiment 4 (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(to chlorobenzene formacyl) benzene oxygen]-2 Methylpropionic acid ester (after (being called for short BOA-2) 250mg pulverizing, injection VT 18 75g; Medium chain fatty acid ester 25g, Yelkin TTS 12g, polyoxyethylene glycol 50g; Glycerine 20g, water for injection 1000ml disperses on the high speed homogenizer; 25mg/100ml fat emulsion intravenous fluid injection liquid is promptly processed in sterilization.Follow fatty liver patient's consumption every day 100-300ml of hyperlipemia.
Below prove beneficial effect of the present invention through concrete pharmacodynamics test.
1 test materials and method
1.1 trial drug
Receive the reagent thing: numbering BOA-1 ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Chlorophibrinic Acid ester), i.e. embodiment 2 compounds; BOA-2 ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(to chlorobenzene formacyl) benzene oxygen]-2 Methylpropionic acid ester), i.e. embodiment 4 compounds; Numbering BOA-3 ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 5-(2, the 5-dimethyl phenoxy)-2,2-dimethyl-penten acid esters), i.e. embodiment 8 compounds; BOA-4 ((5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(2,2-dichloro cyclopropyl) benzene oxygen]-2 Methylpropionic acid ester), i.e. embodiment 9 compounds.Grind earlier during experiment, use 0.5% Xylo-Mucine (CMC) to press design concentration again and prepare with an amount of tween.
Control drug: 1. 2. 3. 5-(p-methoxyphenyl)-1 of clofibrate of Polyene Phosphatidylcholine, 2-two sulphur rings penta-4-alkene-3-thioketones (numbering 3S) grinds with an amount of tween earlier during experiment, uses 0.5% Xylo-Mucine (CMC) to press design concentration again and prepares.
1.2 experimental animal
The Wistar rat, body weight 180~220g, male, 180, every group of 20 rats, animal conformity certification number: 410117, effluent south medical university Experimental Animal Center provides.
1.3 reagent
SUV (Long Huagongshijichang of Chengdu section), tween-80 (Long Huagongshijichang of Chengdu section), tetracol phenixin (Long Huagongshijichang of Chengdu section); Sodium cholic acid (Shanghai Solarbio), propylthiouracil sheet (Shanghai Fosun Zhaohui Pharmaceutical Co., Ltd.), 1; 2-Ucar 35 (Tianjin Da Mao chemical reagent factory); Xylo-Mucine (Shanghai San Pu chemical industry ltd), lard, Beijing Erguotou wine.
1.4 divide into groups and the dosage setting
Table 1 divides into groups and the dosage setting
1.5 data statistical approach
Metering experiment result representes with
, uses the SPSS-10.0 statistical software and carries out variance analysis; The counting test-results adopts nonparameter test (analysis of Kruskal-Wallis method).
1.6 TP and step
After 3 days, every morning is respectively organized rat respectively by table 1 design dosed administration with the raising of rat flexibility, and blank control group gives corresponding C MC suspension.
All the other were respectively organized rat and irritated stomach respectively and give high fat liquor (10% lard, 4% SUV, 0.6% Sodium cholic acid and 0.3% propylthiouracil) 1ml/100g, give liquor 1ml/100g behind the 1h again, continuous 18 days except that blank control group afternoon.
Except that blank control group, all the other respectively organize the rat CCl of abdominal injection 10% every other day in addition
4Rapeseed oil solution, ID is: 0.08ml/100g, blank control group is injected in same area with isometric(al) saline water.
Fasting 16 hours (can't help water) after last administration in the 18th day, animal is weighed, and femoral artery is got blood, centrifugal and separation of serum ,-30 ℃ of cryopreservation, the biochemical indicator in the test serum.Other wins liver and weighs, and after the observation general appearance, gets 2 of lefts lobe of liver for every and is put in 10% neutral formalin solution respectively, waits to do liver histopathology inspection (after fixing, paraffin embedding is cut into slices, and does HE dyeing and fat stains respectively).
2 test-results
2.1 the mensuration of the 18th day each test group biochemical indicator of administration
Annotate: compare with model group, ▲ ▲ P<0.01, ▲ P<0.05;
Compare with the clofibrate group,
*<0.01,
*<0.05
And 3S (trithioanethole group) is relatively, ● ●<0.01, ●<0.05.
Can know by last table, administration the 18th day, model group and normal control group compare, rat blood serum ALT (SGPT), AST (aspartic transaminase), TG (triglyceride), CHOL (SUV) activity significantly increases.
With model group relatively, receive reagent thing BOA-1, BOA-2 can significantly reduce the activity rising degree of ALT, AST, again can triglyceride reducing, SUV; BOA-3 can significantly reduce ALT, again can triglyceride reducing, SUV; BOA-4 can significantly reduce AST, again can triglyceride reducing, SUV.
With the clofibrate group relatively, receive reagent thing BOA-1, BOA-2, BOA-3, BOA-4 reduction effect there was no significant difference to TG, CHOL.Simultaneously, receive reagent thing BOA-1, BOA-2, BOA-3, BOA-4 can significantly reduce AST, BOA-2, BOA-3 can significantly reduce ALT, and clofibrate does not all have remarkable reduction effect to this.
Compare with 3S (trithioanethole) group, receive reagent thing BOA-1, BOA-2, BOA-3 reduction effect there was no significant difference, receive reagent thing BOA-1, BOA-2, BOA-4 can significantly reduce AST ALT; Simultaneously, receive reagent thing BOA-1, BOA-2, BOA-3, BOA-4 can significantly reduce TG, CHOL, and the 3S group does not all have remarkable reduction effect to this.
2.2 the liver histopathology inspection is analyzed: (HE dyeing, 100 *)
All get the rat liver middle period, fix with 4% Paraformaldehyde 96, the routine paraffin wax embedded section, h and E dyeing, opticmicroscope is observed the histological change of hepatic pathology down, and its histological variation is with reference to table 3 scoring, and the hepatic tissue pathology result sees table 4.
Table 3 hepatic tissue pathology damage judgement criteria
Table 4 medicine causes the influence of fatty liver rat model hepatic pathology to complex method
Annotate: compare with model group, ▲ ▲ P<0.01, ▲ P<0.05
Statistical method: the nonparameter test analytical procedure that test of significance utilization SPSS 11.0 softwares of group difference provide.
Model group and blank group relatively hepatocellular sex change and necrosis have occurred, through nonparameter test, have significant difference (▲ ▲ P<0.01), show the modeling success.
With model group relatively, clofibrate is to hepatocellular oedema, steatosis, cell infiltration and downright bad there are no significant improvement effect; 3S can significantly improve the liver cell oedema, but to steatosis, cell infiltration and downright bad no significance improvement effect; Receive reagent thing BOA-1, BOA-2, BOA-3, BOA-4 all can significantly improve the liver cell oedema; BOA-2 can significantly improve hepatic cell fattydegeneration; BOA-1, BOA-3 can significantly improve the infiltration of inflammatory cell.
2.3 liver fat stains (Sudan III dyeing).
Hepatic tissue after 11% formaldehyde solution is fixing, frozen section (thick 6~8 μ m), zero(ppm) water is washed slightly; Phenodin dyes nuclear 1~2min, turns blue after washing; Develop a film quarter with 70% alcohol again; Go into Sudan III staining agent 5~10min (seal as far as possible in the dyeing and prevent the reagent volatilization, as the 56 ℃ of times of heating can shorten); The unnecessary dye liquor of 70% alcohol flush away; With the glycogelatin mounting.The result: neutral fat is orange red, and it is blue that nuclear is.The variation of its liver fat stains is with reference to table 5 scoring, and liver fat stains result sees table 6.
Table 5 liver fat stains judgement criteria
Table 6 liver fat stains appraisal result
Annotate: compare with model group, ▲ ▲ P<0.01, ▲ P<0.05
Above result shows: model group and blank group relatively hepatic cell fattydegeneration occurred, through the check of nonparametric number, have significant difference (▲ ▲ P<0.01), show through complex factors and have caused rat fat liver model.
With model group relatively, clofibrate group and the liver fat stains of 3S group are marked all and the model group there was no significant difference; Receive the liver fat stains scoring of reagent thing BOA-2, BOA-3, BOA-4 all significantly to be better than model group; Receive the liver cell fat stains scoring of reagent thing BOA-1 to have the trend of reduction.
3 conclusions
Above-mentioned pharmacodynamics test proves, receives reagent thing BOA-1, BOA-2, BOA-3, BOA-4 on the basis of reduce fat with fibrate and trithioanethole and liver protecting therapy effect, also has other beyond thought effects, and is specific as follows:
Receiving reagent thing BOA-1, BOA-2, BOA-3, BOA-4 is special carboxylic acid of shellfish and the conjugate that removes the first trithioanethole, and relative Bei Te of molecular weight and trithioanethole increase greatly, and dosage is 27mg/kg.With BOA-1 is example; As being pharmacophoric group metering with removing the first trithioanethole with chlorine shellfish butyric acid; New compound BOA-1 molecular weight after the coupling increases by 1 times than clofibrate and trithioanethole, therefore identical dosage have only 1/2 dosage chlorine shellfish butyric acid and 1/2 dosage remove the first trithioanethole.
Can know through above-mentioned test-results: detect in the test at biochemical indicator, clofibrate can significantly reduce TG, CHOL, but ALT, AST are not had influence, and 3S only significantly reduces ALT, and The compounds of this invention all is significantly improved to four indexs; The liver histopathology inspection is analyzed; Clofibrate is all invalid for liver cell oedema, steatosis, cell infiltration, necrosis; 3S is only effective to the liver cell oedema; And The compounds of this invention all has obvious effects to three kinds of indexs except that necrosis, and especially BOA-3 has improvement extremely significantly for the liver cell oedema; Liver fat stains test shows, clofibrate, and 3S is invalid to hepatic cell fattydegeneration, and The compounds of this invention has the significant effect of improving to hepatic cell fattydegeneration.
Above-mentioned experiment shows; Compound of the present invention not only can significantly reduce TG, CHOL, ALT, AST; And to the hepatic pathology damage, especially hepatic cell fattydegeneration has obvious improvement effect, and visible The compounds of this invention has good therapeutic action to fatty liver; And when using separately with the clofibrate of The compounds of this invention significant quantity same dose or trithioanethole; Invalid to the treatment hepatic cell fattydegeneration, damage does not obviously improve yet to hepatic pathology, and only trithioanethole has certain improvement to the liver oedema.
Industrial applicability
The present invention's (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) fibrate carboxylate compounds is through specific pharmacophoric group amalgamation; Not only have the effect for reducing fat of fibrate and the function for protecting liver and reducing enzyme activity of trithioanethole class medicine; And The compounds of this invention has outstanding therapeutic action to the liver cell fat lesion, and this curative effect is that trithioanethole class and fibrate are not available; Therefore, The compounds of this invention has very good prospects for application aspect the treatment fatty liver.
Simultaneously, general formula compound of the present invention has good reducing blood lipid, and can alleviate the spinoffs such as hepar damnification of fibrate, has the application prospect of good curing hyperlipidaemic conditions.
Claims (10)
1. (5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) fibrate carboxylate compounds shown in the general formula (I):
Wherein:
R represents list or multi-substituent, is selected from hydrogen, halogen, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkyl, amino, sulfydryl, carboxyl, nitro, alkylsulfonyl, halogen-substituted formyl radical, halogen substituted cyclopropane base, (the substituted benzoylamino of halogen) ethyl;
X is selected from O, S, NH, CH
2
N represents the integer of 0-4.
2. compound according to claim 1, it is characterized in that: halogen is selected from F, Cl, Br, I.
3. compound according to claim 2, its characteristic is being: halogen is selected from Cl.
4. compound according to claim 1 is characterized in that, described compound is selected from:
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Chlorophibrinic Acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(to chlorobenzene formacyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-{ is right-[2-(to chlorobenzamide) ethyl] benzene oxygen }-the 2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(2,2-dichloro cyclopropyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 5-(2,5 3,5-dimethylphenyl)-2,2-dimethyl-penten acid esters,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) to toluene oxygen isobutyrate,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) to the methoxycarbonyl phenoxy isobutyrate,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Bezalip Tablets ester.
5. compound according to claim 4 is characterized in that, compound preferably from:
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) Chlorophibrinic Acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(to chlorobenzene formacyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 2-[right-(2,2-dichloro cyclopropyl) benzene oxygen]-2 Methylpropionic acid ester,
(5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones) 5-(2, the 5-3,5-dimethylphenyl)-2,2-dimethyl-penten acid esters.
6. each described compound of claim 1-5 is treated the purposes in the fatty liver medicine in preparation.
7. each described compound of claim 1-5 is treated the purposes in the high blood cholesterol drug in preparation.
8. method for preparing the described compound of claim 1 is characterized in that:
With special carboxylic acid compound of shellfish and 5-(p-hydroxybenzene)-1,2-two sulphur rings penta-4-alkene-3-thioketones is condensed into ester and gets;
The structural formula of the special carboxylic acid compound of said shellfish does
Wherein:
R represents list or multi-substituent, is selected from hydrogen, halogen, hydroxyl, C
1-4Alkoxyl group, C
1-4Alkyl, amino, sulfydryl, carboxyl, nitro, alkylsulfonyl, halogen-substituted formyl radical, halogen substituted cyclopropane base, (the substituted benzoylamino of halogen) ethyl;
X is selected from O, S, NH, CH
2
N represents the integer of 0-4.
9. pharmaceutical composition of treating fatty liver or hyperlipidemia, it be by each described compound among the claim 1-5 of significant quantity or its pharmaceutically acceptable salt be active ingredient, add the medicament that pharmaceutical carrier is prepared from.
10. pharmaceutical composition according to claim 9 is characterized in that: described medicament is oral prepns or non-intestinal drug delivery agent.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008800003290A CN101541780B (en) | 2007-06-08 | 2008-06-06 | Fibrate carboxylate compounds, preparation methods and uses thereof |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200710100373 | 2007-06-08 | ||
CN200710100373.6 | 2007-06-08 | ||
PCT/CN2008/001108 WO2008151515A1 (en) | 2007-06-08 | 2008-06-06 | Fibrate carboxylate compounds, preparation methods and uses thereof |
CN2008800003290A CN101541780B (en) | 2007-06-08 | 2008-06-06 | Fibrate carboxylate compounds, preparation methods and uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101541780A CN101541780A (en) | 2009-09-23 |
CN101541780B true CN101541780B (en) | 2012-12-05 |
Family
ID=40129226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008800003290A Active CN101541780B (en) | 2007-06-08 | 2008-06-06 | Fibrate carboxylate compounds, preparation methods and uses thereof |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN101541780B (en) |
WO (1) | WO2008151515A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105693517A (en) * | 2016-02-26 | 2016-06-22 | 西安交通大学 | 3,4-dihydroxyl phenethyl alcohol fibrate carboxylic ester compound and preparation method and application thereof |
CN105753702A (en) * | 2016-02-26 | 2016-07-13 | 西安交通大学 | 3,4-dihydroxyphenylethanol fenofibrate acid ester as well as preparation method and application thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012145899A1 (en) * | 2011-04-27 | 2012-11-01 | 上海医药工业研究院 | Ester compound, preparation method and application thereof |
CN115381807A (en) * | 2022-02-16 | 2022-11-25 | 陕西中医药大学 | Application of guaiacol chlorobebutryate in liver protection activity |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006125295A1 (en) * | 2005-05-27 | 2006-11-30 | Antibe Therapeutics Inc. | Derivatives of 4-or 5-aminosalicylic acid |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1645288A1 (en) * | 2004-10-07 | 2006-04-12 | CTG Pharma S.r.l. | New nuclear transcription factors regulators |
ITMI20050680A1 (en) * | 2005-04-18 | 2006-10-19 | Ctg Pharma S R L | NEW ANTI-INFLAMMATORY COMPOUNDS |
US20060270635A1 (en) * | 2005-05-27 | 2006-11-30 | Wallace John L | Derivatives of 4- or 5-aminosalicylic acid |
-
2008
- 2008-06-06 CN CN2008800003290A patent/CN101541780B/en active Active
- 2008-06-06 WO PCT/CN2008/001108 patent/WO2008151515A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006125295A1 (en) * | 2005-05-27 | 2006-11-30 | Antibe Therapeutics Inc. | Derivatives of 4-or 5-aminosalicylic acid |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105693517A (en) * | 2016-02-26 | 2016-06-22 | 西安交通大学 | 3,4-dihydroxyl phenethyl alcohol fibrate carboxylic ester compound and preparation method and application thereof |
CN105753702A (en) * | 2016-02-26 | 2016-07-13 | 西安交通大学 | 3,4-dihydroxyphenylethanol fenofibrate acid ester as well as preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN101541780A (en) | 2009-09-23 |
WO2008151515A1 (en) | 2008-12-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100534992C (en) | Silybin esters derivatives and preparation and use thereof | |
CN101596191B (en) | Method for treatment of disease using malonyl-coa decarboxylase inhibitor | |
CN1750758B (en) | Compounds for the treatment of metabolic disorders | |
CN101541780B (en) | Fibrate carboxylate compounds, preparation methods and uses thereof | |
CN105982884B (en) | A kind of purposes of Corylifolin methyl ether and the like | |
CN101437506A (en) | Compounds for the treatment of metabolic disorders | |
CN102838505A (en) | Amide compound and preparation method as well as application thereof | |
CN102666553A (en) | Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts | |
CN106749089A (en) | The preparation of new fluoro thiazole hydrazone compounds and its application in antineoplastic | |
CN106748939B (en) | A kind of novel bromine phenol thiosemicarbazide compound and its preparation and drug and purposes | |
CN105982885A (en) | Application of bavachinin and analogs of bavachinin | |
CN110143890A (en) | A kind of chalcone derivative and synthetic method and its preparing the application in anti-nonalcoholic steatohepatitis drug | |
CN102342935B (en) | Berberine-phenylacetic acid derivative, pharmaceutically acceptable salt thereof and application thereof | |
CN106349099B (en) | Caffeic acid-lysine and its derivative, preparation method and purposes | |
CN105732561A (en) | Homoisoflavonoids aromatic acid, aromatic acid ester derivative, method for preparing homoisoflavonoids aromatic acid and aromatic acid ester derivative and medicinal application thereof | |
KR20040051485A (en) | Optically active bicyclol, preparation thereof and composition containing the same and the use | |
CN102993200B (en) | Paliperidone amino-acid ester and preparation method thereof | |
CN101768149B (en) | Beta- aminoketone (alkamine) derivatives and use thereof | |
CN1358096A (en) | Remedies for diabetes | |
CN111419842A (en) | Application of inflammasome inhibitor CY-09 to preparation of medicine for treating non-alcoholic steatohepatitis | |
CN106749088A (en) | The new bromine phenol thiazole compound of one class and its preparation and medicine and purposes | |
CN102382036A (en) | Phenoxyacetic acid compound, preparation method thereof and drug application | |
CN105147677A (en) | A group of 2-substituted formamido-3-alkyloxypyridine derivatives and pharmaceutical application thereof | |
CN106242987B (en) | A kind of prevention and treatment diabetes and medicine for treating diabetic nephropathy and its synthetic method and application | |
CN101613346B (en) | Preparation method of silibinin ether substituted by A ring and medical application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |