CN105287527A - Composition and application of composition in anti-hepatic-fibrosis medicine - Google Patents
Composition and application of composition in anti-hepatic-fibrosis medicine Download PDFInfo
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- CN105287527A CN105287527A CN201510760610.6A CN201510760610A CN105287527A CN 105287527 A CN105287527 A CN 105287527A CN 201510760610 A CN201510760610 A CN 201510760610A CN 105287527 A CN105287527 A CN 105287527A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry, in particular to a composition, a preparation method and an application of the composition in preparing anti-hepatic-fibrosis medicine, and discloses a composition and a preparation method thereof. Pharmacological experiments indicate that the composition has the function of resisting hepatic fibrosis, and has the value of developing the anti-hepatic-fibrosis medicine.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to compositions, preparation method and its usage.
Background technology
Hepatic fibrosis is the dynamic process of chronic hepatic injury to cirrhosis progress, show as extracellular matrix (ECM) synthesis in a large number, secretion, and degraded is absolute or relative deficiency, makes ECM fill the air deposition in liver.It is downright bad that it originates in hepatocyte (HC), and be inflammatory reaction, the release of fiber generation medium, hepatic stellate cell (FSC) activates, finally with the obvious disequilibrium of the synthetics and degradation of liver connective tissue elements thereupon.Hepatic fibrosis is the common pathological process of multiple chronic hepatopathy, is the key factor affecting prognosis.
Between 20 years of past, the research of hepatic fibrosis makes significant progress, and confirms that hepatic fibrosis is all reversible with liver cirrhosis to a certain degree.Some Strategies of Anti-fibrosis Therapy methods are there are in recent years successively, comprise chemical drugs, biological preparation, Chinese medicine and gene therapy etc., but desirable clinical treatment means still lack (Liu Ping. strengthen the research of effect of anti hepatic fibrosis mechanism. Chinese hepatopathy magazine, 2005,8 (13): 561).The key of current anti-treating the liver fiber is for the link relevant to hepatic stellate cell activator, mainly: alleviate hepatic injury; Suppress stellate cell activator, reduce extracellular matrix and produce; Adjustment cytokine is disorderly, promotes activated hepatic stellate cells apoptosis; The fibroblastic propagation of liver and stellate cell activator is suppressed to secrete the fibroblastic propagation of induced liver in a large number.
From natural product, find compound or lead compound and carry out structural modification and obtain its derivant, thus the potential drug obtaining high-efficiency low-toxicity there is important value most.
The Compound I that the present invention relates to is one and delivers (AyumiOhsakietal. in 2011,2011.SalviskinoneA, aditerpenewithanewskeletonfromSalviaprzewalskii.Tetrahed ronLetters52 (2011) 1375 – 1377) compound, we have carried out structural modification to Compound I, obtain two new derivants and compound III and compound IV, and prepared compositions by compound III and compound IV and said composition anti-hepatic fibrosis activity is evaluated, it has anti-hepatic fibrosis activity.
Due to the activation of hepatic stellate cell, thus cause a large amount of secretions of multiple somatomedin, the fibroblastic fast breeding of these somatomedin meeting induced liver, thus accelerating fibers, wherein one of most important somatomedin is exactly TGF.Therefore, an important thinking of screening anti-hepatic fibrosis medicines is exactly that screening can suppress the medicine of liver fibroblast proliferation or screening can suppress fibroblastic propagation of the growth factor-induced such as TGF, screening is usually carried out on fibroblast, and NIH/3T3 cell is the most frequently used cell strain.
Summary of the invention
The invention discloses a new compositions, said composition is made up of compound III and compound IV, and in said composition, the mass percent of compound III and compound IV is respectively 65% and 35%.
Compositions disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, compositions of the present invention has good effect of anti hepatic fibrosis.Pharmaceutically acceptable salt of the present invention has same drug effect.
Further, the experiment in vitro of compositions shows, compositions has the activity of very strong anti-fibroblast proliferation, and therefore compositions of the present invention is expected to be used to prepare novel anti-hepatic fibrosis medicines.
Further, the experiment in vitro of compositions shows, compositions has the activity of the fibroblast proliferation of very strong anti-growth factor-induced, and compositions is the compound of a great exploitation potential for its, and it can be directly used in the treatment of corresponding disease and the preparation of related drugs.
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Detailed description of the invention
The preparation of embodiment 1 compound S alviskinoneA
Document (the AyumiOhsakietal. that the people such as the preparation method reference AyumiOhsaki of compound S alviskinoneA (I) deliver, 2011.SalviskinoneA, aditerpenewithanewskeletonfromSalviaprzewalskii.Tetrahed ronLetters52 (2011) 1375 – 1377) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2SalviskinoneA
By Compound I (312mg, 1.00mmol) be dissolved in 15mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.08g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 12h at 35 degrees Celsius.After 12h, reactant liquor is poured in frozen water, use dichloromethane extraction twice immediately, merge organic phase solution.Then use water and saturated common salt water washing 4 times successively to organic phase solution, then use anhydrous sodium sulfate drying, last concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:1.5, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (327mg, 78%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ6.63(s,1H),6.37(s,1H),5.81(s,1H),4.51(s,2H),3.84(s,1H),3.79(s,2H),2.15(s,1H),2.04(s,1H),1.91(s,1H),1.65(s,1H),1.39(s,3H),1.08(s,6H),0.99(s,6H).
13CNMR(125MHz,DMSO-d6)δ188.07(s),183.70(s),154.38(s),147.57(s),140.21(s),136.40(s),134.71(s),131.25(s),128.40(s),118.83(s),72.12(s),45.49(s),37.54(s),33.58(s),31.78(s),26.17(s),25.12(s),24.66(s),23.51(s),23.17(s),22.65(s).
HRMS(ESI)m/z[M+H]
+calcdforC
22H
28BrO
3:419.1222；found419.1220.
The synthesis of O-(imidazole radicals) ethyl derivative (III) of embodiment 3SalviskinoneA
Compound II per (209mg, 0.5mmol) is dissolved in the middle of 30mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (252mg, 1.5mmol) and imidazoles (870mg, 10mmol), mixture reflux 4h.After reaction terminates, reactant liquor is poured in 45mL frozen water, with equivalent dichloromethane extraction 3 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.2, v/v), collects brown concentrated elution band and flings to the Light brown solid (144.1mg, 71%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ7.91(s,1H),7.16(s,1H),6.65(d,J＝103.6Hz,2H),6.41(s,1H),5.76(s,1H),4.50(s,2H),4.39(s,2H),3.82(s,1H),2.05(s,1H),1.94(s,1H),1.87(s,1H),1.61(s,1H),1.30(s,3H),0.99(s,6H),0.90(s,6H).
13CNMR(125MHz,DMSO-d6)δ187.81(s),183.33(s),153.90(s),147.28(s),139.81(s),139.19(s),136.14(s),134.34(s),130.77(s),128.43(s),128.01(s),118.85(s),118.53(s),69.03(s),45.02(s),43.70(s),37.46(s),33.09(s),25.87(s),25.06(s),24.29(s),23.03(s),23.05(s),22.41(s).
HRMS(ESI):m/z[M+H]
+calcdforC
25H
31N
2O
3:407.2335；found:407.2331。
The synthesis of O-(triazolyl) ethyl derivative (IV) of embodiment 4SalviskinoneA
By Compound II per (209mg, 0.5mmol) be dissolved in the middle of 20mL acetonitrile, add Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and 1,2,3-triazole (2760mg, 40mmol), mixture reflux 4h.After reaction terminates, reactant liquor is poured in 20mL frozen water, with equivalent dichloromethane extraction 3 times, merge organic facies.Organic facies after merging with water and saturated common salt water washing successively, then use anhydrous sodium sulfate drying, concentrating under reduced pressure is removed solvent and is obtained product crude product.Product crude product purification by silica gel column chromatography (mobile phase is: petroleum ether/acetone=100:0.5, v/v), collects the yellow yellow powder (134.3mg, 66%) concentrating elution band namely to obtain compound IV.
1HNMR(500MHz,Chloroform-d1)δ8.37(s,1H),7.95(s,1H),6.35(s,1H),6.14(s,1H),5.35(s,1H),4.13(s,1H),4.42(d,J＝16.4Hz,3H),3.71(s,1H),2.13(s,1H),2.05(s,1H),1.81(s,1H),1.63(s,1H),1.30(s,3H),1.08(s,6H),0.97(s,6H).
13CNMR(125MHz,DMSO-d6)δ188.09(s),183.61(s),154.18(s),147.26(s),139.72(s),136.40(s),136.32(s),134.52(s),130.95(s),127.99(s),120.16(s),118.62(s),67.14(s),46.27(s),45.18(s),37.69(s),33.32(s),26.14(s),25.01(s),24.41(s),23.23(s),23.06(s),22.47(s).
HRMS(ESI):m/z[M+H]
+calcdforC
24H
30N
3O
3:408.2287；found:408.2282。
Embodiment 5 compositions anti-hepatic fibrosis is active
Due to the activation of hepatic stellate cell, thus cause a large amount of secretions of multiple somatomedin, the fibroblastic fast breeding of these somatomedin meeting induced liver, thus accelerating fibers, wherein one of most important somatomedin is exactly TGF.Therefore, an important thinking of screening anti-hepatic fibrosis medicines is exactly that screening can suppress the medicine of liver fibroblast proliferation or screening can suppress fibroblastic propagation of the growth factor-induced such as TGF, screening is usually carried out on fibroblast, and NIH/3T3 cell is the most frequently used cell strain.
The preparation of compositions: loaded by the powder of 35mg compound IV crossing 200 order nets after crossing the powder of the 65mg compound III of 200 order nets and grinding after grinding to mix in tubule with cover and with turbine stirring instrument and namely obtain 100mg compositions, obtains the solution of compositions by the compositions of this 100mg of water dissolution during use.
Experimental example 1: the inhibitory action that compositions is bred fibroblast NIH/3T3
One, experimental technique:
NIH/3T3 cell strain is purchased from Shanghai cell institute of the Chinese Academy of Sciences cell bank drawn from ATCC (AmericanTypeCultureCollection).
NIH/3T3 cell 0.25% trypsinization of being merged the Asia of exponential phase, washing, after centrifugal, makes 1 × 10 with DMEM culture fluid (containing 10%FCS)
4the cell suspension of cell/ml, Trypan Blue qualification survival rate is greater than 95%, adds in 96 orifice plates, at 37 DEG C, 5%CO by every hole 100ul
2after cultivation 24h synchronously processes, abandon supernatant, add DMEM culture fluid (containing the 10%FCS) 200ul containing medicine, cultivate 48h, every hole adds MTT solution and hatches 4h.Discard culture fluid, add 150ulDMSO, vibrate 10 minutes, make dissolving crystallized, microplate reader 490nm place reads OD value, and result is with OD
490represent.
Two, experimental result:
1, morphological observation
NIH/3T3 stretches well before medication, and refractivity is more weak, has directivity, and radially, the speed of cell proliferation is fast; And after adding compositions 24h, fibroblast decreased number, shape becomes irregular, and projection shortens, and cell arrangement is chaotic, and intracellular products increases.Compound III and compound IV act on without this.
Mtt assay detection composition is to the inhibitory action of NIH/3T3 cell proliferation.
The inhibitory action that table 1:MTT method detection composition is bred NIH/3T3
Note: *, with cell negative control P<0.05
Result: compositions has significant inhibitory action at the cell proliferation of 20ug/ml to fibroblast NIH/3T3.Show that composition is outer and have remarkable inhibitory action to fibroblastic propagation.Compound III and compound IV act on without this.
Experimental example 2: compositions is to transforming growth factor-β
1(TGF-β
1) inhibitory action of fibroblast proliferation of inducing
TGF-β
1be promote cell proliferation and collagenogenic strong active factors, in cell, add TGF-β
110ng/ml stimulates cellular proliferation, then detection of drugs is to the inhibitory action of the cell proliferation that TGF-β 1 induces, to analyze the mechanism of action judging compositions.
Table 2:MTT method detection composition induces the inhibitory action of NIH/3T3 propagation to TGF
Note: *, contrasts P<0.05 with cell+TGF
Result: compositions at 20ug/ml to fibroblast NIH/3T3 at TGF-β
1induction under cell proliferation have significant inhibitory action, compound III and compound IV act on without this.Show that the outer inhibitory action to fibrocyte proliferation of composition may realize by intervening TGF signal path.
Conclusion: compositions has significant inhibitory action to the cell proliferation of fibroblast NIH/3T3 under the stimulation of 10% calf serum; Compositions to fibroblast NIH/3T3 at TGF-β
1induction under cell proliferation have significant inhibitory action.Compositions can be used for preparing anti-hepatic fibrosis medicines.Compound III and compound IV to the cell proliferation of fibroblast NIH/3T3 under the stimulation of 10% calf serum without significant inhibitory action, to fibroblast NIH/3T3 at TGF-β
1induction under cell proliferation without significant inhibitory action, be not available to prepare anti-hepatic fibrosis medicines.
The preparation of embodiment 6 composition tablet involved in the present invention
Get 2 grams of compositionss, add the customary adjuvant 18 grams preparing tablet, mixing, conventional tablet presses makes 100.
The preparation of embodiment 7 composition capsule involved in the present invention
Get 2 grams of compositionss, add prepare capsule customary adjuvant as starch 18 grams, mixing, encapsulatedly makes 100.
Claims (6)
1. a compositions, it is characterized by said composition and be made up of compound III and compound IV, in said composition, the mass percent of compound III and compound IV is respectively 65% and 35%,
2. the preparation method of compositions as claimed in claim 1, is characterized by: the powder of compound III and the powder of compound IV are respectively 65% and 35% according to mass percent and fully mix.
3. the application of compositions as claimed in claim 1 in treatment hepatic fibrosis medicines.
4. the application of compositions as claimed in claim 3 in treatment hepatic fibrosis medicines, is characterized by described compositions and is suppressed to fibrocyte proliferation.
5. the application of compositions as claimed in claim 3 in treatment hepatic fibrosis medicines, is characterized by the fibroblast proliferation of described compositions Developing restraint factor induction.
6. the application of compositions as claimed in claim 5 in treatment hepatic fibrosis medicines, it is characterized by described somatomedin is TGF-β 1.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5929124A (en) * | 1997-08-22 | 1999-07-27 | Hostettmann; Kurt | Antimicrobial diterpenes |
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2015
- 2015-11-10 CN CN201510760610.6A patent/CN105287527A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5929124A (en) * | 1997-08-22 | 1999-07-27 | Hostettmann; Kurt | Antimicrobial diterpenes |
Non-Patent Citations (2)
| Title |
|---|
| AYUMI OHSAKI等: "Salviskinone A, a diterpene with a new skeleton from Salvia przewalskii", 《TETRAHEDRON LETTERS》 * |
| 孙瑞芳等: "丹参酮ⅡA对小鼠肝纤维化的干预作用", 《中国中西医结合杂志》 * |
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Application publication date: 20160203 |