CN105250312A - Composition and application thereof to medicines for preventing or treating pancreatic fibrosis - Google Patents
Composition and application thereof to medicines for preventing or treating pancreatic fibrosis Download PDFInfo
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- CN105250312A CN105250312A CN201510751978.6A CN201510751978A CN105250312A CN 105250312 A CN105250312 A CN 105250312A CN 201510751978 A CN201510751978 A CN 201510751978A CN 105250312 A CN105250312 A CN 105250312A
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Abstract
The invention relates to the field of organic synthesis and medicinal chemistry and in particular relates to a composition, a preparation method and an application of the composition to preparation of medicines for preventing or treating pancreatic fibrosis. The invention discloses the composition and the preparation method thereof. Pharmacological experiments show that the composition has the function of preventing or treating pancreatic fibrosis and has the value in developing the medicines for preventing or treating pancreatic fibrosis.
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
Pancreatic gland fibrosis is the common trait of chronic pancreatitis caused by a variety of causes, is also the Histopathological characteristics adjoint with it simultaneously, shows as a large amount of fibroblast proliferation and the extracellular matrix being rich in conjunctive tissue.Be the result that many reasons causes injury of pancreas to be repaired, find that pancreatic stellate cells is relevant with pancreatic gland fibrosis with cytokine profiles in the recent period, the current sickness rate of pancreatic gland fibrosis is more and more high, is badly in need of the anti-pancreatic gland fibrosis medicine of research and development high-efficiency low-toxicity.
There is the problem that toxicity is large, safety is low in the current existing medicine for the treatment of of pancreatic gland fibrosis, finds compound or lead compound and carry out structural modification to obtain its derivant from natural product, thus the potential drug obtaining high-efficiency low-toxicity has important value most.
The Compound I that the present invention relates to is one and delivers (MengShaoetal. in 2011, 2010.PsiguadialsAandB, TwoNovelMeroterpenoidswithUnusualSkeletonsfromtheLeaveso fPsidiumguajava.OrganicLetters12 (2010) 5040 – 5043) 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 the anti-pancreatic gland fibrosis activity of said composition is evaluated, it is active that it has anti-pancreatic gland fibrosis.
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 anti-pancreatic gland fibrosis effect.Pharmaceutically acceptable salt of the present invention has same drug effect.
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 PsiguadialA
Document (the MengShaoetal. that the people such as the preparation method reference MengShao of compound PsiguadialA (I) deliver, 2010.PsiguadialsAandB, TwoNovelMeroterpenoidswithUnusualSkeletonsfromtheLeaveso fPsidiumguajava.OrganicLetters12 (2010) 5040 – 5043) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2PsiguadialA
By Compound I (474mg, 1.00mmol) be dissolved in 20mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.16g), 1,50% sodium hydroxide solution of 2-Bromofume (7.520g, 40.00mmol) and 12mL.Mixture stirs 8h at 35 degrees Celsius.After 8h, 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 3 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=100:0.5, v/v), collects brown concentrated elution band and flings to the brown ceramic powder (502mg, 73%) that namely solvent obtains Compound II per.
1HNMR(500MHz,DMSO-d
6)δ10.44(s,2H),7.24(s,2H),7.20(d,J＝10.0Hz,3H),4.31(s,4H),3.89(s,1H),3.74(s,4H),2.30(s,1H),2.12(s,1H),2.02(s,1H),1.92(s,1H),1.79(s,1H),1.73(s,1H),1.51(d,J＝19.8Hz,3H),0.99(s,3H),0.95(d,J＝4.7Hz,7H),0.85(s,3H),0.53(s,1H),0.43(s,1H).
13CNMR(125MHz,DMSO-d6)δ188.69(s),170.54(s),165.42(s),163.38(s),142.72(s),129.71(s),127.96(s),127.08(s),118.00(s),116.82(s),114.82(s),72.73(s),40.19(s),34.75(s),34.32(s),31.75(s),30.93(s),28.09(s),26.43(s),24.48(s),23.74(s),21.18(s),20.77(s),19.99(s),14.39(s).
HRMS(ESI)m/z[M+H]
+calcdforC
34H
41Br
2O
5:689.1300；found689.1303.
The synthesis of the O-(nafoxidine base) ethyl derivative (III) of embodiment 3PsiguadialA
Compound II per (344mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (168mg, 1.0mmol) and pyrrolidine (2840mg, 40mmol), mixture reflux 6h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction 4 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=100:1.5, v/v), collects yellow concentrated elution band and flings to the yellow powder (223.8mg, 67%) that namely solvent obtains compound III.
1HNMR(500MHz,DMSO-d6)δ10.43(s,2H),7.21(s,2H),7.15(d,J＝10.0Hz,3H),3.99(d,J＝19.6Hz,5H),2.57(s,4H),2.43(s,8H),2.21(s,1H),1.95(s,1H),1.85(d,J＝7.5Hz,2H),1.78(s,1H),1.62(d,J＝12.9Hz,9H),1.39(s,2H),1.37(s,1H),1.25(s,1H),0.93(s,3H),0.90(s,6H),0.83(s,3H),0.46(s,1H),0.21(s,1H).
13CNMR(125MHz,DMSO-d6)δ188.52(s),170.23(s),164.97(s),163.14(s),142.38(s),129.22(s),127.70(s),126.72(s),117.54(s),116.59(s),114.44(s),69.04(s),54.36(d,J＝16.6Hz),39.83(s),34.29(s),34.09(s),30.56(s),27.62(s),26.19(s),24.93(s),24.03(s),23.47(s),20.81(s),20.41(s),19.54(s),14.11(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
57N
2O
5:669.4267；found:669.4261。
The synthesis of O-(morpholinyl) ethyl derivative (IV) of embodiment 4PsiguadialA
Compound II per (344mg, 0.5mmol) is dissolved in the middle of 20mL acetonitrile, adds Anhydrous potassium carbonate (690mg wherein, 5.0mmol), potassium iodide (168mg, 1.0mmol) and morpholine (1742mg, 20mmol), mixture reflux 7h.After reaction terminates, reactant liquor is poured in 20mL frozen water, with equivalent dichloromethane extraction 2 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=100:1.5, v/v), collects the yellow yellow gummy solid (252.1mg, 72%) concentrating elution band namely to obtain compound IV.
1HNMR(500MHz,DMSO-d6)δ10.53(s,2H),8.69–6.34(m,5H),4.11(dd,J＝30.6,16.3Hz,5H),3.61(t,J＝9.4Hz,8H),2.74(t,J＝14.3Hz,4H),2.56(t,J＝9.3Hz,8H),2.30–2.13(m,1H),2.07–1.62(m,5H),1.57–1.28(m,4H),1.06(s,3H),1.02(s,6H),0.94(d,J＝12.9Hz,3H),0.61(d,J＝1.5Hz,1H),0.32(dt,J＝21.0,17.3Hz,1H).
13CNMR(125MHz,DMSO-d6)δ188.63(s),170.36(s),165.06(s),163.25(s),142.49(s),129.33(s),127.81(s),126.83(s),117.65(s),116.70(s),114.55(s),69.15(s),66.69(s),54.73(s),52.73(s),39.83(s),34.62(s),34.09(s),30.56(s),27.95(s),26.19(s),24.14(s),23.58(s),20.92(s),20.41(s),19.87(s),14.11(s).
HRMS(ESI):m/z[M+H]
+calcdforC
42H
57N
2O
7:701.4166；found:701.4163。
The anti-pancreatic gland fibrosis of embodiment 5 compositions is active
1 material
1.1 animal Wistar rats, male, body weight 180-200g.
1.2 composition dosage: 0.9mg/kg.
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.
2 experimental techniques
2.1 modeling methods: Wistar rat, with lumbar injection dl-ethionine 250mg/ days, continuous 2 months, can occur that pancreas glandular cell reduces, adipocellular hypertrophy in interstitial.
2.2 grouping and medications
Rat model is divided into model group at random, and compositions 0.9mg/kg group, compound III 0.9mg/kg group and compound IV 0.9mg/kg group, separately establish blank group.Administration group starts rear administration in modeling, oral continuous 30 days; Animal is dissected when 60 days.
2.3 Testing index
2.3.1 get pancreas at the end of experiment to weigh.
2.3.2 pancreas hydroxyproline content measures and gets the homogenate in water of 100mg sample, is hydrolyzed 20 hours in 110 DEG C of 10NHCl.HCl nitrogen volatilizees, and hydrolyzate filters after dissolving with distilled water.Get 0.5ml liquid to mix with the 1M periodic acid that 3ml citric acid phosphate buffer (0.15M citric acid adds 0.6M sodium hydrogen phosphate) and 0.5ml are dissolved in 9M phosphoric acid.Add 1.75ml Extraction buffer (5 parts of toluene: 5 parts of 2-methyl isophthalic acid-propanol: 2 parts of 1-propanol), concussion 30min, centrifugal.Organize phase (0.6ml) and Ehrlich
,15min is placed in the mixing of s reagent.Measure trap at 565nm, with 4-hydroxyl-1-proline production standard curve calculating concentration, content represents with ug/g tissue.
2.3.3 histological examination pancreatic tissues 10% formalin is fixed, paraffin embedding, microscopy after dyeing.To fibrosis situation scoring (0-3 divides).
3 results
3.1 compositionss are on the impact of rat pancreas organ coefficient
At the end of experiment, rat put to death, dissect, to weigh in and pancreas weighs and calculates the ratio (pancreas organ coefficient) of itself and body weight, the results are shown in Table 1.Compositions, on the impact of pancreas organ coefficient, compares with model group and has significant difference.Compound III and compound IV, on the impact of pancreas organ coefficient, compare there was no significant difference with model group.
Table 1
* represent p<0.05, compare with model group
3.2 pancreas hydroxyproline contents measure
At the end of experiment, carry out pulmonary's hydroxyproline content mensuration to each group of rat, result is as table 2.Compositions, on the impact of hydroxyproline content, compares with model group and has significant difference.Compound III and compound IV, on the impact of hydroxyproline content, compare there was no significant difference with model group.
Table 2
* represent p<0.05, compare with model group
3.3 histological examination
At the end of experiment, rat put to death, dissect; The embedding of specimen routine, fixing, HE dyeing, microscopy.
Result: model group visible pancreas surrounding catheter extensive inflammation reaction in the 60th day; Addicted to middle granulocyte karyolymph cellular infiltration, interstitial edema, hemorrhage and accidental pancreas cystencyte is downright bad; Fibrosis is there is between pancreas cystencyte disappearance position and pancreas bubble.
Compositions can reduce inflammatory reaction and fibrosis.Appraisal result is in table 3.Compositions, on the impact of scoring, compares with model group and has significant difference.
Table 3
* represent p<0.05, compare with model group; The inflammatory cell infiltration of blank group and Fibrosis score are all 0.
Conclusion: the present invention on the Fibrotic impact of pancreas in rat, confirms that compositions has the effect of anti-pancreatic gland fibrosis by compositions.Therefore, compositions can be used as the medicine of active component for the preparation of anti-pancreatic gland fibrosis.And compound III and compound IV are without this activity, can not for the preparation of the medicine of anti-pancreatic gland fibrosis.
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 pancreatic gland fibrosis medicine.
4. the application of compositions as claimed in claim 3 in treatment pancreatic gland fibrosis medicine, is characterized by: the pancreas organ coefficient that described compositions reverses caused by pancreatic gland fibrosis declines.
5. the application of compositions as claimed in claim 3 in treatment pancreatic gland fibrosis medicine, is characterized by: the hydroxyproline content that described compositions reverses caused by pancreatic gland fibrosis raises.
6. the application of compositions as claimed in claim 3 in treatment pancreatic gland fibrosis medicine, is characterized by: the inflammatory cell infiltration that described compositions reverses caused by pancreatic gland fibrosis raises.
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| CN201510751978.6A CN105250312A (en) | 2015-11-06 | 2015-11-06 | Composition and application thereof to medicines for preventing or treating pancreatic fibrosis |
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| CN201510751978.6A CN105250312A (en) | 2015-11-06 | 2015-11-06 | Composition and application thereof to medicines for preventing or treating pancreatic fibrosis |
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2015
- 2015-11-06 CN CN201510751978.6A patent/CN105250312A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| 王萌等: "过氧化物酶体增殖物激活受体-γ与胰腺疾病的关系", 《中国实用医药》 * |
| 蒋利荣等: "番石榴叶中二醛杂源萜类化学成分研究", 《广州化工》 * |
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