CN104825466A - Applications of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for preventing or treating pancreatic fibrosis - Google Patents
Applications of cleistanone O-(benzimidazolyl) ethyl derivative in preparation of drugs for preventing or treating pancreatic fibrosis Download PDFInfo
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- CN104825466A CN104825466A CN201510212594.7A CN201510212594A CN104825466A CN 104825466 A CN104825466 A CN 104825466A CN 201510212594 A CN201510212594 A CN 201510212594A CN 104825466 A CN104825466 A CN 104825466A
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Abstract
The invention relates to the fields of organic synthesis and pharmaceutical chemistry, and specifically relates to a cleistanone O-(benzimidazolyl) ethyl derivative, a preparation method thereof, and applications of the cleistanone O-(benzimidazolyl) ethyl derivative in the preparation of drugs for preventing or treating pancreatic fibrosis. A novel cleistanone O-(benzimidazolyl) ethyl derivative is synthesized, and a preparation method thereof is disclosed. Pharmacology experiment results show that the provided cleistanone O-(benzimidazolyl) ethyl derivative has an effect on preventing or treating pancreatic fibrosis, and thus the cleistanone O-(benzimidazolyl) ethyl derivative is advantageously used to produce drugs for preventing or treating pancreatic fibrosis.
Description
Technical field
The present invention relates to organic synthesis and medicinal chemistry art, be specifically related to O-(benzimidazolyl) ethyl derivative, the preparation method and its usage of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
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 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone that the present invention relates to is one and within 2011, delivers (Van Trinh ThiThanh et al., 2011.Cleistanone:A Triterpenoid from Cleistanthus indochinensis witha New Carbon Skeleton.
volume 2011, Issue 22,pages 4108 – 4111, August 2011) compound, we have carried out structural modification to compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, obtain O-(benzimidazolyl) ethyl derivative of a new Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, and its anti-pancreatic gland fibrosis activity is evaluated, it is active that it has anti-pancreatic gland fibrosis.
Summary of the invention
The invention discloses O-(benzimidazolyl) ethyl derivative of a Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone, its structure is:
O-(benzimidazolyl) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention is by method preparation below:
(1) Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) and glycol dibromide are obtained by reacting the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone;
(2) the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone obtains Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III) with benzimidazole generation substitution reaction.
The preparation method of O-(benzimidazolyl) ethyl derivative (III) of further Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone is:
(1) 440mg compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) is dissolved in 10mL benzene, in solution, adds the tetrabutyl ammonium bromide of 0.04g, the glycol dibromide of 3.760g and 50% sodium hydroxide solution of 6mL; Mixture stirs 24h at 25 degrees Celsius; After 24h, 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=100:1, v/v, collects the yellow yellow solid concentrating elution band namely to obtain the O-bromoethyl derivant (II) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone.
(2) the O-bromoethyl derivant of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr of 273mg wood ketone Cleistanone is dissolved in the middle of 15mL acetonitrile, adds the Anhydrous potassium carbonate of 345mg wherein, the potassium iodide of 84mg and the benzimidazole of 1180mg, mixture reflux 5h; After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three 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 brown solid that namely brown concentrated elution band obtains Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone derivant (III).
Compound disclosed by the invention can make pharmaceutically acceptable salt or pharmaceutically acceptable carrier.
Pharmacodynamic experiment shows, O-(benzimidazolyl) ethyl derivative (III) of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of the present invention has good anti-pancreatic gland fibrosis effect.Pharmaceutically acceptable salt of the present invention has same drug effect with its compound.
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 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Document (the Van Trinh Thi Thanh et al. that the people such as the preparation method reference Van Trinh Thi Thanh of compound Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone (I) deliver, 2011.Cleistanone:A Triterpenoid fromCleistanthus indochinensis with a New Carbon Skeleton.Volume 2011, Issue 22, pages 4108 – 4111, August 2011) method.
The synthesis of the O-bromoethyl derivant (II) of embodiment 2 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
By Compound I (440mg, 1.00mmol) be dissolved in 10mL benzene, add in solution tetrabutyl ammonium bromide (TBAB) (0.04g), 1,50% sodium hydroxide solution of 2-Bromofume (3.760g, 20.00mmol) and 6mL.Mixture stirs 24h at 25 degrees Celsius.After 24h, 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=100:1, v/v), collects the yellow yellow solid (344mg, 63%) concentrating elution band namely to obtain Compound II per.
1H NMR(500MHz,DMSO-d
6)δ5.04(s,1H),4.82(s,1H),3.94(d,J＝26.5Hz,1H),3.87(d,J＝26.5Hz,2H),3.57(s,2H),2.40(d,J＝14.0Hz,1H),2.39(d,J＝14.0Hz,1H),2.27(s,1H),2.21(s,1H),2.15(s,1H),1.82(s,1H),1.62(s,2H),1.57(d,J＝3.3Hz,1H),1.54(d,J＝3.3Hz,1H),1.50(d,J＝1.2Hz,1H),1.47(d,J＝1.2Hz,1H),1.39(d,J＝15.3Hz,2H),1.34(d,J＝15.3Hz,1H),1.26(dd,J＝32.6,13.7Hz,4H),1.13(d,J＝18.0Hz,2H),1.05(s,6H),0.98(s,1H),0.88(s,12H),0.78(s,3H),0.74(s,1H)。
13C NMR(125MHz,DMSO-d6)δ216.59(s),154.50(s),105.23(s),74.63(s),69.85(s),59.71(s),52.55(s),51.21(s),47.92(s),44.10(s),42.25(s),41.73(s),40.64(s),40.16(s),38.88(s),38.65(s),37.21(s),36.23(s),33.34(d,J＝1.1Hz),32.96(s),29.91(s),27.18(s),26.03(s),24.23(s),23.96(s),20.77(s),18.48(s),17.98(s),16.93(s)。
HRMS(ESI)m/z[M+H]
+calcd for C
32H
52BrO
2:547.3151；found 547.3159.
The synthesis of O-(benzimidazolyl) ethyl derivative (III) of embodiment 3 Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone
Compound II per (273mg, 0.5mmol) is dissolved in the middle of 15mL acetonitrile, adds Anhydrous potassium carbonate (345mg wherein, 2.5mmol), potassium iodide (84mg, 0.5mmol) and benzimidazole (1180mg, 10mmol), mixture reflux 5h.After reaction terminates, reactant liquor is poured in frozen water, with equivalent dichloromethane extraction three 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 brown concentrated elution band, the concentrated brown solid (105.2mg, 36%) namely obtaining compound III.
1H NMR(500MHz,DMSO-d6)δ8.27(s,1H),7.68(d,J＝25.0Hz,2H),7.31(s,1H),7.21(s,1H),4.65(s,1H),4.56(s,1H),4.14(d,J＝7.9Hz,2H),4.05(s,1H),3.93(s,2H),2.51(d,J＝127.9Hz,1H),2.37(s,1H),2.28(d,J＝15.8Hz,2H),2.22(s,1H),1.90(s,2H),1.83(s,1H),1.66(s,2H),1.62–1.49(m,4H),1.29(t,J＝17.7Hz,3H),1.19(d,J＝14.3Hz,2H),1.11(d,J＝7.6Hz,7H),1.02(dd,J＝42.5,9.8Hz,13H),0.88(s,3H),0.80(s,1H),0.63(s,1H).
13C NMR(125MHz,DMSO-d6)δ216.57(s),154.46(s),146.57(s),139.24(s),134.35(s),124.01(s),123.47(s),118.67(s),110.97(s),105.19(s),74.62(s),67.84(s),59.73(s),52.52(s),51.17(s),47.88(s),45.48(s),44.08(s),42.26(s),41.75(s),40.61(s),40.13(s),38.83(s),38.62(s),37.22(s),36.24(s),33.30(s),32.92(s),29.86(s),27.16(s),26.04(s),24.24(s),23.92(s),20.75(s),18.43(s),17.97(s),16.93(s).
HRMS(ESI):m/z[M+H]
+calcd for C
39H
57N
2O
2:585.4420；found:585.4416。
The anti-pancreatic gland fibrosis of O-(benzimidazolyl) ethyl derivative of embodiment 4Cleistanone is active
1 material
1.1 animal Wistar rats, male, body weight 180-200g.
O-(benzimidazolyl) the ethyl derivative dosage of 1.2Cleistanone: 0.9mg/kg.
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 O-(benzimidazolyl) the ethyl derivative 0.9mg/kg group of Cleistanone, separately establishes blank group, start 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 10N HCl.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
O-(benzimidazolyl) ethyl derivative of 3.1Cleistanone is 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.O-(benzimidazolyl) ethyl derivative of Cleistanone, on the impact of pancreas organ coefficient, compares with model group and has significant difference.
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.O-(benzimidazolyl) ethyl derivative of Cleistanone, on the impact of hydroxyproline content, compares with model group and has significant difference.
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.
O-(benzimidazolyl) ethyl derivative of Cleistanone can reduce inflammatory reaction and fibrosis.Appraisal result is in table 3.O-(benzimidazolyl) ethyl derivative of Cleistanone, 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 O-(benzimidazolyl) ethyl derivative of Cleistanone has the effect of anti-pancreatic gland fibrosis by O-(benzimidazolyl) ethyl derivative of Cleistanone.Therefore, O-(benzimidazolyl) ethyl derivative of Cleistanone can be used as the medicine of active component for the preparation of anti-pancreatic gland fibrosis.
The preparation of O-(benzimidazolyl) the ethyl derivative tablet of embodiment 5 Cleistanone involved in the present invention
Get the one in the middle of O-(benzimidazolyl) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add the customary adjuvant 180 grams preparing tablet, mixing, conventional tablet presses makes 1000.
The preparation of O-(benzimidazolyl) the derivatized composite capsule of embodiment 6 Cleistanone involved in the present invention
Get the one in the middle of O-(benzimidazolyl) ethyl derivative of 20 grams of Cleistanone or its pharmaceutically acceptable salt, add prepare capsule customary adjuvant as starch 180 grams, mixing, encapsulatedly makes 1000.
Claims (4)
1. there is O-(benzimidazolyl) ethyl derivative and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof of the Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone of structure shown in formula III,
2. O-(benzimidazolyl) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 1 and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof, is characterized by: the pancreas organ coefficient that O-(benzimidazolyl) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis declines.
3. O-(benzimidazolyl) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 1 and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof, is characterized by: the hydroxyproline content that O-(benzimidazolyl) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis raises.
4. O-(benzimidazolyl) ethyl derivative of Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone as claimed in claim 1 and the application of pharmaceutically acceptable salt in treatment pancreatic gland fibrosis medicine thereof, is characterized by: the inflammatory cell infiltration that O-(benzimidazolyl) ethyl derivative of described Cleistanthus sumafranus (Miq) Muell-Arg-C. Saichikii Merr wood ketone Cleistanone and pharmaceutically acceptable salt thereof reverse caused by pancreatic gland fibrosis raises.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106038554A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of anti-hepatic fibrosis drugs |
| CN106038553A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of pancreatic fibrosis control drugs |
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| CN104147019A (en) * | 2014-07-31 | 2014-11-19 | 南京大学 | Application of O-(tetrahydropyrrole) ethyl derivative of cleistanone in preparation of medicines for preventing or treating pancreatic fibrosis |
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Patent Citations (1)
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| CN104147019A (en) * | 2014-07-31 | 2014-11-19 | 南京大学 | Application of O-(tetrahydropyrrole) ethyl derivative of cleistanone in preparation of medicines for preventing or treating pancreatic fibrosis |
Non-Patent Citations (2)
| Title |
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| VAN TRINH THI THANH, ET AL.: "Cleistanone: A Triterpenoid from Cleistanthus indochinensis with a New Carbon Skeleton", 《EUR. J. ORG. CHEM.》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106038554A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of anti-hepatic fibrosis drugs |
| CN106038553A (en) * | 2016-06-13 | 2016-10-26 | 南京广康协生物医药技术有限公司 | Application of composition of Schiglautone A derivatives in preparation of pancreatic fibrosis control drugs |
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