CN115611964B - Ursolic acid saponin with inflammatory bowel disease treatment effect, derivative thereof, preparation method and application - Google Patents

Ursolic acid saponin with inflammatory bowel disease treatment effect, derivative thereof, preparation method and application Download PDF

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CN115611964B
CN115611964B CN202110799642.2A CN202110799642A CN115611964B CN 115611964 B CN115611964 B CN 115611964B CN 202110799642 A CN202110799642 A CN 202110799642A CN 115611964 B CN115611964 B CN 115611964B
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beta
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arabinopyranosyl
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CN115611964A (en
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李宁
刘洋
程卯生
陈刚
周地
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The invention belongs to the technical field of medicines, and relates to ursolic acid saponin with a novel structure, a derivative thereof, a preparation method and application thereof in preparing medicines for treating inflammatory bowel diseases. The ursolic acid saponin is a compound shown in the following structural formula, and an optical active body or diastereoisomer thereof; the compound shown in the following structural formula is 19 alpha-hydroxy ursolic acid-3 beta-O-alpha-L-arabinopyranosyl-28-O-beta-D-xylopyranoside (W1) or 19 alpha-hydroxy ursolic acid-3 beta-O-alpha-L-arabinopyranosyl-28-O-beta-D-galactopyranoside (W2); the compound and the pharmaceutical composition thereof are derived from a mother nucleus with a natural structure, have better long-term administration safety, and can not interfere the immune system of a human body like hormone, immunosuppressant, anti-inflammatory medicine sulfasalazine and the like.

Description

Ursolic acid saponin with inflammatory bowel disease treatment effect, derivative thereof, preparation method and application
Technical Field
The invention belongs to the technical field of medicines, and relates to ursolic acid saponin with a novel structure, a derivative thereof, a preparation method and application thereof in preparing medicines for treating inflammatory bowel diseases.
Background
Inflammatory bowel disease is an intestinal disease with complex pathogenesis and difficult to cure after repeated attacks for a long time, and clinically mainly comprises ulcerative colitis and Crohn's disease. Because of the ambiguous pathogenesis, the treatment of inflammatory bowel disease is still carried out by the scheme of inhibiting inflammatory immune response such as hormone, anti-inflammatory drugs, immunosuppressant and the like, and the treatment of inflammatory bowel disease is not carried out by targeted intervention treatment on the etiology of inflammatory bowel disease on the basis of the treatment of inflammation. The result is that the canceration rate of patients with inflammatory bowel disease in the course of more than 10 years is higher, and different statistical sources show that the canceration conversion rate of inflammatory bowel disease is more than 4%. Therefore, the development of novel drugs which have high safety for long-term administration, significantly improve clinical symptoms and can inhibit the occurrence of atypical hyperplasia of colorectal has wide clinical demands for inflammatory bowel diseases. The ursolic acid component is an important natural product in the natural world, has various activities through in vitro researches, but is not reported in research on intervention treatment aiming at pathogenesis of inflammatory bowel disease. Therefore, the discovery of novel ursolic acid glycosides with pathogenesis aiming at inflammatory bowel disease would have important significance.
Disclosure of Invention
The invention aims to provide ursolic acid saponin with an inflammatory bowel disease treatment effect, a derivative thereof, a preparation method and application.
In order to accomplish the purpose of the present invention, the following technical scheme may be adopted:
a ursolic acid saponin with inflammatory bowel disease treating effect is shown in the following structural formula, and its optical active body or diastereoisomer;
the compound shown in the following structural formula is 19 alpha-hydroxy ursolic acid-3 beta-O-alpha-L-arabinopyranosyl-28-O-beta-D-xylopyranoside (W1) or 19 alpha-hydroxy ursolic acid-3 beta-O-alpha-L-arabinopyranosyl-28-O-beta-D-galactopyranoside (W2);
the derivative is a compound shown in the following structural formula, and an optical active body or diastereoisomer thereof;
the compounds shown in the following structural formulas are N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxyl-12-alkene-28-oxo-ursan-28-yl ] -glycine (W3), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxyl-12-alkene-28-oxo-ursan-28-yl ] -glutamic acid (W4), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxyl-12-alkene-28-oxo-ursan-28-yl ] -serine (W5), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxyl-12-alkene-28-oxo-ursan-28-yl ] -tyrosine (W6), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxyl-12-alkene-28-oxo-28-yl ] -proline (W7-yl);
the preparation method of the ursolic acid saponin comprises the following steps:
the reaction formula is as follows:
taking monosaccharide as a raw material, adding acetic anhydride into pyridine solution, protecting all exposed hydroxyl groups by acetyl groups, and reacting with hydrogen bromide acetic acid solution to obtain terminal bromo-1; dissolving sanguisorbin II (2) by pyridine, adding acetic anhydride, and reacting to obtain a compound 3; reacting the compound 3 with the compound 1 by using dichloromethane as a solvent, TBAB as a phase transfer catalyst and potassium carbonate as an acid applying agent to generate an intermediate 4, and finally removing acetyl in a methanol solution of sodium methoxide to generate a product ursolic acid saponin; wherein the monosaccharide is galactose or xylose.
A preparation method of ursolic acid saponin derivative comprises dissolving sanguisorbin II (2) with pyridine, adding acetic anhydride, and reacting to obtain compound 3; the compound 3 reacts with oxalyl chloride in dry dichloromethane to prepare acyl chloride 6, dichloromethane and excessive oxalyl chloride are distilled off under the condition of reduced pressure, the obtained product is dissolved in anhydrous dichloromethane again, anhydrous dichloromethane solution of amino acid methyl ester (5) and DIPEA are added dropwise, intermediate 7 is obtained through reaction, and finally acetyl and methyl ester are removed by 1M sodium methoxide methanol solution to obtain the product W3-W7;
wherein the amino acid methyl ester is glycine methyl ester, glutamic acid methyl ester, serine methyl ester, tyrosine methyl ester or proline methyl ester.
A pharmaceutical composition comprising said compound and its optically active forms, diastereomers and/or said derivatives and its optically active forms, diastereomers.
A pharmaceutical formulation comprising an active ingredient and a pharmaceutically acceptable carrier; wherein the active ingredient accounts for 0.1-99% of the mass of the preparation; the active ingredient is one or more of the compound and the optical active body, diastereoisomer, the derivative and the optical active body, diastereoisomer and the pharmaceutical composition.
The application of the compound and the optical active body, diastereoisomer or the pharmaceutical composition or the pharmaceutical preparation thereof in preparing medicines for treating inflammatory bowel diseases.
The use of said compounds and their optically active forms, diastereomers or said pharmaceutical compositions or said pharmaceutical preparations for the preparation of a medicament for the prophylaxis or treatment of colorectal dysplasia.
The use of said compounds and their optically active forms, diastereomers or said pharmaceutical compositions or said pharmaceutical preparations for the preparation of a medicament for the prophylaxis or treatment of colorectal dysplasia caused by inflammatory bowel disease.
The invention has the advantages that:
the compound and the pharmaceutical composition thereof are derived from a mother nucleus with a natural structure, have better long-term administration safety, and can not interfere the immune system of a human body like hormone, immunosuppressant, anti-inflammatory medicine sulfasalazine and the like. Meanwhile, the compound and the pharmaceutical composition and preparation thereof can target miR-31-5p (Gastroenterology, 2019,156:2281-2296) which is a key target for treating inflammatory bowel diseases, so that the pathogenesis of inflammatory bowel diseases is treated in a targeted manner.
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FIG. 1 is a diagram showing the pharmacological research process of the synthetic product of the present invention.
Detailed Description
The invention is further described below in connection with examples, but embodiments of the invention are not limited to the following examples.
Example 1:19 alpha-hydroxy ursolic acid-3 beta-O-alpha-L-arabinopyranosyl-28-O-beta-D-xylopyranoside (W1)
Xylose (1.0 eq) was added to a 500ml eggplant-type bottle, dissolved with pyridine, acetic anhydride (6.0 eq) was added, and then 0.1 eq of 4-Dimethylaminopyridine (DMAP) was added, reacted at room temperature for 3h, and TLC monitored complete arabinose reaction. The reaction solution was diluted with methylene chloride, quenched with water, and the organic layer was extracted 3 times with water, washed with dilute hydrochloric acid 1 time to wash out pyridine, washed with saturated aqueous sodium bicarbonate 1 time, finally washed with saturated aqueous sodium chloride 1 time, and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent was evaporated to dryness to give a pale yellow oil, the pale yellow oil (1.0 eq) was dissolved in an appropriate amount of dichloromethane, then a solution of hydrogen bromide in acetic acid (4.0 eq) was slowly added dropwise to the mixture under ice-bath conditions using a dropping funnel, the reaction was continued for 2h at 20℃and TLC was monitored to end. The reaction solution was diluted with dichloromethane, quenched with water, the organic phase was extracted 3 times with water, washed 1 time with saturated sodium bicarbonate solution, finally with saturated sodium chloride solution 1 time, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness, and separated by flash column chromatography (eluent petroleum ether: ethyl acetate=5:1) to give the terminal bromo 1 in a total yield of 77.3%.
Compound 2[ sanguisorbin II (1.0 eq) ] was dissolved in pyridine, acetic anhydride (5.0 eq.) was added, the reaction was carried out at 20℃for about 2h, and TLC monitored for the end of the reaction. The reaction solution was diluted with methylene chloride, quenched with water, the organic layer was extracted 3 times with water, washed with dilute hydrochloric acid 1 time to wash out pyridine, washed with saturated aqueous sodium bicarbonate 1 time, finally washed with saturated aqueous sodium chloride 1 time, and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent gave white solid 3 in 81.19% yield.
Compound 3 (1.0 equivalent) and compound 1 (1.2 equivalent) were reacted at 50 ℃ for 3 hours with ethyl acetate as a solvent, tetrabutylammonium bromide as a phase transfer catalyst, and an aqueous potassium carbonate solution. After the completion of the TLC, the reaction solution was diluted with ethyl acetate, quenched with water, extracted 3 times with ethyl acetate, and the organic layer was collected. Anhydrous sodium sulfate is added for drying, and the white solid 4 is obtained after evaporation to dryness, and the yield is 86.3%.
Compound 4 (1.0 eq) was dried in dichloromethane: methanol (1:1) was dissolved, and 1mol/L of sodium methoxide in methanol (1.5 eq.) was added dropwise thereto under ice-bath conditions. The reaction was stirred at 20 ℃, monitored by TLC, the reaction was completed, the PH of the solution was adjusted to neutral with a cation exchange resin, filtered, the filtrate was evaporated to dryness, and column chromatography (eluent dichloromethane: methanol=20:1, 0.3% formic acid) gave white solid A1. The total yield was 73.4% (compound 2, i.e. from sanguisorbin II). 1 H-NMR(400MHz, Pyridine-d 5 )δ H 6.20(d,J＝6.5Hz,1H),5.57(s,1H),4.76(d,J＝6.9Hz,1H), 4.47-4.34(m,2H),4.34-4.28(m,2H),4.23(t,J＝6.5Hz,3H),4.16(dd,J＝8.7,3.0Hz,1H),3.83(d,J＝10.7Hz,2H),3.34(dd,J＝11.6,4.1Hz,1H),3.12(dd, J＝16.8,12.8Hz,1H),2.97(s,1H,H-18)，2.44(dd,J＝13.5,9.1Hz,1H),1.70(s,3H),1.39(s,3H),1.27(s,3H),1.17(s,3H),1.07(d,J＝6.7Hz,3H),0.98(s, 3H),0.92(s,3H)； 13 C-NMR(100MHz,Pyridine-d 5 )δ C 177.1,139.3,128.4, 107.5,96.3,88.8,78.3,74.6,73.6,72.9,72.6,70.9,69.5,67.7,66.7,55.9,54.3, 48.8,47.7,42.1,42.1,40.5,39.5,38.9,37.9,37.0,33.5,29.2,28.2,27.0,26.7,26.7,26.0,24.6,24.0,18.7,17.4,16.9,16.7,15.6；ESI-MS(m/z):759.8 [M+Na] + 。
Example 2:19 alpha-hydroxy ursolic acid-3 beta-O-alpha-L-arabinopyranosyl-28-O-beta-D-galactopyranoside (W2)
The compound of example 2 was prepared in the same manner as in example 1 except that galactose was used instead of xylose, to obtain W2 as a white solid in 73.3% yield. 1 H NMR(400MHz,Pyridine-d 5 )δ H 6.24(d,J ＝8.2Hz,1H),5.56(s,1H),4.77(d,J＝7.0Hz,1H),4.52(dd,J＝10.9,6.6Hz,2H),4.46(d,J＝7.1Hz,1H),4.38(m,3H),4.29-4.26(m,1H),4.24(d,J＝4.6 Hz,1H),4.23-4.19(m,2H),3.84(d,J＝11.4Hz,1H),3.34(dd,J＝11.6,4.0Hz,1H),2.93(s,1H),1.70(s,3H),1.40(s,3H),1.27(s,3H),1.16(s,3H),1.07(d,J ＝6.5Hz,3H),0.98(s,3H),0.93(s,3H)； 13 C NMR(100MHz,Pyridine-d 5 )δ C 177.0,139.1,128.3,107.3,96.2,88.7,77.5,75.5,74.4,72.8,72.5,71.3,69.8,69.4,66.6,61.7,55.8,54.3,48.5,47.6,42.0,41.9,40.4,39.4,39.4,37.6,36.9, 33.4,29.8,28.1,26.9,26.6,26.6,25.9,24.4,23.9,18.6,17.3,16.8,16.5,15.5； ESI-MS(m/z):789.8[M+Na] + 。
Example 3: n- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -glycine (W3)
Compound 3 (1.0 eq.) was dissolved in dry dichloromethane and oxalyl chloride (4.0 eq.) was slowly added dropwise at 20℃and after stirring for 1h, the reaction was complete by TLC. Evaporating the reaction liquid, adding toluene for dissolving, evaporating again, repeating for three times to remove the solvent, and obtaining the pale yellow foam compound 6 with the yield of 92.3%.
Compound 6 (1.0 eq) was dissolved in anhydrous dichloromethane, a solution of methyl glycine (3.0 eq) in anhydrous dichloromethane and DIPEA (3 drops) were added dropwise, stirred at 20 ℃ for 2.5 hours, reacted completely, washed with water, and the organic layer was dried by spin to give compound 7 in 91.5% yield.
Compound 7 was dissolved in dry sodium methoxide-methanol solution (1.0 mol/L) and reacted overnight at 20 ℃. Neutralization to ph=7 with formic acid, filtration, column chromatography (eluent dichloromethane: methanol=15:1, 0.3% formic acid) was concentrated to give a pale yellow solid in 87.2% yield. 1 H NMR(400MHz,Pyridine-d 5 )δ H 7.85 (s,1H),5.64(s,1H),4.78(d,J＝6.2Hz,1H),4.55(dd,J＝17.5,4.8Hz,1H), 4.43(t,J＝7.1Hz,2H),4.32(d,J＝9.3Hz,2H),4.17(d,J＝8.1Hz,1H),3.84(d,J＝12.3Hz,1H),3.35(dd,J＝11.3,3.2Hz,1H),3.22(t,J＝13.0Hz,1H), 2.92(s,1H),1.73(s,3H),1.41(s,3H),1.28(s,3H),1.10(d,J＝6.4Hz,3H),1.02(s,3H),0.98(s,3H),0.91(s,3H)； 13 C NMR(100MHz,Pyridine-d 5 )δ C 178.4,173.4,139.9,128.5,107.5,88.8,74.6,73.0,72.9,69.5,66.7,55.9,54.6,48.0,47.8,42.6,42.3,42.1,40.4,39.6,38.9,38.9,37.0,33.4,28.9,28.3,27.2, 27.1,26.7,26.3,24.7,24.1,18.7,16.9,16.9,16.8,15.6；ESI-MS(m/z):660.8 [M-H] - 。
Example 4: n- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -glutamic acid (W4)
The procedure for the preparation of the compound of example 4 is as in example 3, except that methyl glutamate is used instead of glycineMethyl acid ester gave W4 as a white solid in 61.8% yield. 1 H NMR(400MHz,Pyridine-d 5 )δ H 7.76(s,1H),5.72(s,1H),5.18(s,1H),4.78(d,J＝7.1Hz,1H),4.45(d,J＝7.2Hz),4.34(s,2H),4.19(s,1H),3.84(d,J＝11.3Hz,1H),3.41-3.29(m,1H), 3.05(dd,J＝15.4,7.2Hz,1H),2.93(s,1H),2.89-2.82(m,1H),2.70-2.56(m,1H),1.74(s,3H),1.41(s,3H),1.27(s,3H),1.08(d,J＝6.6Hz,3H),1.06(s, 3H),0.93(s,3H),0.84(s,3H)； 13 C NMR(100MHz,Pyridine-d 5 )δ C 178.4, 175.8,175.6,139.5,128.8,107.5,88.8,74.6,72.9,72.9,69.5,66.7,55.9,54.6,53.4,49.7,48.2,47.8,42.3,42.1,40.4,39.6,39.0,38.8,37.0,33.5,31.5,29.0, 28.3,27.2,27.0,26.7,26.2,24.7,24.1,18.7,17.2,16.9,16.8,15.5；ESI-MS(m/z):732.8[M-H] - 。
Example 5: n- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -serine (W5)
The compound of example 5 was prepared in the same manner as in example 3 except that serine methyl ester was used instead of glycine methyl ester, to obtain white solid W5 in 84.5% yield. 1 H NMR(400MHz,Pyridine-d 5 )δ H 5.63(s,1H),5.22(m,1H),4.78(d,J＝6.8Hz,1H),4.64(t,J＝9.4Hz,1H), 4.49-4.38(m,1H),4.34(s,2H),4.18(d,J＝6.6Hz,1H),3.84(d,J＝11.4Hz,1H),3.38-3.31(m,1H),3.21(d,J＝12.4Hz,1H),2.93(s,1H),1.74(s,3H), 1.38(s,3H),1.29(s,3H),1.11-1.03(m,6H),0.98(s,3H),0.89(s,3H)； 13 C NMR(100MHz,Pyridine-d 5 )δ C 178.2,174.7,139.5,128.3,107.6,88.9,74.7, 73.0,73.0,69.6,66.8,63.5,63.4,56.0,54.8,48.2,47.8,42.3,42.2,40.5,39.6,39.1,38.9,37.0,33.5,28.9,28.3,27.2,26.7,26.3,24.9,24.7,24.2,18.7,17.4, 17.0,16.8,15.6；ESI-MS(m/z):690.7[M-H] - 。
Example 6: n- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -tyrosine (W6)
The compound of example 6 was prepared in the same manner as in example 3 except that methyl tyrosine was used instead of methyl glycine, to give W6 as a white solid in 78.0% yield. 1 H NMR(400MHz,Pyridine-d 5 )δ H 7.53(d,J＝6.0Hz,1H),7.50(d,J＝8.1Hz,2H),7.47(d,J＝10.8Hz,1H),5.59 (s,1H),5.28-5.17(m,1H),4.77(d,J＝7.1Hz,1H),4.48-4.39(m,1H),4.33(s,2H),4.23-4.13(m,1H),3.83(d,J＝11.2Hz,1H),3.66(dd,J＝13.7,4.6Hz, 1H),3.44(dd,J＝13.4,7.0Hz,1H),3.33(dd,J＝11.4,4.7Hz,1H),3.25-3.13(m,1H),2.81(s,1H),1.71(s,3H),1.33(s,3H),1.26(s,3H),1.06(d,J＝6.6 Hz,3H),0.94(s,3H),0.87(s,6H)； 13 C NMR(100MHz,Pyridine-d 5 )δ C 178.2, 175.7,157.9,139.5,131.3,128.8,128.6,116.2,107.5,88.8,74.6,72.9,72.9,69.5,66.7,55.9,55.8,54.5,48.0,47.8,42.3,42.1,40.4,39.6,38.8,38.8,37.4, 37.0,33.3,28.9,28.3,27.1,27.1,26.7,26.2,24.7,24.1,18.7,16.9,16.8,16.7, 15.6；ESI-MS(m/z):766.2[M-H] - 。
Example 7: n- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -proline (W7)
The compound of example 7 was prepared in the same manner as in example 3 except that methyl proline was used instead of methyl glycine to give W7 as a white solid in 64.5% yield. 1 H NMR(400MHz,Pyridine-d 5 )δ H 5.59(s,1H),4.90(d,J＝8.8Hz,1H),4.79(d,J＝6.7Hz,1H),4.46-4.43(m,1H),4.32(s,2H),4.18(d,J＝6.7Hz),3.87(m,3H),3.43-3.32(m,1H),3.27 (s,1H),2.93(s,1H),1.75(s,3H),1.44(s,3H),1.32(s,3H),1.09(d,J＝6.5Hz,3H),1.01(s,3H),0.94(s,3H),0.85(s,3H)；ESI-MS(m/z):700.6[M-H] - 。
Pharmacological investigation of the synthetic products of the invention
Adopting 6-8 week old balb/c mice, and adaptively feeding 10mg/kg of cancerogenic agent AOM into a model group after one week; normal mice were intraperitoneally injected with an equivalent amount of physiological saline instead. After one week, the model group was free to drink the inflammatory agent 2.0% dss for one week, and was stopped for two weeks as one cycle, for three cycles to establish a colonic cancer model associated with colitis. Gastric administration (20 mg/kg) was started after the third week (drug was the compound prepared in the above example and the control drug sulfasalazine) until the end of the experiment. The general state, hematochezia, rectocele and other symptoms of the experimental inflammatory bowel disease mice are observed and recorded. Mice were sacrificed after week 10 (calculated from the completion of 3 DSS cycles for one week dosing and 2 weeks recovery) and samples were collected as shown in figure 1.
Disease activity index (DAI, disease activity index) scores (scoring criteria are shown in table 1 below) were performed with reference to classical scoring system methods and the distribution of the degree of colorectal dysplasia and the modulation of the key target miR-31-5p for inflammatory bowel disease in each group were recorded and the results are shown in table 2.
TABLE 1 DAI scoring criteria
Weight loss (%) The character of answering and distinguishing Fecal occult blood/macroscopic blood stool Scoring of
0 Normal state Normal state 1
1-5 Loosening Cryptographic blood positivity 2
5-10 3
10-15 Thin stool Blood stool with naked eyes 4
>15 5
TABLE 2 DAI scoring Table for mice of each groupn=15) and distribution of degree of atypical hyperplasia of colorectal (using distribution number of surviving mice as statistical index)
The experimental result shows that the compound with a brand new structure obtained by the invention has remarkable treatment effect on inflammatory bowel diseases and can inhibit the occurrence of intestinal atypical hyperplasia caused by the inflammatory bowel diseases. Meanwhile, the RT-Q-PCR result shows that the novel compound has remarkable regulation effect on the key target miR-31-5p of inflammatory bowel disease. Therefore, the compound disclosed by the invention can target to a key target miR-31-5p of inflammatory bowel disease, so that the therapeutic effect of inflammatory bowel disease and the prevention and treatment effect of atypical hyperplasia of intestinal tracts are achieved, and the compound has the potential of being developed into an inflammatory bowel disease therapeutic drug which can be taken for a long time.

Claims (7)

1. A derivative of ursolic acid saponin with inflammatory bowel disease treatment effect, characterized in that: the ursolic acid saponin derivative is a compound shown in the following structural formula;
the compounds shown are N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -glycine (W3), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -glutamic acid (W4), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -serine (W5), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-ursan-28-yl ] -tyrosine (W6), N- [ 3-O-alpha-L-arabinopyranosyl-3 beta, 19 alpha-dihydroxy-12-en-28-oxo-28-yl ] -proline (W7);
。
2. the process for preparing a derivative of ursolic acid saponin according to claim 1, characterized in that: the reaction formula is:
；
dissolving sanguisorbin II2 by pyridine, adding acetic anhydride, and reacting to obtain a compound 3; reacting the compound 3 with oxalyl chloride in dry dichloromethane to prepare acyl chloride, steaming dichloromethane and excessive oxalyl chloride under reduced pressure, dissolving the obtained product in anhydrous dichloromethane again, dropwise adding an anhydrous dichloromethane solution of amino acid methyl ester and DIPEA, reacting to obtain an intermediate, and finally removing acetyl and methyl ester by using a 1M sodium methoxide methanol solution to obtain a product W3-W7;
wherein the amino acid methyl ester is glycine methyl ester, glutamic acid methyl ester, serine methyl ester, tyrosine methyl ester or proline methyl ester.
3. A pharmaceutical composition characterized by: a composition comprising the derivative of claim 1.
4. A pharmaceutical formulation characterized in that: the preparation is an active ingredient and a pharmaceutically acceptable carrier; wherein the active ingredient accounts for 0.1-99% of the mass of the preparation; the active ingredient is one or more of the derivatives as claimed in claim 1 and the pharmaceutical compositions as claimed in claim 3.
5. An application, characterized in that: use of a derivative according to claim 1 or a pharmaceutical composition according to claim 3 or a pharmaceutical formulation according to claim 4 for the manufacture of a medicament for the treatment of inflammatory bowel disease.
6. The use according to claim 5, wherein: use of a derivative according to claim 1 or a pharmaceutical composition according to claim 3 or a pharmaceutical formulation according to claim 4 for the preparation of a medicament for the prevention or treatment of colorectal dysplasia.
7. The use according to claim 6, wherein: use of a derivative according to claim 1 or a pharmaceutical composition according to claim 3 or a pharmaceutical formulation according to claim 4 for the preparation of a medicament for the prevention or treatment of colorectal dysplasia caused by inflammatory bowel disease.
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