CN115505021B - Ursolic acid derivative with inflammatory bowel disease treatment effect and preparation method and application thereof - Google Patents

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

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CN115505021B
CN115505021B CN202110694621.4A CN202110694621A CN115505021B CN 115505021 B CN115505021 B CN 115505021B CN 202110694621 A CN202110694621 A CN 202110694621A CN 115505021 B CN115505021 B CN 115505021B
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urs
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ursolic acid
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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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Abstract

The invention belongs to the technical field of medicines, and relates to a ursolic acid derivative with a novel structure, a preparation method thereof and a treatment effect on inflammatory bowel disease, and potential application of the ursolic acid derivative in preparation of inflammatory bowel disease treatment medicines. The ursolic acid derivative is a compound shown in a general formula (I), an optical active body or a diastereoisomer thereof, and substituent groups are selected in detail in the specification, and the compound, the pharmaceutical composition and the preparation thereof can target miR-31-5p which is a key target of inflammatory bowel disease, so that a specific treatment effect is achieved for the inflammatory bowel disease.

Description

Ursolic acid derivative with inflammatory bowel disease treatment effect and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to a ursolic acid derivative with a novel structure, a preparation method thereof and a treatment effect on inflammatory bowel disease, and potential application of the ursolic acid derivative in preparation of inflammatory bowel disease treatment medicines.
Background
Inflammatory bowel disease is a chronic disease with complex pathogenesis, an undefined long-term recurrence and incurable disease, mainly including ulcerative colitis and Crohn's disease. Because the pathogenesis is complicated, anti-inflammatory drugs (such as sulfasalazine and the like), hormones or immunosuppressants and the like are clinically used for treating the inflammation symptoms, and the long-term administration has potential risks and meanwhile, the targeted treatment for the pathogenesis of the diseases is lacking. The ursolic acid component is an important natural molecule in the natural world, and has various activities, but research reports on treatment of inflammatory bowel disease pathogenesis are not seen. Recent researches show that miR-31 is remarkably abnormally and highly expressed in the pathogenesis and canceration process of inflammatory bowel disease, and the regulation of the level of miR-31 can play a positive therapeutic role in improving symptoms of inflammatory bowel disease and preventing canceration (Gastroenterology, vol.156:2281-2296). The invention synthesizes a series of ursolic acid derivatives with novel structure, which can play a role in treating inflammatory bowel disease by regulating the expression of mir-31, and belongs to novel inflammatory bowel disease treatment medicines with novel structure and action mechanism.
Disclosure of Invention
The invention aims to design and synthesize the ursolic acid derivative with novel structure, the preparation method thereof, the regulation efficacy on the key target point of inflammatory bowel disease and the treatment effect on inflammatory bowel disease, and has potential application in preparing the inflammatory bowel disease treatment medicine.
In order to accomplish the purpose of the present invention, the following technical scheme may be adopted:
a ursolic acid derivative is a compound shown in a general formula (I) and an optical active body or diastereoisomer thereof:
wherein R is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group or a halogen atom.
Preferably, the ursolic acid derivative is a compound shown in a general formula (I) and an optical active body or diastereoisomer thereof; wherein R is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a halogen atom.
Further preferred are said derivatives and their optically active forms, diastereoisomers, wherein,
r is methyl, C1-C4 haloalkyl, methoxy or halogen atom.
Still further preferred, the derivatives and optically active, diastereoisomers thereof, wherein,
r is methyl, trifluoroalkyl, methoxy, fluorine, chlorine or bromine.
More preferably, the derivative is
B1: n- (2' -methyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b2: n- (2' -methoxy-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b3: n- (2' -fluoro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b4: n- (2' -chloro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b5: n- (2' -bromo-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b6: n- (2' -trifluoromethyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b7: n- (4' -methyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b8: n- (4' -methoxy-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b9: n- (4' -fluoro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b10: n- (4' -chloro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b11: n- (4' -bromo-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b12: n- (4' -trifluoromethyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
the structure is as follows:
a preparation method of a derivative shown in a general formula (I) comprises the following steps:
further, the 3 beta-hydroxy acetylation intermediate 2 and the 23-hydroxy acetylation intermediate 2 of the holly bark acid are prepared by taking the holly bark acid 1 as a starting material, pyridine as a solvent, acetic anhydride as an acylating agent and DMAP as a catalyst and reacting at normal temperature;
the intermediate 2 reacts with oxalyl chloride in anhydrous dichloromethane under ice bath condition to prepare an holly bark acid 28-position acyl chloride intermediate 3;
the intermediate 3 and the aniline compound 4 with different substituents react in anhydrous dichloromethane at normal temperature by taking DIPEA as an acid-binding agent to prepare different intermediates 5, acetyl is removed by 1mol/L MeOH/MeONa, and the compound shown in the general formula (I) is obtained by purifying by silica gel column chromatography (PE: EA=3:1).
Wherein, different substituents shown in the aniline compound with different substituents are the same as R in the above description.
A pharmaceutical composition comprising said derivative and its optically active form, diastereoisomer and pharmaceutically acceptable carrier.
A pharmaceutical formulation comprising said derivative and an optically active form, diastereomer or said pharmaceutical composition thereof.
Use of a derivative and an optically active form thereof, a diastereoisomer or said pharmaceutical composition or said pharmaceutical formulation for the manufacture of a medicament for the treatment of inflammatory bowel disease.
The use of said derivatives 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, the pharmaceutical composition and the preparation thereof can target miR-31-5p which is a key target of inflammatory bowel disease, thereby playing a specific therapeutic role for inflammatory bowel disease. In addition, the compound, the pharmaceutical composition and the preparation thereof are derived from the structural derivative of the natural product ursolic acid contained in the traditional medicine, and compared with the clinical anti-inflammatory medicines such as sulfasalazine, the compound has better long-term administration safety in treating inflammatory bowel disease and does not interfere with the immune system of a human body.
Detailed description of the preferred embodiments
The following description of the embodiments of the present invention is further provided in connection with the accompanying examples, and it should be noted that the embodiments described herein are for the purpose of illustration and explanation only, and are not limiting of the invention.
Description of the drawings:
FIG. 1 Process for pharmacological investigation of the synthetic products of the invention
Example 1:3β,19α, 23-trihydroxy-ursolic acid-28-O- α -L-arabinopyranoside (B1)
The rotundic acid (50 mg,0.10 mmol) is added into a 50mL eggplant-shaped bottle, dissolved by 3mL pyridine, then acetic anhydride (48.3 mu L,0.50 mmol) and a proper amount of DMAP are added for reaction for 2h at room temperature, TLC monitors that the reaction is complete, after water is added into the reaction solution, dichloromethane (20 mL multiplied by 3) is used for extraction, the organic layer is combined, diluted hydrochloric acid is used for washing twice, saturated NaHCO is obtained 3 The solution was washed once with saturated brine once, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and concentrated to give compound 2 (foamy solid 67 mg) in 62.52% yield.
Compound 2 (3, 23-di-O-acetyl-holly bark acid) was dissolved in 5ml of dry dichloromethane, oxalyl chloride (25.3. Mu.L, 0.30 mmol) was added, the reaction was stirred at room temperature for 2h, TLC monitoring was complete, and evaporated to dryness to give 72mg (compound 3) as a pale yellow foamy solid in 72.16% yield.
Compound 3 was dissolved in 10mL of dry dichloromethane, o-methylaniline (0.20 mmol), DIPEA (34.8. Mu.L, 0.20 mmol) were added, the reaction was stirred at room temperature for 4h, TLC was monitored to complete, after the reaction solution was added with water, dichloromethane (20 mL. Times.3) was extracted, the organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and concentrated to give 0.113g (Compound 5) as a pale yellow solid in 85.34% yield.
Compound 5 was dissolved in 6mL of DCM/MeOH (2:1), 1mol/L MeOH/MeONa (0.5 mL) was added, the reaction was stirred overnight at 0 ℃, TLC monitored for completion, cation exchange resin was added, ph=7 was adjusted, washed with methanol, evaporated to dryness and concentrated, silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give B1 as a white solid in 95.06% yield. 1 H NMR (600MHz,Pyridine-d 5 )δ H 8.16(s,1H),7.87(dd,J＝5.6,3.3Hz,1H),7.52(dd, J＝5.7,3.3Hz,1H),7.34(t,J＝7.5Hz,1H),7.13(t,J＝7.3Hz,1H),5.66(s,1H),5.21(s,1H),4.38(t,J＝6.6Hz,1H),4.18(d,J＝9.9Hz,2H),3.73(d,J＝ 10.3Hz,1H),3.32(s,1H),3.04(s,1H),2.43(s,3H),2.35-1.78(m,12H),1.70(s,3H),1.45(s,3H),1.35(d,J＝7.6Hz,4H),1.13(d,J＝6.5Hz,3H),1.08(s, 3H),1.05(s,3H),0.98(s,3H)； 13 C NMR(150MHz,Pyridine-d 5 )δ C 177.5, 140.8,139.0,132.4,131.7,130.2,129.5,127.6,126.2,74.4,73.9,66.6,55.5,50.0,49.6,48.7,43.8,43.2,41.4,40.3,39.8,38.1,34.3,31.71,29.9,28.6,28.0, 27.2,25.5,25.0,20.3,19.1,18.8,17.7,16.9,14.7,14.0；ESI-MS(m/z):600.2 [M+Na] + 。
Example 2: n- (2' -methoxy-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B2)
The synthesis method of the compound B2 is the same as that of B1, but o-methylaniline is replaced by o-methoxyaniline, so that white solid is obtained, and the yield is 79.02%. 1 H NMR 600MHz,Pyridine-d 5 )δ H 8.67(s,1H), 7.94-7.82(m,1H),7.08(dd,J＝6.1,3.5Hz,2H),7.03-6.99(m,1H),5.78-5.71(m,1H),5.31(s,1H),4.17(t,J＝10.0Hz,2H),3.87(s,3H),3.70(d,J＝10.4 Hz,1H),3.29–3.16(m,1H),2.77(s,1H),2.26-1.87(m,15H),1.67(s,3H),1.46(s,3H),1.41-1.29(m,4H),1.11(d,J＝6.5Hz,3H),1.05(s,3H),0.93(s,3H), 0.83(s,3H)； 13 C NMR(150MHz,Pyridine-d 5 )δ C 177.7,140.5,132.4,130.2, 129.2,127.3,122.2,121.2,111.5,74.4,73.9,68.8,66.6,56.7,56.0,50.5,49.5,48.6,43.8,41.2,43.1,39.8,38.0,33.8,31.7,29.8,28.6,28.0,27.6,25.5,25.0, 19.5,17.7,16.8,14.7,14.08；ESI-MS(m/z):616.3[M+Na]+。
Example 3: n- (2' -fluoro-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B3)
The synthesis method of the compound B3 is the same as that of B1, but o-fluoroaniline is used for replacing o-methylaniline, and the yield is 75.60% of a white solid. 1 H NMR(600MHz,Pyridine-d 5 )δ H 8.81(s,1H),8.60(td,J ＝8.3,1.8Hz,1H),7.87(dd,J＝5.7,3.3Hz,1H),7.52(dd,J＝5.7,3.3Hz,1H),7.11-7.02(m,1H),5.72(s,1H),5.30(s,1H),4.38(t,J＝6.6Hz,2H),4.17(s, 2H),3.71(d,J＝10.3Hz,1H),3.28(s,1H),2.90(s,1H),2.09(dd,J＝6.5,9.4Hz,1H),1.69(s,3H),1.44(s,3H),1.40-1.28(m,6H),1.12(s,3H),1.06(s,3H), 0.98(s,3H),0.96(s,3H),0.85(t,J＝7.4Hz,2H)； 13 C NMR(150MHz, Pyridine-d 5 )δ C 178.0,140.7,134.0,132.4,130.2,130.0,128.8,125.7,116.4, 74.4,73.8,66.6,55.7,50.3,49.4,48.6,43.8,43.1,41.2,39.8,38.0,34.0,31.7,29.8,28.6,27.9,27.2,25.5,25.0,20.3,19.5,18.0,17.6,16.9,14.7,14.0； ESI-MS(m/z):604.3[M+Na] + 。
Example 4: n- (2' -chloro-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B4)
The synthesis method of the compound B4 is the same as that of B1, but o-chloroaniline is used for replacing o-methylaniline, and the yield is 62.08% of a white solid. 1 H NMR(600MHz,Pyridine-d 5 )δ H 8.79(s,1H),8.67(s, 1H),7.46(d,J＝8.0Hz,1H),7.33(t,J＝7.2Hz,1H),7.02(t,J＝7.7Hz,1H),5.71(s,1H),5.35(s,1H),4.19(s,2H),3.70(s,1H),3.27(s,1H),2.86(s,1H), 2.24-1.86(m,14H),1.68(s,3H),1.46(s,3H),1.38-1.23(m,5H),1.12(d,J＝6.6Hz,3H),1.05(s,3H),0.96(s,3H),0.91(s,3H)； 13 C NMR(150MHz, Pyridine-d 5 )δ C 177.8,140.3,132.4,130.5,130.3,129.2,128.9,127.3,125.8, 74.4,73.8,68.7,55.8,50.6,49.4,48.6,43.8,43.1,43.1,41.3,39.9,39.8,38.0,33.9,29.8,28.6,28.0,27.9,27.6,25.6,25.0,19.5,18.1,17.7,16.9,14.0； ESI-MS(m/z):621.2[M+Na] + 。
Example 5: n- (2' -bromo-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B5)
The synthesis method of the compound B5 is the same as that of B1, but o-bromoaniline is used for replacing o-methylaniline, and the yield is 57.78% of white solid. 1 H NMR(600MHz,Pyridine-d 5 )δ H 8.77(d,J＝8.2Hz,1H), 8.61(s,1H),7.63(d,J＝9.0Hz,1H),7.35(s,1H),6.96(t,J＝7.7Hz,1H),5.71(s,1H),5.34(s,1H),4.15(s,2H),3.71(d,J＝10.3Hz,1H),3.31(t,J＝11.4Hz, 1H),2.89(s,1H),2.19-1.85(m,12H),1.68(s,3H),1.46(s,3H),1.40-1.20(m, 7H),1.12(d,J＝6.6Hz,3H),1.06(s,3H),0.95(s,3H),0.92(s,3H)； 13 C NMR (150MHz,Pyridine-d 5 )δ C 174.7,137.1,130.7,129.3,127.4,127.2,126.5,71.3, 70.8,65.7,52.7,47.5,46.4,45.6,40.8,40.1,40.0,36.9,36.7,35.0,30.9,26.7,25.6,25.0,24.8,24.4,22.6,21.9,16.5,15.2,14.6,13.8,11.0；ESI-MS(m/z): 665.7[M+Na] + 。
Example 6: n- (2' -trifluoromethyl-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B6)
The synthesis method of the compound B6 is the same as that of B1, except that o-trifluoromethylaniline is used for replacing o-methylaniline, and the compound B6 is white solid, and the yield is 24.75%. 1 H NMR(600MHz,Pyridine-d 5 )δ H 8.52(s,1H), 7.87(dd,J＝8.5,5.1Hz,1H),7.65(d,J＝8.1Hz,1H),7.58(s,1H),7.52(dd,J＝5.7,3.3Hz,1H),5.63(d,J＝9.6Hz,1H),5.30(s,1H),4.38(t,J＝6.6Hz,1H), 4.19(ddt,J＝10.0,5.9,3.4Hz,2H),3.73(s,1H),2.22-1.82(m,14H),1.68(s,3H),1.44(s,3H),1.40-1.31(m,6H),1.12(d,J＝6.6Hz,3H),1.07(s,3H),1.03 (s,3H),0.98(s,3H)； 13 C NMR(150MHz,Pyridine-d 5 )δ C 176.6,139.0,133.0, 132.8,131.2,129.1,128.6,128.1,126.3,126.1,73.3,72.7,67.8,65.4,54.4,49.1,48.4,47.5,42.6,42.1,40.2,38.6,37.0,33.0,30.6,28.5,27.4,26.9,24.3,23.8, 19.2,18.5,17.3,16.5,15.7,13.5,12.8；ESI-MS(m/z):654.3[M+Na] + 。
Example 7: n- (4' -methyl-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B7)
The synthesis method of the compound B7 is the same as that of B1, except that p-methylaniline is used for replacing o-methylaniline, and the compound B7 is white solid, and the yield is 43.97%. 1 H NMR(600MHz,Pyridine-d 5 )δ H 9.06(s,1H),7.96(d, J＝8.4Hz,2H),5.71(t,J＝3.2Hz,1H),5.17(s,1H),4.19(d,J＝16.4Hz,2H),3.72(d,J＝10.3Hz,1H),3.05(s,1H),2.20(s,3H),2.17-1.86(m,10H),1.68(s, 3H),1.61(s,3H),1.42(s,3H),1.30(s,3H),1.09(d,J＝6.6Hz,3H),1.07(s,3H),1.02(s,3H),0.98(s,3H)； 13 C NMR(150MHz,Pyridine-d 5 )δ C 177.7, 141.0,138.9,133.7,130.5,129.3,122.1,74.4,73.6,68.8,55.2,49.8,49.5,48.7, 43.8,43.0,41.3,39.8,39.7,38.1,34.0,29.9,28.6,28.0,26.9,25.6,25.1,21.7,19.6,18.4,17.6,16.9,14.0.ESI-MS(m/z):600.2[M+Na] + 。
Example 8: n- (4' -methoxy-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B8)
The synthesis method of the compound B8 is the same as that of B1, but p-methoxyaniline is used for replacing o-methylaniline, and the yield is 19.75% of white solid. 1 H NMR(600MHz,Pyridine-d 5 )δ H 9.11(s,1H),7.97 (d,J＝9.0Hz,2H),7.03(d,J＝9.0Hz,2H),5.71(s,1H),5.14(s,1H),4.19(dd, J＝12.0,7.6Hz,2H),3.72(d,J＝10.3Hz,1H),3.65(s,3H),3.06(s,1H),2.29–1.83(m,13H),1.68(s,3H),1.43(s,3H),1.35-1.25(m,7H),1.09(d,J＝ 6.6Hz,3H),1.07(s,3H),1.05(s,3H),1.00(s,3H)； 13 C NMR(150MHz, Pyridine-d 5 )δ C 174.1,153.8,131.0,127.6,125.7,111.7,70.9,70.3,65.3,52.7, 51.7,46.1,46.0,45.1,40.3,39.5,37.8,36.2,34.6,30.5,27.4,26.4,25.0,24.4,23.3,22.1,21.5,16.0,14.9,14.1,13.4,10.5；ESI-MS(m/z):616.3[M+Na] + 。
Example 9: n- (4' -fluoro-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B9)
The synthesis method of the compound B9 is the same as that of B1, but p-fluoroaniline is used for replacing o-methylaniline, and the yield is 63.83% of white solid. 1 H NMR(600MHz,Pyridine-d 5 )δ H 9.26(s,1H),8.00(dd, J＝8.6,5.0Hz,2H),7.15(d,J＝5.0Hz,2H),5.70(s,1H),5.18(s,1H),4.17(s,2H),3.72(d,J＝10.3Hz,1H),3.04(s,1H),2.25-1.86(m,14H),1.68(s,3H),1.41(s,3H),1.36-1.18(m,6H),1.09(d,J＝6.6Hz,6H),1.02(s,3H),1.00(s, 3H)； 13 C NMR(150MHz,Pyridine-d 5 )δ C 176.7,159.8,139.8,131.2,129.7, 129.1,128.2,115.3,115.2,73.3,72.7,67.7,54.0,48.7,48.4,47.5,42.7,41.9,40.2,38.6,38.5,37.0,32.9,28.7,27.5,26.8,25.6,24.5,23.9,18.4,17.2,16.5, 15.8,12.9.ESI-MS(m/z):604.3[M+Na] + 。
Example 10: n- (4' -chloro-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B10)
The synthesis method of the compound B10 is the same as that of B1, but p-chloroaniline is used for replacing o-methylaniline, and the yield is 63.83% of white solid. 1 H NMR(600MHz,Pyridine-d 5 )δ H 9.30(s,1H),8.02(d, J＝8.7Hz,2H),7.41(d,J＝8.7Hz,2H),5.70(s,1H),5.20(s,1H),4.38(t,J＝6.6Hz,2H),3.72(d,J＝10.3Hz,1H),3.03(s,1H),2.26-1.85(m,14H),1.67(s, 3H),1.41(s,3H),1.38-1.25(m,6H),1.08(s,6H),1.02-0.97(m,6H)； 13 C NMR (150MHz,Pyridine-d 5 )δ C 175.0,165.7,137.9,131.0,129.4,127.2,126.9, 126.4,126.2,71.4,70.8,63.6,52.1,46.9,46.5,45.7,40.8,40.1,38.4,36.8,35.1,31.0,28.7,26.8,25.6,24.9,23.8,22.6,22.0,17.3,16.6,15.3,14.6,13.9,11.7, 11.0；ESI-MS(m/z):621.2[M+Na] + 。
Example 11: n- (4' -bromo-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-acyl (B11)
The synthesis method of the compound B11 is the same as that of B1, but p-bromoaniline is used for replacing o-methylaniline, and the yield is 33.45% of white solid. 1 H NMR(600MHz,Pyridine-d 5 )δ H 9.30(s,1H),7.97(d, J＝8.8Hz,2H),7.91(dd,J＝5.7,3.3Hz,1H),7.53(d,J＝3.3Hz,1H),5.69(s,1H),5.20(s,1H),4.46-4.35(m,3H),4.18(d,J＝10.1Hz,2H),3.03(s,1H), 2.71(s,1H),2.61(s,1H),2.16-2.02(m,6H),1.67(s,3H),1.41(s,3H),1.30-1.24(m,10H),1.08(d,J＝4.0Hz,6H),0.99(d,J＝4.8Hz,6H)； 13 C NMR (150MHz,Pyridine-d 5 )δ C 174.9,137.7,130.9,129.7,129.3,127.7,127.1, 126.2,113.8,71.2,70.6,66.0,52.0,46.8,46.3,45.5,40.7,39.9,38.2,36.8,34.9, 30.9,28.4,26.9,24.8,23.6,22.4,21.9,21.0,16.4,15.1,14.4,13.8,12.0,10.9,8.9；ESI-MS(m/z):665.7[M+Na] + 。
Example 12: n- (4' -trifluoromethyl-phenyl) -3β,19α, 23-trihydroxy-urso-12-en-28-yl (B12)
Compound B12 was synthesized in the same manner as B1 except that p-trifluoromethylaniline was used instead of o-methylaniline, as a white solid, with a yield of 54.14%. 1 H NMR(600MHz,Pyridine-d 5 )δ H 9.53(s,1H), 8.19(d,J＝8.5Hz,2H),7.69(d,J＝8.6Hz,2H),5.71(s,1H),5.23(s,1H),4.38 (t,J＝6.6Hz,4H),4.18(d,J＝10.2Hz,2H),3.72(d,J＝10.3Hz,1H),3.24(t,J＝13.4Hz,1H),3.05(s,1H),2.22-1.90(m,15H),1.67(s,4H),1.41(s,3H),1.08 (d,J＝6.7Hz,6H),0.99(s,6H)； 13 C NMR(150MHz,Pyridine-d 5 )δ C 178.4, 168.8,144.9,140.8,134.0,132.3,130.2,129.5,127.2,121.6,74.5,73.8,68.9,66.6,55.1,50.2,49.6,48.7,43.8,43.0,41.3,39.8,38.1,34.0,31.7,29.8,28.6, 27.9,26.7,25.6,25.1,20.3,18.2,17.6,16.9,14.7,14.0；ESI-MS(m/z):654.3 [M+Na] + 。
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 groups of mice were intraperitoneally injected with an equivalent amount of physiological saline instead of 15 mice per group. After one week, the model group was free to drink drinking water containing 2.0% dss for one week, and was stopped for two weeks as one cycle, and a colonic cancer model associated with colitis was established for a total of three cycles. And after the third week, gastric lavage administration (20 mg/kg) is started, namely the medicines are the compounds B1-B12 prepared in the embodiment and the positive medicine sulfasalazine, and the experiment is finished. 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
TABLE 2 DAI scoring Table for groups of miceDistribution of extent of atypical hyperplasia of colorectal cancer (statistical index of distribution number of surviving mice)
Experimental results show that the ursolic acid derivative with a brand new structure can increase the survival number of inflammatory bowel disease mice, play a role in treating inflammatory bowel disease, inhibit intestinal atypical hyperplasia caused by inflammatory bowel disease, and have an effect obviously superior to that of a control group. Meanwhile, the compound disclosed by the invention has an obvious regulation effect on the key therapeutic target miR-31-5p of the inflammatory bowel disease, and the novel structure disclosed by the invention can be targeted to the key target miR-31-5p of the inflammatory bowel disease so as to achieve the effects of treating the inflammatory bowel disease and inhibiting atypical hyperplasia of intestinal tracts, and can be developed into a therapeutic medicament for the inflammatory bowel disease which can be taken for a long time.

Claims (10)

1. A ursolic acid derivative characterized in that: the ursolic acid derivative is a compound shown in a general formula (I):
wherein R is a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group or a halogen atom.
2. The ursolic acid derivative of claim 1, wherein: the ursolic acid derivative is a compound shown in a general formula (I);
wherein R is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group or a halogen atom.
3. The ursolic acid derivative according to claim 2, wherein: the ursolic acid derivative is a compound shown in a general formula (I), wherein,
r is methyl, C1-C4 haloalkyl, methoxy or halogen atom.
4. A ursolic acid derivative according to claim 3, wherein: the ursolic acid derivative is a compound shown in a general formula (I), wherein,
r is methyl, trifluoroalkyl, methoxy, fluorine, chlorine or bromine.
5. The ursolic acid derivative of claim 4 wherein: the ursolic acid derivative is a compound shown in a general formula (I) and is selected from the following compounds:
b1: n- (2' -methyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b2: n- (2' -methoxy-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b3: n- (2' -fluoro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b4: n- (2' -chloro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b5: n- (2' -bromo-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b6: n- (2' -trifluoromethyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b7: n- (4' -methyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b8: n- (4' -methoxy-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b9: n- (4' -fluoro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b10: n- (4' -chloro-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b11: n- (4' -bromo-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
b12: n- (4' -trifluoromethyl-phenyl) -3β,19α, 23-trihydroxy-urs-12-en-28-yl,
the structure is as follows:
6. a process for the preparation of a compound of formula (I) according to claim 1, characterized in that: the reaction formula is as follows:
taking holly bark acid 1 as a starting material, carrying out acetylation reaction on pyridine and acetic anhydride to obtain a holly bark acid 3 beta-position and 23-position diacetylated intermediate 2, reacting the intermediate 2 with oxalyl chloride to obtain a holly bark acid 28-position acyl chloride intermediate 3, carrying out nucleophilic substitution reaction on the intermediate 3 and aniline compounds with different substituents to prepare different intermediates 5, and carrying out deacetylation protection on 1mol/L MeOH/MeONa to obtain a compound shown in a general formula (I); wherein, different substituents in the aniline compound with different substituents are the same as R in claim 1.
7. A pharmaceutical composition comprising a compound of any one of claims 1-5 and a pharmaceutically acceptable carrier.
8. A pharmaceutical formulation characterized in that: the preparation comprises an active ingredient and pharmaceutically acceptable auxiliary agents, wherein the active ingredient accounts for 0.1-99% of the mass of the preparation, and the active ingredient comprises the compound of any one of claims 1-5 or the pharmaceutical composition of claim 7.
9. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 7 or a pharmaceutical formulation according to claim 8 for the manufacture of a medicament for the treatment of inflammatory bowel disease.
10. The use according to claim 9, wherein: use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 7 or a pharmaceutical formulation according to claim 8 for the preparation of a medicament for the prevention or treatment of colorectal dysplasia caused by inflammatory bowel disease.
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