CN101182345A - Ursolic acid oxazoline new drugs having antiphlogistic activity and preparation method thereof - Google Patents
Ursolic acid oxazoline new drugs having antiphlogistic activity and preparation method thereof Download PDFInfo
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- CN101182345A CN101182345A CNA2007100507976A CN200710050797A CN101182345A CN 101182345 A CN101182345 A CN 101182345A CN A2007100507976 A CNA2007100507976 A CN A2007100507976A CN 200710050797 A CN200710050797 A CN 200710050797A CN 101182345 A CN101182345 A CN 101182345A
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Abstract
The invention discloses an antiphlogistic ursolic acid derivative and a preparation method thereof. The compound has good antiphlogistic function. A novel drug of the ursolic acid derivative has a chemical formula (I) as follows. The ursolic acid derivative provided by the invention has the antiphlogistic activity, the ursolic acid is considered as a parent compound which is processed for the structural modification according to the medical structure-activity molecular theory to design and prepare for the compound with the function of remedy inflammation and the high activity.
Description
Technical background
The present invention relates to natural product and its structure of modification, particularly relates to have the synthetic of antiphlogistic ursolic acid derivative.
Ursolic acid i.e. 3 beta-hydroxies-black bearberry-12-alkene-28-acid (3 β-hydroxy-urs-12-en-28-oic acid, 1) belongs to α-amyrin (type pentacyclic triterpenoid of α-amyrin), it is an occurring in nature natural radioactivity compound distributed more widely, has multiple biological activity, as protect the liver, multiple effect such as anti-inflammatory, antitumor, anti AIDS virus, and side effect is little, and toxicity is low, demonstrates bigger clinical application potentiality.
The structural formula of ursolic acid:
Studies show that ursolic acid on Carrageenan and dextran inductive mouse pawl oedema and cotton balls inductive chronic granuloma have significant anti-inflammatory activity.
At present, ursolic acid is more as the report of preparation, and to apply for a patent.At publication number is among the CN1410064, has reported ursolic acid fabaceous lecithin nano particle freeze-dried powder injection and preparation method; Publication number is for providing a kind of ursolic acid cyanoacrylate nano particle freeze-dried powder injection and preparation method among the CN1410065; Publication number is to disclose ursolic acid polylactic acid nano particle lyophilized injectable powder and preparation method among the CN1410066; Publication number is to disclose a kind of ursolic acid fat scholar injection and preparation method thereof among the CN1771968; Publication number is to disclose a kind of Ursolate microballoon preparation and preparation method thereof among the CN1857273.
The pharmacological research of relevant ursolic acid also has a lot, as Xiong Bin etc. " the pharmacological progress of ursolic acid " (" foreign medical science pharmacy fascicle ", 2004,31[3]); " the ursolic acid antitumor action progress " of Xia Guohao etc. (" foreign medical oncology credit volume ", 2002,29[6]); " the ursolic acid Advance on Pharmacological Activities " of Wang Ting etc. (" Chinese medical research magazine "); Or the like.
Summary of the invention
One of purpose of the present invention is to be lead compound with the ursolic acid, thereby to the synthetic novel derivative of its structural modification.
Two of purpose of the present invention is synthetic a series of new anti-inflammatory drugs with better pharmacologically active.
Three of purpose of the present invention provides with these compounds and is used for anti-inflammatory drug as effective active pharmaceutical ingredients, makes doctor and/or patient can increase selection to available medicine to the control of disease the time.
The present invention is lead compound with the ursolic acid, and to the compound that its structure of modification obtains, its structural formula is suc as formula shown in (I):
Wherein, the R in the formula, R ' they can be hydrogen, phenyl, and ursolic acid derivative Is as mentioned above such as substituted-phenyl, methyl are prepared by following steps:
The present invention reacts in acetone with ursolic acid and ethyl chloroacetate and makes ursolic acid ethoxycarbonyl methyl esters 2,2 and hydrazine hydrate and reflux in dehydrated alcohol and make 3,3 and do at glacial acetic acid and to obtain 4,4 with the carbonyl compound condensation under the catalyzer obtain I under the acetic anhydride cyclization.
Aforesaid ursolic acid derivative has and protects the liver and anti-inflammatory activity, can be used for treating hepatitis and inflammatory disease.
As mentioned above, it is short that the present invention has synthetic route, and cost is low, is easy to realize advantages such as suitability for industrialized production.
Zooperal result shows that the above-mentioned compound (I) of the present invention can have the anti-inflammatory activity effect of strengthening ursolic acid, strengthens drug effect.
According to " new drug preclinical study governing principle " requirement, adopted dimethylbenzene to mouse right ear to cause inflammation, the way that left ear compares, the present invention has carried out the contrast experiment to above-claimed cpd (I) and the ursolic acid of parent compound shown in 1.
The mice caused by dimethylbenzene xylene auris dextra causes scorching experiment: compound 5a～5g and UA (ursolic acid) are mixed with 0.2% concentration suspension with 0.5%CMC (Xylo-Mucine) liquid, organize in contrast with 0.5%CMC liquid and 0.75% aspirin solution, get 66 of Kunming mouses, be divided into 11 groups at random by body weight, every group 6, male and female half and half. each organizes mouse, be administered once every day, successive administration six days, 30min after the last administration, smear every mouse auris dextra with dimethylbenzene 0.05ml/ mouse and cause inflammation, left ear compares, and causes scorching back 30 minutes and takes off cervical vertebra execution mouse, take off an ear edge left side with 7mm diameter punch tool, the auris dextra sheet, use scales/electronic balance weighing respectively, with the right side, left side auricle weight difference is represented the swelling degree, organizes and asks that significance difference is relatively. experimental result sees Table 1.
The anti-inflammatory activity of table 1 target compound
Table?1?Anti-inflammatory?activities?for?target?compounds
Above-mentioned contrast and experiment shows that ursolic acid compounds of the present invention and its parent compound 1 relatively have better effect aspect anti-inflammatory.
According to foregoing, under the prerequisite that does not break away from the above-mentioned basic fundamental thought of the present invention,, modification, replacement or the change of various ways can also be arranged to its content according to the ordinary skill knowledge and the customary means of this area.
Once, implementation content of the present invention is further described in detail again by the embodiment of embodiment form.But the scope that this should be interpreted as the above-mentioned theme of the present invention only limits to example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment
The present invention finishes through the following steps:
1. ursolic acid 1 obtains compound 2 with ethyl chloroacetate
2. compound 2 refluxes in dehydrated alcohol with hydrazine hydrate and obtains compound 3
3. compound 3 obtains compound 4 with the further condensation of carbonyl compound
Wherein R, R ' are H, CH
3, Ph and substituted-phenyl etc.
4. compound 4 obtains Compound I with the diacetyl oxide cyclization
Compound (4i) compound (5i) R R '
a a C
6H
5 H
b b p-CH
3OC
6H
4 H
c c m-NO
2C
6H
4 H
d d p-NO
2C
6H
4 H
e e C
6H
5 CH
3
f f p-CH
3C
6H
4 CH
3
g g p-ClC
6H
4 CH
3
Illustrate below:
Embodiment 1
The preparation of compound (2) is dissolved in 4.560g (10mmol) 1 in the 250ml acetone, and reflux is fully dissolved it, treats to stop heating after the solution clarification, adds 2.073g (15mmol) K
2CO
3, after stirring at room solution becomes oyster white, with 0.0498g (0.3mmol) KI and 4ml Et
3N joins in this solution, slowly drips 4mlClCH
2COOC
2H
5(28.2mmol), room temperature reaction, TLC monitoring reaction. after reaction finishes, filter, the small amount of acetone flushing adds saturated aqueous common salt behind the concentrating under reduced pressure, ethyl acetate extraction 3 times, combined ethyl acetate layer, organic layer are used anhydrous Na after being washed to neutrality
2SO
4Drying is filtered, is concentrated, and products therefrom gets colourless particulate state crystal 2 with the dehydrated alcohol recrystallization, productive rate 95%, m.p.174～175 ℃.
Embodiment 2
The preparation of compound (3) is heating reflux reaction in the 20ml dehydrated alcohol with 2.710g (5mmol) 2 and 2mL80% hydrazine hydrate, the TLC monitoring reaction. after reaction finishes, be cooled to room temperature, the adularescent solid is separated out, suction filtration, oven dry, crude product dehydrated alcohol recrystallization, white needle-like crystals 3, productive rate 93%.m.p.256～257 ℃;
1HNMR (400MHz, CDCl
3) δ: 0.69 (s, 3H, CH
3), 0.78 (s, 3H, CH
3), 0.87 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.94 (d, J=6.0HZ, 3H, CH
3), 0.99 (s, 3H, CH
3), 1.10 (3H, s, CH
3), 2.22 (d, J=12.0HZ, 1H, H-18), 3.21 (dd, J=11.2,4.8HZ, 1H, H-3), 4.30 (brs, 2H, NH), 4.32 (d, J=16.0HZ, 1H, COOCH
aCOO), 4.83 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.33 (t, J=3.6HZ, 1H, H-12), 9.00 (s, 1H, NH); IR (KBr) v:3330,3278,2920,1728,1663,1602cm
-1MS m/z (%): 551.4 ([M+Na]
+); HRMS (ESI) calcd for C
32H
52N
2O
4Na[M+Na]
+551.3822 found 551.3819
Embodiment 3
The preparation of compound (4) is dissolved in 3 of 1.056g (2mmol) phenyl aldehyde (glacial acetic acid that adds catalytic amount) that adds 2.6mmol in the 30ml dehydrated alcohol, stir, heating reflux reaction, the TLC monitoring reaction, after reaction finishes, cooling, leave standstill suction filtration behind the 2h, get compound 4a. white solid with ethyl alcohol recrystallization, productive rate 89%, m.p.290～292 ℃;
1HNMR (CDCl
3, 400MHz) δ: 0.71 (s, 3H, CH
3), 0.78 (s, 3H, CH
3), 0.83 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.94 (d, J=6.0HZ, 3H, CH
3), 0.98 (s, 3H, CH
3), 1.10 (s, 3H, CH
3), 2.29 (d, J=11.6HZ, 1H, H-18), 3.21 (dd, J=10.8,4.8HZ, 1H, H-3), 5.00 (d, J=16.0HZ, 1H, COOCH
aCOO), 5.14 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.28 (t, J=3.6HZ, 1H, H-12), 7.40～7.70 (m, 5H, PhH), 8.78 (s, 1H, N=CH), 11.40 (s, 1H, NH); IR (KBr) v:3446,3248,2920,1730,1701,1667cm
-1MS m/z (%): 639.4 ([M+Na]
+); HRMS (ESI) calcd forC
39H
56N
2O
4Na[M+Na]
+639.4159, found 639.4132.
With the synthetic 4a～4g. of method
4b: white solid, productive rate 85%, m.p.214～215 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.75 (s, 3H, CH
3), 0.78 (s, 3H, CH
3), 0.83 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.94 (d, J=6.0HZ, 3H, CH
3), 0.99 (s, 3H, CH
3), 1.09 (s, 3H, CH
3), 2.29 (d, J=11.6HZ, 1H, H-18), 3.21 (dd, J=10.8,4.8HZ, 1H, H-3), 3.84 (s, 3H, OCH
3), 4.98 (d, J=16.0HZ, 1H, COOCH
aCOO), 5.12 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.28 (t, J=3.6HZ, 1H, H-12), 6.90～7.57 (m, 4H, PhH), 8.60 (s, 1H, N=CH), 11.32 (s, 1H, NH); IR (KBr) v:3435,2927,1710,1685cm
-1MS m/z (%): 669.4 ([M+Na]
+); HRMS (ESI) calcd for C
40H
58N
2O
5Na[M+Na]
+669.4262, found 669.4238.
4c: white solid, productive rate 90%, m.p.276～277 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.74 (s, 3H, CH
3), 0.78 (s, 3H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.94 (d, J=6.0HZ, 3H, CH
3), 0.99 (s, 3H, CH
3), 1.10 (s, 3H, CH
3), 2.29 (d, J=11.6HZ, 1H, H-18), 3.21 (dd, J=10.8,4.8HZ, 1H, H-3), 5.02 (d, J=16.0HZ, 1H, COOCH
aCOO), 5.15 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.28 (t, J=3.6HZ, 1H, H-12), 7.59～8.27 (m, 4H, PhH), 8.81 (s, 1H, N=CH), 11.45 (s, 1H, NH); IR (KBr) v:3435,3256,2927,1710,1677cm
-1MS m/z (%): 684.3 ([M+Na]
+); HRMS (ESI) calcd for C
39H
55N
3O
6Na[M+Na]
+684.3976, found 684.3983.
4d: yellow solid, productive rate 95%, m.p.273～274 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.75 (s, 3H, CH
3), 0.78 (s, 3H, CH
3), 0.87 (d, J=6.4HZ, 3H, CH
3), 0.92 (s, 3H, CH
3), 0.95 (d, J=6.4HZ, 3H, CH
3), 0.98 (s, 3H, CH
3), 1.10 (s, 3H, CH
3), 2.29 (d, J=10.8HZ, 1H, H-18), 3.21 (dd, J=11.2,5.2HZ, 1H, H-3), 5.02 (d, J=16.0HZ, 1H, COOCH
aCOO), 5.14 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.27 (t, J=3.6HZ, 1H, H-12), 7.77～8.28 (m, 4H, PhH), 8.70 (s, 1H, N=CH), 11.50 (s, 1H, NH); IR (KBr) v:3512,3119,2920,1718,1680cm
-1MS m/z (%): 684.3 ([M+Na]
+); HRMS (ESI) calcd for C
39H
55N
3O
6Na[M+Na]
+684.3973, found 684.3983.
4e: white solid, productive rate 82%, m.p.215～217 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.78 (s, 3H, CH
3), 0.81 (s, H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.92 (s, H, CH
3), 0.95 (d, J=6.4HZ, 3H, CH
3), 0.99 (s, 3H, CH
3), 1.10 (s, 3H, CH
3), 2.19 (s, 3H, CH
3), 2.29 (d, J=11.6HZ, 1H, H-18), 3.20 (dd, J=11.6,5.6HZ, 1H, H-3), 5.01 (d, J=16.0HZ, 1H, COOCH
aCOO), 5.17 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.27 (t, J=3.6HZ, 1H, H-12), 7.39～7.71 (m, 5H, PhH), 8.48 (s, 1H, N=CH), 11.20 (s, 1H, NH); IR (KBr) v:3444,3265,2930,1740,1688cm
-1MS m/z (%): 653.4 ([M+Na]
+); HRMS (ESI) calcdfor C
40H
58N
2O
4Na[M+Na]
+653.4319, found 653.4289.
4f: white solid, productive rate 79%, m.p.178～180 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.73 (s, 3H, CH
3), 0.80 (s, 3H, CH
3), 0.86 (d, J=6.0HZ, 3H, CH
3), 0.92 (s, 3H, CH
3), 0.95 (d, J=6.0HZ, 3H, CH
3), 0.99 (s, 3H, CH
3), 1.09 (s, 3H, CH
3), 2.17 (s, 3H, CH
3), 2.29 (d, J=11.6HZ, 1H, H-18), 3.21 (dd, J=12.0,5.6HZ, 1H, H-3), 5.00 (d, J=16.0HZ, 1H, COOCH
aCOO), 5.16 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.27 (t, J=3.6HZ, 1H, H-12), 7.18～7.60 (m, 4H, PhH), 8.43 (s, 1H, N=CH), 11.15 (s, 1H, NH); IR (KBr) v:3444,3250,2926,1721,1689cm
-1MS m/z (%): 667.4 ([M+Na]
+); HRMS (ESI) calcd for C
41H
60N
2O
4Na[M+Na]
+667.4461, found 667.4445.
4g: white solid, productive rate 83%, m.p.179～180 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.74 (s, 3H, CH
3), 0.80 (s, 3H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.92 (s, 3H, CH
3), 0.95 (d, J=6.4HZ, 3H, CH
3), 0.99 (s, 3H, CH
3), 1.10 (s, 3H, CH
3), 2.17 (s, 3H, CH
3), 2.28 (d, J=11.6HZ, 1H, H-18), 3.21 (dd, J=12.0,5.2HZ, 1H, H-3), 4.99 (d, J=16.0HZ, 1H, COOCHaCOO), 5.14 (d, J=16.0HZ, 1H, COOCH
bCOO), 5.27 (t, J=3.6HZ, 1H, H-12), 7.35～7.65 (m, 4H, PhH), 8.50 (s, 1H, N=CH), 11.25 (s, 1H, NH); IR (KBr) v:3444,2927,1720,1692cm
-1MS m/z (%): 687.3 ([M+Na]
+); HRMS (ESI) calcd forC
40H
57ClN
2O
4Na[M+Na]
+687.3870, found 687.3899.
Embodiment 4
The 4a that 0.616g (1mmol) is got in the preparation of compound 5 joins in the reaction flask of 25ml, adds 10mlAc
2O, reflux 1h pours into after the cooling in the frozen water, and vigorous stirring is to the oily matter completely solidified, filters, washing, thick product drying is after purification by silica gel column chromatography gets target product 5a. white solid, productive rate 60%, m.p.84～86 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.70 (s, 3H, CH
3), 0.75 (s, 3H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.94 (d, J=6.4HZ, 3H, CH
3), 0.98 (s, 3H, CH
3), 1.09 (s, 3H, CH
3), 2.04 (s, 3H, OCOCH
3), 2.09 (s, 3H, NCOCH
3), 2.27 (d, J=10.8HZ, 1H, H-18), 4.52 (t, J=7.6HZ, 1H, H-3), 4.70 (m, 2H, COOCH
2COO), 5.24 (t, J=4.0HZ, 1H, H-12), 6.87 (s, 1H, 2-H), 7.39～7.90 (m, 5H, PhH); IR (KBr) ν: 2926,1732,1682,1244,1027cm
-1MS m/z (%): 723.4 ([M+Na]
+); HRMS (ESI) calcdfor C
43H
60N
2O
6Na[M+Na]
+723.4310, found 723.4344.
Get 5b～5g with legal system
5b: white solid, productive rate 58%, m.p.106～108 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.73 (s, 3H, CH
3), 0.85 (s, 3H, CH
3), 0.87 (d, J=6.4HZ, 3H, CH
3), 0.90 (s, 3H, CH
3), 0.93 (d, J=6.0HZ, 3H, CH
3), 0.96 (s, 3H, CH
3), 1.09 (s, 3H, CH
3), 2.04 (s, 3H, OCOCH
3), 2.09 (s, 3H, NCOCH
3), 2.25 (d, J=11.2HZ, 1H, H-18), 3.89 (s, 3H, OCH
3), 4.51 (t, J=7.6HZ, 1H, H-3), 4.67 (m, 2H, COOCH
2COO), 5.24 (t, J=3.6HZ, 1H, H-12), 6.67 (s, 1H, 2-H), 7.00～7.86 (4H, m, PhH); IR (KBr) v:2946,1733,1679,1248,1030cm
-1MS m/z (%): 753.4 ([M+Na]
+); HRMS (ESI) calcd forC
44H
62N
2O
7Na[M+Na]
+753.4416, found 753.4449.
5c: white solid, productive rate 62%, m.p.119～121 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.75 (s, 3H, CH
3), 0.83 (s, 3H, CH
3), 0.86 (d, J=6.0HZ, 3H, CH
3), 0.90 (s, 3H, CH
3), 0.93 (d, J=6.4HZ, 3H, CH
3), 0.96 (s, 3H, CH
3), 1.08 (s, 3H, CH
3), 2.04 (s, 3H, OCOCH
3), 2.15 (s, 3H, NCOCH
3), 2.27 (d, J=10.8HZ, 1H, H-18), 4.47 (t, J=7.6HZ, 1H, H-3), 4.74 (m, 2H, COOCH
2COO), 5.24 (t, J=3.6HZ, 1H, H-12), 6.93 (s, 1H, 2-H), 7.59～8.26 (m, 4H, PhH); IR (KBr) v:2949,1733,1715,1698,1244,1027cm
-1MSm/z (%): 768.4 ([M+Na]
+); HRMS (ESI) calcd for C
43H
59N
3O
8Na[M+Na]
+768.4193, found 768.4194.
5d: white solid, productive rate 70%, m.p.120～122 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.74 (s, 3H, CH
3), 0.84 (s, 3H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.93 (d, J=6.4HZ, 3H, CH
3), 1.00 (s, 3H, CH
3), 1.08 (s, 3H, CH
3), 2.04 (s, 3H, OCOCH
3), 2.14 (s, 3H, NCOCH
3), 2.27 (d, J=10.8HZ, 1H, H-18), 4.49 (t, J=7.6HZ, 1H, H-3), 4.77 (m, 2H, COOCH
2COO), 5.23 (t, J=3.6HZ, 1H, H-12), 6.94 (s, 1H, 2-H), 7.59～8.26 (4H, m, PhH) .IR (KBr): 2947,1732,1694,1244,1027cm
-1MSm/z (%): 768.4 ([M+Na]
+); HRMS (ESI) calcd for C
43H
59N
3O
8Na[M+Na]
+768.4185, found 768.4194.
5e: white solid, productive rate 50%, m.p.96～98 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.79 (s, 3H, CH
3), 0.82 (s, 3H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.93 (d, J=6.4HZ, 3H, CH
3), 0.96 (s, 3H, CH
3), 1.09 (s, 3H, CH
3), 2.04 (s, 3H, OCOCH
3), 2.09 (s, 3H, NCOCH
3), 2.20 (s, 3H, 2-CH
3), 2.27 (d, J=10.8HZ, 1H, H-18), 4.47 (t, J=7.6HZ, 1H, H-3), 4.69 (m, 2H, COOCH
2COO), 5.22 (t, J=3.6HZ, 1H, H-12), 7.36～7.51 (m, 5H, PhH) .IR (KBr): 2947,1733,1678,1244,1028cm
-1MSm/z (%): 737.4 ([M+Na]
+); HRMS (ESI) calcd for C
44H
62N
2O
6Na[M+Na]
+737.4466, found 737.4500.
5f: white solid, productive rate 45%, m.p.94～96 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.79 (s, 3H, CH
3), 0.82 (s, 3H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.93 (d, J=6.4HZ, 3H, CH
3), 0.96 (s, 3H, CH
3), 1.09 (s, 3H, CH
3), 2.04 (s, 3H, OCOCH
3), 2.09 (s, 3H, NCOCH
3), 2.20 (s, 3H, 2-CH
3), 2.27 (d, J=10.8HZ, 1H, H-18), 4.47 (t, J=7.6HZ, 1H, H-3), 4.69 (m, 2H, COOCH
2COO), 5.22 (t, J=3.6HZ, 1H, H-12), 7.16～7.38 (m, 5H, PhH) .IR (KBr): 2948,1733,1678,1244,1027cm
-1MSm/z (%): 751.4 ([M+Na]
+); HRMS (ESI) calcd for C
45H
64N
2O
6Na[M+Na]
+751.4656 found 751.4657.
5g: white solid, productive rate 50%, m.p.91～93 ℃,
1HNMR (CDCl
3, 400MHz) δ: 0.79 (s, 3H, CH
3), 0.83 (s, 3H, CH
3), 0.86 (d, J=6.4HZ, 3H, CH
3), 0.91 (s, 3H, CH
3), 0.95 (d, J=6.4HZ, 3H, CH
3), 0.99 (s, 3H, CH
3), 1.09 (s, 3H, CH
3), 2.04 (s, 3H, COCH
3), 2.10 (s, 3H, NCOCH
3), 2.21 (s, 3H, 2-CH
3), 2.27 (d, J=10.8HZ, 1H, H-18), 4.47 (t, J=7.6HZ, H, H-3), 4.70 (m, 2H, COOCH
2COO), 5.22 (t, J=3.6HZ, 1H, H-12), 7.33～7.45 (m, 4H, PhH); IR (KBr) v:2948,1734,1676,1244,1027; MS m/z (%): 771.4 ([M+Na]
+); HRMS (ESI) calcd for C
44H
61ClN
2O
6Na[M+Na]
+771.4096, found 771.4110.
Claims (3)
1. a class has antiphlogistic Xiong Guo Suan oxadiazole quinoline derivant, and its structure is suc as formula (I)
Wherein, the R in the formula, R can be hydrogen, phenyl, substituted-phenyl, methyl etc.
2. be the synthetic method of the compound of representative with chemical formula (1); it is characterized in that the reaction of ursolic acid and ethyl chloroacetate makes ursolic acid ethoxycarbonyl methyl esters; the latter and hydrazine hydrate reaction obtain corresponding hydrazides; hydrazides and substituted carbonyl compound are done to reflux under the solvent at ethanol and are obtained the ursolic acid acylhydrazone, and the ursolic acid acylhydrazone obtains compound (I) under the cyclizing agent effect.
3. The compounds of this invention can be made tablet, pill, granule, capsule and injection or other clinical acceptable suitable dosage forms.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558279A (en) * | 2011-11-09 | 2012-07-11 | 四川国康药业有限公司 | Synthesis and anti-tumor activity research of ursolic acid-3'-substituted propanol ester derivatives |
| CN103626828A (en) * | 2013-11-20 | 2014-03-12 | 沈阳化工大学 | Anti-tumor active ursolic acid chemical modifier and preparation method thereof |
| CN107033212A (en) * | 2017-05-16 | 2017-08-11 | 烟台大学 | A kind of ursolic acid derivative with anti-inflammatory activity and its production and use |
| CN113105520A (en) * | 2021-05-12 | 2021-07-13 | 张洪胜 | Ephedrine derivative for treating rheumatoid arthritis and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5212189A (en) * | 1991-12-17 | 1993-05-18 | Warner-Lambert Company | Thiadiazole or oxadiazole analogs of fenamic acids containing substituted hydroxamate side chains as antiinflammatory agents |
| DE10215055A1 (en) * | 2002-04-03 | 2003-10-30 | Univ Schiller Jena | Antiinflammatory or pre-neoplastic lesion inhibiting medicaments containing caffeic acid triterpene or sterol esters having radical scavenging action, also useful in cosmetic or nutraceutical compositions |
| CN1546041A (en) * | 2003-12-02 | 2004-11-17 | 北京正大绿洲医药科技有限公司 | Ursolic acid dripping pills and its preparation process |
| CN101020062A (en) * | 2007-03-14 | 2007-08-22 | 四川大学 | Hydrophilic polyglycol supported ursolic acid medicines and their prepn process |
-
2007
- 2007-12-14 CN CN2007100507976A patent/CN101182345B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5212189A (en) * | 1991-12-17 | 1993-05-18 | Warner-Lambert Company | Thiadiazole or oxadiazole analogs of fenamic acids containing substituted hydroxamate side chains as antiinflammatory agents |
| DE10215055A1 (en) * | 2002-04-03 | 2003-10-30 | Univ Schiller Jena | Antiinflammatory or pre-neoplastic lesion inhibiting medicaments containing caffeic acid triterpene or sterol esters having radical scavenging action, also useful in cosmetic or nutraceutical compositions |
| CN1546041A (en) * | 2003-12-02 | 2004-11-17 | 北京正大绿洲医药科技有限公司 | Ursolic acid dripping pills and its preparation process |
| CN101020062A (en) * | 2007-03-14 | 2007-08-22 | 四川大学 | Hydrophilic polyglycol supported ursolic acid medicines and their prepn process |
Non-Patent Citations (1)
| Title |
|---|
| FA OMAR,NM MAHFOUZ,MA RAHMAN: "Design,synthesis and antiinflammatory activity of some 1,3,4-oxadiazole derivatives", EUR.J.MED.CHEM * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558279A (en) * | 2011-11-09 | 2012-07-11 | 四川国康药业有限公司 | Synthesis and anti-tumor activity research of ursolic acid-3'-substituted propanol ester derivatives |
| CN102558279B (en) * | 2011-11-09 | 2014-09-17 | 四川国康药业有限公司 | Synthesis and anti-tumor activity research of ursolic acid-3'-substituted propanol ester derivatives |
| CN103626828A (en) * | 2013-11-20 | 2014-03-12 | 沈阳化工大学 | Anti-tumor active ursolic acid chemical modifier and preparation method thereof |
| CN107033212A (en) * | 2017-05-16 | 2017-08-11 | 烟台大学 | A kind of ursolic acid derivative with anti-inflammatory activity and its production and use |
| CN113105520A (en) * | 2021-05-12 | 2021-07-13 | 张洪胜 | Ephedrine derivative for treating rheumatoid arthritis and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101182345B (en) | 2011-03-30 |
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