CN1916015A - Amine, heterocycle of chemical modification object of ursolic acid - Google Patents

Abstract

This invention relates to a natural product ursolic acid and amine and heterocylic compounds synthesized from ursolic acid. The method comprises: (1) reacting ursolic acid (I) with acetic anhydride to obtain 3-acetoxyursolic acid (II); (2) reacting 3-acetoxyursolic acid with oxalyl chloride, and then reacting with amine to obtain compounds (III-VI); (3) hydrolyzing compounds (III-VI) to obtain compounds (VII-IX). Pharmacological experiment results show that the series of ursolic acid analogs (VII-IX) have better inhibitive activity to human cervical carcinoma cells than ursolic acid.

Description

Ursolic acid chemical modified compound amine, heterocycle

Technical field

The present invention relates to a kind of natural product and its semisynthetic, particularly relate to a kind of ursolic acid chemical modified compound amine, heterocycle with anti-tumor activity.

Background technology

(ursolic acid, UA) (compound 1) has another name called urson, ursonic acid to ursolic acid, belongs to pentacyclic triterpenoid.It is widely distributed at occurring in nature, and has the various biological effect, and neural system is had obviously stable and cooling effect; External to G ⁺And G ^-Bacterium and yeast all have anti-microbial activity; Have reducing blood-fat, study of anti-atherogenic effect; Protect the liver in addition, antihepatitic activity.

The chemical structural formula of ursolic acid:

Studies show that ursolic acid not only has resistant function to multiple carcinogenic, short cancer thing, and multiple malignant tumour such as P-388 and L-1210 leukemia cell, A-549 human lung adenocarcinoma cell are had the growth of inhibition effect; Can induce the F9 teratocarcinoma cell to become the endoderm cell; T cell lymphoma Jurkat cell strain had the restraining effect of killing and wounding; In addition, also has the effect that antineoplastic vascular generates.

Summary of the invention

The object of the present invention is to provide a kind of the present invention to have multiple bioactive ursolic acid, design chemical modification object amine, the heterocycle of a series of ursolic acid as lead compound.

The objective of the invention is to be achieved through the following technical solutions:

Ursolic acid chemical modified compound amine, heterocycle, its structural formula is as follows:

Wherein: R ₁Be hydroxyl or ethanoyl, R ₂For replacing amine or hydroxyl.

Aforesaid ursolic acid chemical modified compound amine, heterocycle are prepared by following steps:

(1) ursolic acid compound (I) and acetic anhydride make 3-acetoxyl group ursolic acid (II);

(2) 3-acetoxyl group ursolic acid and oxalyl chloride the reaction, again with corresponding amine react compound (III-VI);

(3) compound (III-VI) gets compound (VII-IX) through hydrolysis.

Aforesaid ursolic acid chemical modified compound amine, heterocycle, its modifier has anti-tumor activity, can be used for treating tumor disease.

Advantage of the present invention and effect are:

The present invention carries out chemically modified to the natural product ursolic acid, obtains the analog of a series of ursolic acid, shows that through pharmacological testing they have better inhibited activity to the HELA human body cervical carcinoma cell, and all is better than the parent compound ursolic acid.

Embodiment

Below the present invention is described in detail.

The present invention finishes through the following steps:

1. the extraction using alcohol medicinal extract of Loquat Leaf is with sherwood oil, 1% sodium hydroxide with to be washed to elutant colourless, the dehydrated alcohol heating for dissolving, and activated carbon decolorizing, filtrate placement is separated out white crystals, gets Compound I with recrystallization from hot methanol

2. Compound I and acetic anhydride get Compound I I

3. Compound I I and oxalyl chloride at room temperature react, and further in alkaline condition following and nitrogenous heterocycle or amine reaction, get compound III-VI

R wherein ₂Be nitrogenous heterocycle or amine;

4. compound III-VI gets compound VIII-IX through hydrolysis

R wherein ₂Be nitrogenous heterocycle or amine

Such pentacyclic triterpenoid carries out antineoplastic pharmacological testing proves that it has the obvious suppression effect to the HELA human body cervical carcinoma cell, and the structural modification thing of ursolic acid suppresses the HELA activity and all is higher than the parent compound ursolic acid.The human cancer cell tests the employing mtt assay.The in vitro tests result is by shown in the table 1.

Table 1 ursolic acid structural modification thing is to the restraining effect (inhibiting rate %) of HELA human body cervical carcinoma cell strain

Compound concentration	10 -5mol/l	10 -6mol/l	10 -7mol/l	10 -8mol/l
					I II III IV	12.36 37.83 57.55 72.96	2.24 6.22 19.56 11.04	0.26 2.76 12.50 6.79	0.16 2.07 8.93 5.67

V VI VII VIII IX

26.54 55.66 39.46 26.79 16.51

17.47 26.43 19.57 21.48 13.73

11.42 19.44 12.60 10.98 9.38

4.74 9.62 5.98 4.74 8.62

Illustrate below:

Embodiment 1

The preparation of Compound I I: in 50ml exsiccant eggplant type bottle, add 200mg ursolic acid (0.44mmol) and dissolve with THF, add the 1ml pyridine, a little DMAP stirred 4.5 hours under the room temperature, steaming desolventizes, resistates adds an amount of water, transfers pH3 to 4, suction filtration with the hydrochloric acid of 2N, the washing filter cake is to neutral, column chromatography purification gets Compound I I (182mg, 82.94%) ¹HNMR (300MHz, CDCl ₃) δ: 5.23 (1H, t, H-12), 4.47～4.52 (1H, t, H-3), 2.04 (3H, s, CH ₃CO), 1.07 (6H, s) (7CH ₃), 0.95 (6H, s), 0.86 (3H, s), 0.83 (3H, s), 0.76, (3H, s).

Embodiment 2

The preparation of compound V: 100mg (0.20mmol) the Compound I I dissolving that adds methylene chloride, add the 0.08ml oxalyl chloride, room temperature reaction 24 hours, after reaction mixture removes the gas of methylene dichloride and reaction generation under reduced pressure, add methylene dichloride dissolving resistates again, add triethylamine and transfer pH8 to 9, add aniline 0.1ml, reaction finishes, and adds 4ml water in the reaction also, transfer pH3～4 with 2N hydrochloric acid, remove methylene dichloride under reduced pressure, the residuum filtration under diminished pressure is washed to neutrality, column chromatography purification gets compound V (55mg, 47.9%); ¹HNMR (300MHz, CDCl ₃), δ: 7.69 (1H, s,, NH), 7.43～7.46 (2H, dd, CH, 2` on the phenyl ring, the H on the 6` position), 7.29～7.31 (2H, dd, CH) 3` on the phenyl ring, the H on the 5` position), 7.04～7.07 (1H, t, CH) H on the phenyl ring on the 4` position), 5.49 (1H, t, H-12), 4.48～4.51 (1H, t, H-3), 2.04 (3H, s, CH ₃CO), 1.13 (3H, s), 0.98 (3H, s), 0.93 (3H, s), 0.90 (3H, s), 0.85 (3H, s), 0.82 (3H, s), 0.70 (3H, s) (7 * CH ₃).

Embodiment 3

The preparation of Compound I X: compound V55mg hydrolysis in the alkaline solution of methyl alcohol/tetrahydrofuran (THF), react completely, in mixture, add an amount of water, transfer pH3～4 with 2N hydrochloric acid, remove methyl alcohol/tetrahydrofuran (THF) under reduced pressure, the residuum filtration under diminished pressure is washed to neutrality, get Compound I X (50mg, 98.1%). ¹HNMR (300MHz, DMSO-d ₆), 7.70 (1H, s, NH), 7.43～7.46 (2H, dd, CH, 2` on the phenyl ring, the H on the 6` position), 7.29～7.31 (2H, dd, CH,) 3` on the phenyl ring, the H on the 5` position), 7.04～7.07 (1H, t, CH) H on the phenyl ring on the 4` position), 5.49 (1H, t, H-12), 3.20～3.23 (1H, t, H-3), 1.13 (3H, s), 0.97 (6H, s), 0.91～0.93 (3H, d), 0.88 (3H, s), 0.75 (3H, s), 0.70 (3H, s) (7 * CH ₃).

Claims (3)

1. ursolic acid chemical modified compound amine, heterocycle is characterized in that structural formula is as follows:

Wherein: R ₁Be hydroxyl or ethanoyl, R ₂For replacing amine or hydroxyl.

2. ursolic acid chemical modified compound amine according to claim 1, heterocycle is characterized in that being prepared by following steps:

(1) ursolic acid compound (I) and acetic anhydride make 3-acetoxyl group ursolic acid (II);

(2) 3-acetoxyl group ursolic acid and oxalyl chloride the reaction, again with corresponding amine react compound (III-VI);

(3) compound (III-VI) gets compound (VII-IX) through hydrolysis.

3. ursolic acid chemical modified compound amine according to claim 1, heterocycle is characterized in that they have anti-tumor activity, can be used for treating tumor disease.