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Novel compound, pharmaceutical compositions thereof as well as preparation methods thereof and use of novel compound and pharmaceutical compositions

A compound and composition technology, applied in the fields of drug combination, steroid compound, sugar derivative preparation, etc., can solve the problems of different effects of anti-tumor activity, weak anti-tumor effect, etc., achieve acute liver injury protection, significantly inhibit tumor Growth effect, effect of strong blood pressure lowering effect

Active Publication Date: 2013-09-11
NAT INST OF PHARMA R & D CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in vitro anti-tumor activity screening tests showed that most of the compounds had no effect on mouse autoimmune cell lines (P388) and human lung adenocarcinoma cell lines (A549), only oleanolic acid linked to galactose and arabinose Saponins showed relatively weak effects on both tumor cells (but not enough to show that they have stronger anti-tumor effects than the parent compound), indicating that different sugar groups have different effects on anti-tumor activities, and the underlying rules of sugar chain structure on activity Research is still in progress. At present, oleanolic acid derivatives with excellent biological activity and clinical application have not yet appeared.

Method used

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  • Novel compound, pharmaceutical compositions thereof as well as preparation methods thereof and use of novel compound and pharmaceutical compositions
  • Novel compound, pharmaceutical compositions thereof as well as preparation methods thereof and use of novel compound and pharmaceutical compositions
  • Novel compound, pharmaceutical compositions thereof as well as preparation methods thereof and use of novel compound and pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: the synthesis of oleanolic acid glucosamine side (I)

[0046] (1) 1,3,4, the synthesis of 6-tetraacetyl-α-D-glucosamine sulfate (formula 2)

[0047]Under cooling in an ice bath, glucosamine hydrochloride (Formula 1, 2Kg, 9.30mol) was slowly added to 10.5L of acetic anhydride. Under rapid stirring, the temperature was controlled not to exceed 30°C, and 930 mL of concentrated sulfuric acid was slowly added dropwise. After the dropwise addition was completed, the mixture was stirred and naturally rose to room temperature. React at 20-25°C until the solution is relatively clear. Immediately cool in an ice bath, and control the temperature not to exceed 30°C. Slowly add absolute ethanol (7L) dropwise to the reaction bottle, and a large amount of white solid immediately appears in the reaction bottle. After the dropwise addition, stir in an ice bath for 30 minutes, filter with suction, and wash the filter cake with ethyl acetate until it has no sour smell. Af...

Embodiment 2

[0064] Embodiment 2: the synthesis of oleanolic acid glucosamine potassium salt (NIPxz-qag-K)

[0065] Under stirring, KOH (1.7 g) was dissolved in 510 mL of ethanol, oleanolic acid glucosamine (Formula I, 15 g) was added, stirred, and heated to reflux for 0.5 h. Cool to room temperature, concentrate under reduced pressure and distill out about 300mL of ethanol. Under stirring, acetonitrile was added dropwise, and a large amount of white solid precipitated out. Suction filtration, wash the filter cake with a small amount of ethanol and acetonitrile, and dry to obtain 13.6 g of oleanolic acid glucosamine potassium salt (NIPxz-qag-K) as a white solid, with a yield of 90%.

[0066] ESI-MS (m / z): 616 [M-K] + . 1 H-NMR (CD 3 OD, 300MHz): δ0.66-1.13(m, 25H), 1.30-1.95(m, 17H), 2.59-2.65(m, 1H), 2.89-2.93(m, 1H), 3.17-3.31(m, 11H ), 3.67(dd, 1H, J=4.6Hz, 11.9Hz), 3.81-3.85(m, 1H), 4.28(d, 1H, J=7.9Hz), 5.20(t, 1H, J=3.4Hz); 13 C-NMR (CD 3 OD, 300MHz): δ6.6, 7.9, 8.9, 10.1, 15....

Embodiment 3

[0067] Embodiment 3: the synthesis of oleanolic acid glucosamine sodium salt (NIPxz-qag-Na)

[0068] Under stirring, dissolve NaOH (0.96g) in 510mL ethanol, add oleanolic acid glucosamine (Formula I, 15g), stir, and heat to reflux for 0.5h. Cool to room temperature, concentrate under reduced pressure and distill out about 300mL of ethanol. Under stirring, acetonitrile was added dropwise, and a large amount of white solid precipitated out. Suction filtration, wash the filter cake with a small amount of ethanol and acetonitrile, and dry to obtain 14.3 g of oleanolic acid glucosamine sodium salt (NIPxz-qag-Na) as a white solid, with a yield of 93%.

[0069] ESI-MS (m / z): 616[M-Na] + . 1 H-NMR (CD 3 OD, 300MHz): δ0.72-1.15(m, 25H), 1.30-1.94(m, 17H), 2.56-2.64(m, 1H), 2.91-2.96(m, 1H), 3.19-3.32(m, 11H ), 3.66 (dd, 1H, J = 4.5Hz, 11.9Hz), 3.82-3.87 (m, 1H), 4.28 (d, 1H, J = 7.9Hz), 5.21 (t, 1H, J = 3.4Hz).

[0070] Referring to the method of Example 2 or 3, oleanolic acid gl...

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Abstract

The invention relates to a novel compound, pharmaceutical compositions thereof as well as preparation methods thereof and use of the novel compound and the pharmaceutical compositions, and belongs to the field of pharmacy. The novel compound is oleanolic acid amino glucoside and pharmaceutically acceptable salts. A physical and chemical constant test displays that the solubility of the novel compound is enhanced by tens to hundreds of times in comparison with that of the oleanolic acid. An experiment verifies that the novel compound and the pharmaceutical compositions have more excellent effects than the oleanolic acid in the aspects such as blood pressure reduction, tumor resistance, liver protection and reduction of blood fat.

Description

technical field [0001] The invention belongs to the field of medicines, and in particular relates to oleanolic acid glucosamine and pharmaceutically acceptable salts thereof, and also discloses their uses in the aspects of lowering blood pressure, antitumor, protecting liver, lowering blood fat and the like. Background technique [0002] Most of the ingredients from natural sources are widely distributed, have diverse structures, and have significant activities. Structural modification, transformation, and total synthesis of them have always been a main idea in the development of new drugs. [0003] Oleanane-type pentacyclic triterpenoids represented by oleanolic acid (OA), as one of the most abundant components in natural products, have important functions in liver protection, anti-inflammation, immunosuppression, and anti-inflammatory effects. There are a lot of reports on blood lipid, blood sugar lowering, anticancer, antiulcer and cardiovascular activities (Neoplasma, 20...

Claims

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Application Information

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IPC IPC(8): C07J63/00C07H15/256C07H1/00A61K31/704A61P9/12A61P35/00A61P1/16A61P3/06
Inventor 孙从新邹磊冀蕾郑礼张继昌沙正尧
Owner NAT INST OF PHARMA R & D CO LTD
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