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13-oxidized ingenol derivative and use thereof

a technology of ingenol and derivatives, applied in the field of derivatives of 13-oxidized ingenol, can solve problems such as limiting their us

Pending Publication Date: 2021-05-20
TIANJIN PHARM DA REN TANG GRP CORP LTD TRADITIONAL CHINESE MEDICINE RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds in this patent can kill tumor cells faster than previous treatments and have a higher preference for leukemia cells. They also stimulate the oxidative burst of neutrophils, which are important for the innate immune response. Additionally, the compounds can increase the release of a chemokine called IL-8, which helps induce immune stimulation. Lastly, these compounds are less polar than previous treatments, making them more accessible to the dermis layer.

Problems solved by technology

The naturally occurring 13-oxidized ingenane diterpene ester compounds have a broad spectrum of cytotoxicity, which limits their use.

Method used

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  • 13-oxidized ingenol derivative and use thereof
  • 13-oxidized ingenol derivative and use thereof
  • 13-oxidized ingenol derivative and use thereof

Examples

Experimental program
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Effect test

example 1

Preparation of 13-O-decanoyl-ingenol (Compound 1a), 13-O-(2′E,4′E-decadienoyl)-ingenol (Compound 1b) and 13-O-dodecanoyl-ingenol (Compound 1c), 20-O-deoxy-13-O-dodecanoyl-ingenol (Compound 1d), 6,7-epoxy-20-deoxy-ingenol (Compound 1e), 6,7-epoxy-20-O-(2,3-dimethylbutyryl)-13-O-dodecanoyl-ingenol (Compound 1f)

[0183]20 kg of kansui L. medicinal herbs was cold-soak extracted by 3 to 6 folds amount of 95% ethanol, until complete extraction; the extracting solutions were combined, and concentrated under reduced pressure until an alcohol-free taste to obtain an extract. To the extract, 10 folds amount of a solution of NaOH in methanol (0.5 M) was added, the mixture was stirred for about 2 hours. The mixture was adjusted to pH about 7 with dilute hydrochloric acid, and extracted 3 times with ethyl acetate, and then the ethyl acetate layers were combined, concentrated under reduced pressure to dryness. The extract was purified by normal phase silica gel column chromatography eluted with a g...

example 2

Preparation of 13-O-dodecanoyl-ingenol acetonide

[0198]13-O-dodecanoyl-ingenol (0.2 mmol) was dissolved in 0.5 mg / mL of a solution of p-toluenesulfonic acid monohydrate in acetone and stirred at 30° C. for 12 h. The reaction solution was concentrated to dryness under reduced pressure, re-dissolved in ethyl acetate, and washed with water and saturated aqueous sodium chloride solution, successively, and then the organic layer was concentrated to dryness under reduced pressure. The resulting residual was purified by flash chromatography (petroleum ether: ethyl acetate=10:1 to 6:4) to obtain 13-O-dodecanoyl-ingenol 3,4,5,20-diacetonide (Compound 2a), 13-O-dodecanoyl-ingenol 5,20-acetonide (Compound 2b), 13-O-dodecanoyl-ingenol 3,4-acetonide (Compound 2c), respectively.

[0199]The structural formula and hydrogen nuclear magnetic resonance spectrum (1H-NMR) of the compounds are as follows:

1) 13-O-dodecanoyl-ingenol 3,4,5,20-diacetonide (Compound 2a)

[0200]

[0201]1H-NMR (400 MHz, CDCl3) δ 5.93 ...

example 3

Preparation of 3-O-angeloyl-13-hydroxy-ingenol (Compound 3)

[0206]

[0207]13-O-dodecanoyl-ingenol 3,4,5,20-diacetonide (Compound 2a, for which the preparation procedure may refer to Example 2) (0.5 mmol) was dissolved in diethyl ether, and lithium aluminium hydride was added in the condition of ice water bath and stirred for 15 min. The reaction solution was added with a saturated aqueous sodium sulfate solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, and then concentrated to dryness under reduced pressure. The resulting residual was purified by flash chromatography (petroleum ether: ethyl acetate=7:3) to obtain 13-OH-ingenol 3,4,5,20-diacetonide (Compound 31).

[0208]Compound 31 (0.4 mmol) was dissolved in methanol, 4 M diluted hydrochloric acid was added and stirred at room temperature for 15 h. The reaction solution was poured into water, adjusted to pH about 7 with sodium hydrogen carbonate solution, and extract...

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Abstract

The present invention relates to a derivative of 13-oxidized ingenol, use thereof in the prevention and / or treatment of a disease associated with proliferation or tumor in a subject, or a cosmetic indication, and use thereof in the prevention and / or treatment of a disease responsive to neutrophil oxidative burst, a disease responsive to a release of IL-8 by keratinocyte, or a disease responsive to induction of necrosis.

Description

TECHNICAL FIELD[0001]The present invention relates to a derivative of 13-oxidized ingenol (13-oxyingenol), use thereof in the prevention and / or treatment of a disease associated with proliferation or tumor in a subject, or a cosmetic indication, and use thereof in the prevention and / or treatment of a disease responsive to neutrophil oxidative burst, a disease responsive to a release of IL-8 by keratinocyte, or a disease responsive to induction of necrosis.BACKGROUND ART[0002]Ingenol is a class of tetranuclear diterpenoids, which is mostly present in the form of an ester in the Euphorbia. It was originally isolated as a stimulant and a tumor promotor from Leptochloa chinensis in the 70s of last century. Modern studies have shown that such compounds have antitumor activity (Wang H Y et al, Phytotherapy research, 2012, 26 (6): 853-9), and antiviral activity (Abreu C M et al, PLOS ONE, 2014, 9 (5): e97257), etc., and certain ingenol compounds are PKC agonists (Asada A. et al, The Journa...

Claims

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Application Information

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IPC IPC(8): C07C69/013C07D493/08C07C69/608C07D261/18C07D319/08C07D317/70C07D493/04A61P35/00
CPCC07C69/013C07D493/08C07C69/608C07D261/18C07C2603/86C07D317/70C07D493/04A61P35/00C07D319/08C07C69/33C07C69/533C07D317/18C07D319/06
Inventor WU, XIAOPAN, QINLI, YANYUNYANG, YUGUAN, YUZHENWU, XIAOLEISUN, CHUANTENGWANG, YUAN
Owner TIANJIN PHARM DA REN TANG GRP CORP LTD TRADITIONAL CHINESE MEDICINE RES INST
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