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18beta-glycyrrhetinic acid carbamate derivative, preparation method and application thereof

An acid carbamate, glycyrrhetic acid technology, applied in the direction of drug combinations, steroids, antitumor drugs, etc., can solve the problem of unsatisfactory pharmacological activity, and achieve a new effect of compound structure

Inactive Publication Date: 2019-04-12
JINZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Glycyrrhetinic acid derivatives can produce different degrees of antagonistic effects on human hepatocellular carcinoma, gastric cancer, breast cancer, lung cancer, rectal cancer, melanoma and other tumor cells through various mechanisms [Lallemand B, Gelbcke M, DuboisJ, et al .Mini Reviews in Medicinal Chemistry, 2011,11(10):881-887.Su X,Wu L,HuM,et al.Biomedicine&Pharmacotherapy,2017, 95:670-678.Xu B,Wu G R,Zhang XY,et al. Molecules,2017,22(6):924-948.]; however, most of the pharmacological activities of glycyrrhetinic acid and its derivatives are not completely satisfactory

Method used

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  • 18beta-glycyrrhetinic acid carbamate derivative, preparation method and application thereof
  • 18beta-glycyrrhetinic acid carbamate derivative, preparation method and application thereof
  • 18beta-glycyrrhetinic acid carbamate derivative, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation method of 3β-(((3,4-dichlorophenyl)carbamoyl)oxy group)-11-oxo-olean-12-ene-29-acid (abbreviation: Ia) shown in the following structural formula , including the following steps:

[0044]

[0045] 18β-glycyrrhetinic acid (0.30mmol) and 3,4-dichlorophenylisocyanate (0.36mmol) were added to reflux reaction in ethyl acetate; after the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was passed through a column Purified by chromatography to obtain a white powdery solid with a yield of 78.1%; 1 H NMR(400MHz,Chloroform-d)δ7.63(s,1H,phenyl-H),7.33(d,J=8.7Hz,1H,phenyl-H),7.18(d,J=8.8Hz,1H,phenyl -H),6.71(s, 1H,N-H),5.70(s,1H,CH-12),4.50(dd,J=10.5,5.9Hz,1H,CH-3),2.87–2.77(m,1H, CH-1), 2.37(s,1H,CH-9), 2.18(dd,J=13.8,4.1Hz,1H,CH-16),2.06–1.00(m,17H), 1.37(s,3H,CH 3 -27),1.22(s,3H,CH 3 -25),1.16(s,3H,CH 3 -26),1.12(s,3H,CH 3 -29), 0.93(s,3H,CH 3 -23),0.87(s,3H,CH 3 -24),0.82(s,3H,CH 3 -28),0.80(d,1H,C...

Embodiment 2

[0047] 3β-(((4-chloro-3-(trifluoromethyl)phenyl)carbamoyl)oxy)-11-oxo-olean-12-en-29-acid (referred to as : the preparation method of Ib), comprising the steps of:

[0048]

[0049] 18β-glycyrrhetinic acid (0.30mmol) and 4-chloro-3-(trifluoromethyl)phenylisocyanate (0.36mmol) were added to reflux reaction in dichloromethane; after the reaction was over, the mixture was concentrated under reduced pressure, and The obtained residue was purified by column chromatography; a white powdery solid was obtained with a yield of 87.0%; 1 H NMR (400MHz, Chloroform-d) δ 7.76(s,1H,phenyl-H),7.54(s,1H,phenyl-H),7.40(d,J=8.7Hz,1H,phenyl-H),6.83( s, 1H, N-H), 5.70(s, 1H, CH-12), 4.56–4.47(m, 1H, CH-3), 2.82(d, J=13.6Hz, 1H, CH-1), 2.37(s ,1H,CH-9),2.17(d,J=11.9Hz,1H,CH-16),2.06–1.00(m,17H),1.37(s,3H,CH 3 -27),1.22(s,3H,CH 3 -25),1.16(s,3H,CH 3 -26),1.12(s,3H,CH 3 -29),0.94(s,3H,CH 3 -23),0.88(s,3H,CH 3 -24),0.82(s,3H,CH 3 -28),0.80(d,1H,CH-5); HRMS(m / z):[M +H] + calcd.ForC 38 h ...

Embodiment 3

[0051] The preparation method of 3β-(((3,5-dichlorophenyl)carbamoyl)oxy)-11-oxo-olean-12-ene-29-acid (abbreviation: Ic) as shown in the following structural formula , including the following steps:

[0052]

[0053] 18β-glycyrrhetinic acid (0.30mmol) and 3,5-dichlorophenylisocyanate (0.36mmol) were added to reflux reaction in chloroform; after the reaction was completed, the mixture was concentrated under reduced pressure, and the resulting residue was passed through a column Purified by chromatography to obtain a white powdery solid with a yield of 78.1%; 1 H NMR (400MHz, Chloroform-d) δ7.35(s, 2H, phenyl-H), 7.02(t, J=1.8Hz, 1H, phenyl-H), 6.62(s, 1H, N-H), 5.69(s ,1H,CH-12),4.50 (dd,J=10.7,5.7Hz,1H,CH-3),2.82(d,J=13.2Hz,1H,CH-1),2.37(s,1H,CH- 9), 2.17 (d, J=11.9Hz, 1H, CH-16), 2.03–0.83 (m, 17H), 1.37 (s, 3H, CH 3 -27),1.22(s,3H,CH 3 -25),1.16(s,3H,CH 3 -26),1.12(s,3H,CH 3 -29),0.94(s,3H,CH 3 -23),0.88(s,3H,CH 3 -24),0.82(s,3H,CH 3 -28),0.79–0.73(m,1H,CH-5); HRM...

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Abstract

The invention discloses a 18beta-glycyrrhetinic acid carbamate derivative, which has a structure shown as formula (I) or (II) in the specification. The compound provided by the invention has a brand new structure, and has significant inhibitory effect on lung cancer, liver cancer, colon cancer, breast cancer and prostate cancer cell lines. And the antitumor activity of parts of the compounds is close to crizotinib.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a 18β-glycyrrhetinic acid carbamate derivative and a preparation method and application thereof. Background technique [0002] Most of the triterpene acid compounds are tetracyclic triterpene acid and pentacyclic triterpene acid, among which pentacyclic triterpene acid components are more common in medicinal plants and can be divided into four types in terms of structure, namely ursane type, Argan type, lupine type and suberane type. Glycyrrhetinic acid (glycyrrhetinic acid, GA) belongs to pentacyclic triterpenoids, and there is C=O at the 11th position of the skeleton, which is similar to the 18-H-oleanane structure. [0003] There are different optical isomers in the structure of glycyrrhetinic acid, such as 18α and 18β, and the pharmacological effects of these isomers are not completely the same. Among them, 18α-glycyrrhetinic acid is better in liver targeting a...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61P35/00
CPCA61P35/00C07J63/008
Inventor 蔡东孙玉琦杨殿深宫益霞贾云宏
Owner JINZHOU MEDICAL UNIV
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