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A class of garcinia triazole derivatives, preparation method and medicinal use thereof

A pharmacy and drug technology, applied in the direction of pharmaceutical formula, antineoplastic drugs, drug combinations, etc., can solve the problems of lack of druggability, water solubility, lack of hydrophilic nitrogen atoms, poor activity in vivo, etc., and achieve good antitumor activity in vivo, Good anti-tumor activity, the effect of improving cell membrane permeability

Active Publication Date: 2016-08-24
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, compound 2 lacks the necessary water solubility for druggability: on the one hand, the hydrophilic phenolic hydroxyl group in its structure forms an intramolecular hydrogen bond with the carbonyl group, which is one of the reasons for the low water solubility; on the other hand, the structure Lack of hydrophilic nitrogen atoms in
The low water solubility of compound 2 is an important factor leading to its poor activity in vivo

Method used

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  • A class of garcinia triazole derivatives, preparation method and medicinal use thereof
  • A class of garcinia triazole derivatives, preparation method and medicinal use thereof
  • A class of garcinia triazole derivatives, preparation method and medicinal use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 8-(1-(2-(Dimethylamino)ethyl)-1H-1,2,3-triazol-4-yl)methoxy-3,3-dimethyl-1-(3- Methylbut-2-en-1-yl)-3,3a,4,5-tetrahydro-1,5-methyl-1H,7H-furo[3,4-d]xanthene-7, 13-Diketone (I-1)

[0053]

[0054] (1) Dissolve 1-hydroxy-5,6-bis(2-methylbut-3-en-2-yloxy)-9H-xanthene-9-one (compound 2) (30g, 0.105mol) In anhydrous tetrahydrofuran (400mL), cool in an ice bath to 10°C, add tert-butoxycarbonylmethylbutenol (195g, 1.05mol), and add tetrakistriphenylphosphine palladium (1.2g, 1.05mmol) under nitrogen protection , Reaction at 10°C for 10h. Air was introduced to quench the reaction, and silica gel was used to filter. The filtrate was concentrated by distillation under reduced pressure to obtain compound 3 as a yellow oil. 1 H NMR (300MHz, CDCl 3 ):δ1.56(s,6H),1.57(s,6H),2.48(s,3H),5.04(d,J=10.8Hz,1H),5.17-5.24(m,3H),5.11-6.32( m,2H),6.97(d,J=8.4Hz,1H),7.08(d,J=9.0Hz,1H),7.41(d,J=8.4Hz,1H),7.63(t,J=8.4Hz, 1H), 7.82(d, J=9.0Hz, 1H); EI-MS m / z: 422[M] + (5), 286(12), 244(...

Embodiment 2

[0057] 8-(1-(3-(Dimethylamino)propyl)-1H-1,2,3-triazol-4-yl)methoxy-3,3-dimethyl-1-(3- Methylbut-2-en-1-yl)-3,3a,4,5-tetrahydro-1,5-methyl-1H,7H-furo[3,4-d]xanthene-7, 13-Diketone (I-2)

[0058]

[0059] Compound 3 (0.6g, 1.4mmol) was dissolved in t-BuOH / H 2 In the mixed solution of O (v:v=1:1, 20mL), add the side chain azide N,N-dimethylaminoazidopropane (0.28g, 2.2mmol), sodium ascorbate (0.4mmol), five Copper sulfate water (0.01mmol), N 2 Protection, reaction at room temperature for 24h. Add 40ml of water to the reaction solution, CH 2 Cl 2 Extraction (15mL×4), combined organic layers, anhydrous NaSO 4 Dry, filter with suction, and concentrate the filtrate under reduced pressure to obtain the product as light yellow solid I-2 (0.71 g, 93%). m.p.133-136°C; 1 H NMR (300MHz, CDCl 3 ):δ1.08(s,3H),1.25-1.29(m,4H),1.37(s,3H),1.69(s,3H),2.15-2.25(m,2H),2.28-2.41(m,8H ),2.48-2.53(m,2H),2.61(d,J=7.7Hz,2H,C 11 -H),3.43-3.47(m,1H),4.45-4.49(m,3H),5.31(s,2H),6.71(t,J=7.8H...

Embodiment 3

[0061] 8-(1-(Dimethylaminomethyl)-1H-1,2,3-triazol-4-yl)methoxy-3,3-dimethyl-1-(3-methylbutyl- 2-en-1-yl)-3,3a,4,5-tetrahydro-1,5-methyl-1H,7H-furo[3,4-d]xanthene-7,13-dione (I-3)

[0062]

[0063] Compound 3 (0.6g, 1.4mmol) was dissolved in t-BuOH / H 2 In the mixed solution of O (v:v=1:1, 2mL), add the side chain azide N,N-dimethylaminoazomethane (0.22g, 2.2mmol), sodium ascorbate (0.4mmol), five Copper sulfate water (0.01mmol), N 2 protected and reacted overnight at room temperature. Add 20 mL of water to the reaction solution, CH 2 Cl 2 Extraction (15mL×4), combined organic layers, anhydrous NaSO 4 Dry, filter with suction, and concentrate the filtrate under reduced pressure to obtain the product as light yellow solid I-3 (0.70 g, 93%). m.p.146-148°C; 1 H NMR (300MHz, CDCl 3 ): δ1.01(s,3H),1.18-1.24(m,4H),1.32(s,3H),1.65(s,3H),2.22-2.27(m,7H),2.33(d,J=9.5 Hz,1H),2.54(d,J=7.8Hz,2H),,4.37-4.46(m,1H),4.49(s,1H),4.52(s,2H),5.26(s,2H),6.62- 6.71(m,2H),7.21-7.24(m,1H...

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Abstract

The invention relates to the field of medicinal chemistry and in particular relates to garcinia triazole derivatives (9), a preparation method of the derivatives and medical application of the derivatives in pharmacy. R1, R2 and n are defined as the specification. The derivatives are structural analogues of a garcinia natural product, namely gambogic acid, have the antitumor effects and can be used for preparing antitumor medicines. The structural formula is as shown in the specification.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of gamboge triazole derivatives, a preparation method thereof and an application in pharmacy. The derivative is a structural analogue of gambogic acid, a natural product of the genus Garcinia, has antitumor effect, and can be used for preparing antitumor drugs. Background technique [0002] Gambogic acid, a natural product, is extracted from the colloidal resin secreted after the trunk of the genus Garcinia is split, and is an important anti-tumor active ingredient in the gamboge resin. Studies have shown that gambogic acid can selectively inhibit the growth of transplanted tumors within the effective dose range, and its anti-tumor effect is different from that of general chemotherapy drugs. It can selectively kill a variety of tumor cells, while for normal hematopoietic System and immune function had no significant effect. Gambogic acid can regulate the expression of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/10A61K31/4192A61K31/496A61K31/551A61K31/454A61K31/5377A61P35/00
CPCC07D493/10
Inventor 张晓进尤启冬胡明阳孙昊鹏王艳艳
Owner CHINA PHARM UNIV
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