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Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester

A technology of dioxoolean and methyl acid, which is applied in the direction of steroids, organic chemistry, organic chemistry methods, etc., can solve the problems of low bioavailability, weak biological activity, amorphous thermodynamics, etc., and achieve solvent consumption Effects of non-toxicity, low production cost, and less solvent consumption

Inactive Publication Date: 2013-01-23
CRYSTAL PHARMATECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The biosynthesis of triterpenes is mainly generated by the cyclization of squalene in plants, and its biological activity is relatively weak when used as a raw material drug
However, the anhydrous crystal has poor solubility and low bioavailability
It is amorphous and thermodynamically unstable, and there is a potential risk of transforming into other crystal forms in the presence of seed crystal induction or high temperature and humidity environments
Benzene in the hemibenzene solvate belongs to a class of solvents, which is highly toxic to the human body and cannot be degraded in the human body, so it is not suitable for drug development

Method used

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  • Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester
  • Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester
  • Crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Take 50mg of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-acid methyl ester and dissolve it in 500 μL of toluene, place it in a fume hood for rapid volatilization, and it will disappear after 1 day 53.8 mg of the toluene solvate, namely the crystal form I, was obtained.

[0038] X-ray powder diffraction pattern see figure 1 . For thermogravimetric analysis, see figure 2 . The differential scanning calorimetry diagram is shown in image 3 .

Embodiment 2

[0040] Dissolve 200 mg of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester in 1 ml of 1,4-dioxahexa Ring and water mixed solution, after suspension and stirring at room temperature for 24 hours, 146 mg of white solid was obtained. The purity is 99.48%. The white solid is crystal form II, which is also a half 1,4-dioxane solvate.

[0041] X-ray powder diffraction pattern see Figure 4 . The thermogravimetric analysis spectrum is shown in Figure 5 . The differential scanning calorimetry diagram is shown in Image 6 . See liquid NMR Figure 7 .

Embodiment 3

[0043]Dissolve 16.9 mg of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester in 0.2 ml of tetrahydrofuran solution, and mix it with 4.0 ml of The anti-solvent n-heptane was placed together at -22°C for 1 hour, and 2-cyano-3,12-dioxoolean-1,9(11)-diene was added by reverse anti-solvent addition The tetrahydrofuran solution of -28-acid methyl ester was slowly added dropwise into n-heptane, then suspended and stirred for 24 hours to obtain 11.4 mg of a white solid with a purity of 99.25%. The white solid is crystal form III, that is, half tetrahydrofuran solvate.

[0044] X-ray powder diffraction pattern see Figure 8 . For thermogravimetric analysis, see Figure 9 . The differential scanning calorimetry diagram is shown in Figure 10 . See liquid NMR Figure 11 .

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Abstract

The invention relates to the field of pharmaceutical chemistry, and particularly relates to several crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester suitable for medicament development. The invention is characterized in that the crystal forms are methylbenzene solvate, semi-dioxane solvate and semi-tetrahydrofuran solvate of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester. The several crystal forms have favorable solubility and stability, contain no toxicity and are suitable for being prepared into medicaments.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to several crystal forms of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-acid methyl ester suitable for drug development. Background technique [0002] The biosynthesis of triterpenes is mainly generated by the cyclization of squalene in plants, and its biological activity is relatively weak when used as a raw material drug. Scientists therefore sought synthetic analogs to enhance potency. 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid methyl ester is one of them with good anti-inflammatory, differentiation and anti-proliferative effects, and has the potential for drug development potential drug molecules. Its structural formula is as follows: [0003] [0004] Currently, the patent US8088824B2 reports the anhydrous, amorphous, hemibenzene solvate of 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-acid methyl ester and dimethanol solvates. However, the anhydrous crystal has the pr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00
CPCC07J63/008C07B2200/13
Inventor 杨朝惠高岳君张晓宇汪建明张炎锋陈敏华王鹏李丕旭
Owner CRYSTAL PHARMATECH CO LTD