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Crystal IV of 3-(substituted dihydroisoindolinone-2-yl)-2,6-piperidinediketone and medicinal composite thereof

A technology of isoindole and composition, applied in the preparation method of the crystal and its pharmaceutical composition, 3-piperidine-2 field, can solve the problems of unfavorable industrial scale stable parallel production preparation and no consideration

Active Publication Date: 2013-04-10
NANJING CAVENDISH BIO ENG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Since 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione is almost insoluble in water or hexane, toluene, acetone , acetonitrile, methyl alcohol, ethyl acetate and other organic solvents, even under the heating situation, a large amount of (more than 100 times) solvents need to be used, which is not conducive to the stable parallel production and preparation of industrial scale; in addition, this method of application document CN 1871003A cannot make the product The appearance color has improved from the original light yellow to white or off-white; and it has not been considered that toluene and other organic solvents that are more harmful to the human body should be avoided in the preparation of the final product to reduce the residual organic solvent in the product Adverse effects on the human body

Method used

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  • Crystal IV of 3-(substituted dihydroisoindolinone-2-yl)-2,6-piperidinediketone and medicinal composite thereof
  • Crystal IV of 3-(substituted dihydroisoindolinone-2-yl)-2,6-piperidinediketone and medicinal composite thereof
  • Crystal IV of 3-(substituted dihydroisoindolinone-2-yl)-2,6-piperidinediketone and medicinal composite thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0308] Preparation of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione IV crystals

[0309] 5 grams of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione were dissolved in 350ml of acetonitrile at 60°C under stirring In, add activated carbon 0.25 gram, filter after stirring for ten minutes. The filtrate was cooled to room temperature at a rate gradient of 5° C. every 2 hours with stirring, and then left to stand. The solvent is slowly volatilized at around 20°C for a long time until the crystals are precipitated. The solid was collected by filtration and evaporated to constant weight at room temperature. Weighing: 2.1 g; Yield: 42%.

[0310]

Embodiment 2

[0311] The prescription and preparation technology of embodiment 2 tablet:

[0312] The above-mentioned 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione was prepared with several excipients as follows Crystalline IV is formulated as tablets containing 10 mg each.

[0313] Prescription status:

[0314]

[0315] Preparation process: the preparation method of IV tablets containing 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione crystals is The above-mentioned excipients and 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione crystals were increased in equal amounts Mix evenly, add 10% PVP solution as an appropriate amount of binder, make a soft material, sieve and granulate, dry the wet granules, sieve and granulate, add magnesium stearate, mix evenly, and compress into tablets. See Table 6 for the test results of cumulative dissolution of tablet prescription 1, and see Table 6 for the dissolution curve of tablet prescript...

Embodiment 3

[0320] The prescription and preparation technology of embodiment 3 capsules:

[0321] 3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione crystals were prepared with several excipients as follows IV formulated as capsules containing 10 mg each.

[0322]

[0323] Preparation process: the manufacture method of IV capsules containing 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione crystals is to Mix the above-mentioned excipients with 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione crystals, add 10% The PVP solution is made into wet granules, dried, sieved for granulation, added with magnesium stearate, mixed evenly, and packed into capsules. Or without granulation, mix 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione crystals with the above excipients Mix evenly, sieve, and directly pack into capsules. See Table 8 for the test results of cumulative dissolution of capsule prescription 1, and see Table 8...

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Abstract

The invention discloses a crystal IV of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl) piperidine-2,6-diketone. 2theta expressed by degrees has diffraction peaks between 7.7+ / -0.2 and 11.9+ / -0.2 in the X-ray diffraction pattern of the crystal. Moreover, the invention also discloses a preparation method and a medicinal composite of the crystal.

Description

technical field [0001] The present invention relates to crystalline forms of pharmaceutical compounds, more particularly to 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6 - diketone crystal IV, in addition, the present invention also relates to the preparation method of the crystal and its pharmaceutical composition. Background technique [0002] Muller et al described a kind of in "Amino-substituted thalidomide analogs: Potent inhibitors of TNF-αproduction" (Bioorganic & Medicinal Chemistry Letters, Vol.9, Issue 11, June 7, 1999, pp1625-1630) and Chinese patent ZL97180299.8 3-(Substituted dihydroisoindolin-2-yl)-2,6-piperidinedione, especially 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol Indol-2-yl)piperidine-2,6-dione. In December 2005, 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione (lenalidomide, commercial Named Revlimid TM ), as an immunomodulator with anti-tumor properties, has been approved for marketing in the United States for the t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/454A61P37/02A61P35/00
Inventor 许永翔杨浩严荣
Owner NANJING CAVENDISH BIO ENG TECH
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