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Co-crystals of CDK inhibitor and MEK inhibitor and preparation method of co-crystals

An inhibitor, MEK162 technology, applied in the field of chemical medicine, can solve the problems such as the therapeutic effect of co-crystal made of two active ingredients of medicine has not yet been seen

Active Publication Date: 2016-07-13
CRYSTAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are no related reports on the co-crystal formation of two active ingredients of drugs and the study of their therapeutic effects, especially the report on the formation of co-crystals of two active ingredients of drugs LEE011 and MEK162

Method used

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  • Co-crystals of CDK inhibitor and MEK inhibitor and preparation method of co-crystals
  • Co-crystals of CDK inhibitor and MEK inhibitor and preparation method of co-crystals
  • Co-crystals of CDK inhibitor and MEK inhibitor and preparation method of co-crystals

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preparation example Construction

[0108] In the preparation method of the crystal form of the present invention:

[0109] The "room temperature" refers to 15-25°C.

[0110] The "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, preferably 300-900 rpm.

[0111] The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The operation of "centrifugation" is: put the sample to be separated in a centrifuge tube, and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.

[0112] Unless otherwise specified, the "drying" can be carried out at room temperature or higher. The drying temperature is from room temperature to about 60°C, or to 40°C, or to 50°C. The drying time can be 2-48 hours, or overnight. Drying is carried out in a fume hood, forced air oven or vacuum oven.

[0113] In the present invention, "crystal" or "c...

Embodiment 1

[0154] The preparation method of crystal form I:

[0155] Put 26.6 mg of MEK162 and 4 mL of acetonitrile / water (v:v=19:1) at 50°C and stir for 30 minutes, add 16.0 mg of LEE011, continue stirring overnight and slowly cool down to 20°C, and collect the solid to obtain it.

[0156] Table 1 shows the X-ray powder diffraction data of the crystal forms obtained in this example. Its XRPD pattern is as follows figure 1 , and its DSC graph is shown in figure 2 , and its TGA figure is shown in image 3 . From figure 2 It can be seen that the crystal form I of this example begins to appear the first endothermic peak when heated to around 86-95°C, and the second endothermic peak begins to appear around 130-142°C. From image 3 It can be seen that the crystal form I of this example has a weight loss gradient of about 5-6% when heated to around 110°C.

[0157] Table 1

[0158]

[0159]

Embodiment 2

[0161] The preparation method of crystal form I:

[0162] Mix 9.7mg of MEK162 and 1mL of acetonitrile / water (v:v=1:1) at room temperature (25±3°C) and stir for 30 minutes, add 10.0mg of LEE011, and continue stirring overnight to obtain.

[0163] The X-ray powder diffraction data of the crystal forms obtained in this example are shown in Table 2.

[0164] Table 2

[0165]

[0166]

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Abstract

The invention relates to co-crystals of a CDK inhibitor and an MEK inhibitor and a preparation method of the co-crystals, and particularly provides hydrate or anhydride crystal forms which are named as the crystal form I, the crystal form II and the crystal form III.The co-crystals are good in stability, low in hygroscopicity and higher in solubility and have the important value on future optimization and development of the drugs.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to a co-crystal of a CDK inhibitor (LEE011) and a MEK inhibitor (MEK162) and a preparation method thereof. Background technique [0002] With the continuous emergence of drug resistance in melanoma, the combination of multiple target drugs has become the main development direction of targeted therapy research. NRAS gene mutation is a common type of gene variation in patients with skin malignant melanoma, accounting for about 20%. The prognosis of patients with NRAS gene mutation is poor, and there is a lack of targeted therapeutic drugs. Studies have found that in NRAS-mutant melanoma cells, the MAPK signaling pathway is abnormally activated, and there are multiple cell cycle checkpoint disorders. Therefore, simultaneous inhibition of MEK, a key pathway molecule in MAPK signaling, and CDK4 / 6, a key regulator of cell cycle, may have a synergistic anti-tumor effect and improve anti-...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D235/06A61K31/519A61K31/4184A61P35/00
CPCA61K31/4184A61K31/519C07B2200/13C07D235/06C07D487/04A61K2300/00
Inventor 陈敏华张炎锋杨朝惠夏楠刘启月张晓宇
Owner CRYSTAL PHARMA CO LTD
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