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Cabozantinib mucate and crystal form there of

A technology of mucus salt and crystal form, applied in the field of chemical medicine, can solve the problem of low solubility of free alkali, and achieve the effects of convenient long-term storage, low hygroscopicity, improved bioavailability and curative effect

Active Publication Date: 2015-10-07
CRYSTAL PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] According to reports in the patent US7579473, the solubility of the free base of the compound formula (I) is extremely low

Method used

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  • Cabozantinib mucate and crystal form there of
  • Cabozantinib mucate and crystal form there of
  • Cabozantinib mucate and crystal form there of

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di The preparation method of formamide mucate:

[0057] 200mg N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1 - The powder of diformamide was dissolved in 8.0 mL of acetonitrile solvent system, then 84 mg of mucic acid solid was added to the solution, and magnetically stirred at room temperature to obtain it.

[0058] The mucic acid salt product prepared by the above-mentioned method has the following NMR identification data:

[0059] 1H NMR (400MHz, DMSO) δ10.18(s, 1H), 10.05(s, 1H), 8.47(d, J=5.2Hz, 1H), 7.76(d, J=9.0Hz, 2H), 7.64(dd ,J=9.1,5.1Hz,2H),7.50(s,1H),7.39(s,1H),7.23(d,J=9.0Hz,2H),7.15(t,J=8.9Hz,2H),6.43 (d,J=5.2Hz,1H),4.22(s,2H),3.94(d,J=4.8Hz,6H),3.77(s,2H),1.47(s,4H).

Embodiment 2

[0061] N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1 of the present invention, Comparative study on the solubility of 1-dicarboxamide mucate and malate in CN102388024A:

[0062] The two salts were prepared as saturated solutions with pH 1.8 SGF (simulated gastric juice) and pH 6.5 FaSSIF (artificial intestinal fluid in fasting state) buffers. After 4 hours, measure the concentration of the sample in the saturated solution by high performance liquid chromatography, and the experimental results are as shown in table 1:

[0063] Table 1 Comparative study on solubility of cabozantinib mucate and CN102388024A malate

[0064]

[0065] Detection limit: 0.03 μg / ml

[0066] As can be seen from the above comparison results, N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxyl}benzene of the present invention after being placed in SGF and FaSSIF for 4 hours Base)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide mucate salt has higher solubility than C...

Embodiment 3

[0068] N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di The preparation method of formamide mucate salt crystal form A:

[0069] 10mg N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1 - Diformamide powder was dissolved in 0.4 mL of methanol solvent system, then 4.2 mg of mucic acid solid was added, and stirred at room temperature to obtain Form A. Table 2 shows the X-ray powder diffraction data of Form A 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 .

[0070] Table 2 X-ray powder diffraction data of crystal form A

[0071] 2theta

[0072] 13.28

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Abstract

The invention relates to mucate of N-(4-{[6,7-bis(methoxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dimethanamide and a crystal form thereof, and a preparation method thereof. The solubility of the mucate of a compound as shown in a formula (I) which is described in the specification is higher than the solubility of malate of the compound, which is of important significance to improvement of bioavailability, curative effect and security of the compound.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorobenzene base) mucate salt of cyclopropane-1,1-dicarboxamide and its crystal form. Background technique [0002] N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-di Formamide, also known as cabozantinib, was developed by Exelixis for the treatment of metastatic medullary thyroid cancer. It was approved by the FDA in November 2012 and marketed in the form of malate. The structure of cabozantinib is shown in formula (I): [0003] [0004] Nearly half of the drug molecules are present and administered in the form of salts. Salt formation can improve some undesirable physicochemical or biopharmaceutical properties of drugs, such as changing the solubility or dissolution rate of drugs, reducing hygroscopicity, improving stability, changing melting point, improving grinding perform...

Claims

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Application Information

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IPC IPC(8): C07D215/22A61K31/47A61P35/00
CPCC07B2200/13C07D215/22
Inventor 陈敏华张炎锋李骄洋张晓宇陆飞
Owner CRYSTAL PHARMATECH CO LTD
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