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Niraparib p-toluene sulfonate hydrate crystal form and preparation method thereof

A technology of p-toluenesulfonate and monohydrate, applied in the field of chemical medicine, can solve the problems of loss of activity, DNA damage, cancer cell death, etc., and achieve the effect of low hygroscopicity and good stability

Inactive Publication Date: 2018-09-14
GUANGZHOU BIO CURRENT BIOLOGICAL TECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If any repair mechanism of PARP and BRCA fails, the damaged DNA will accumulate in the cells and lead to canceration, and excessive accumulation will also lead to the death of cancer cells
In some people, due to congenital or acquired reasons, the BRCA gene is mutated and loses its activity, and the accumulation of damaged DNA in the cells will increase the risk of cancer, especially the risk of breast and ovarian cancer
However, BRCA mutant cancer cells are very dependent on PARP for DNA damage repair due to BRCA inactivation. If PARP activity is further inhibited, a large amount of DNA damage will occur when these cells divide, leading to cancer cell death.

Method used

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  • Niraparib p-toluene sulfonate hydrate crystal form and preparation method thereof
  • Niraparib p-toluene sulfonate hydrate crystal form and preparation method thereof
  • Niraparib p-toluene sulfonate hydrate crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Synthesis method of 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonate hydrate crystal form A

[0058] Add 120g of 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-formyl p-toluenesulfonate monohydrate into the reaction flask, 980mL of ethanol, 250mL of water, nitrogen Stir and heat to 80°C under protection, the solid dissolves, slowly cool down to 20°C under stirring and stir at controlled temperature for 2 hours, filter, and vacuum-dry at 40°C to obtain 105g of Form A.

Embodiment 2

[0060] Synthesis method of 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonate hydrate crystal form A

[0061] Add 100g of 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-formyl methanesulfonate and 1000mL of water into the reaction flask, and control the temperature to 20°C-30°C. Under the protection of nitrogen, slowly add 50% (mass fraction) p-toluenesulfonic acid (70g) monohydrate solution, after the addition, control the temperature at 20°C and stir for 4 hours, filter and wash with water, and dry under vacuum at 40°C to obtain 100g of Form A.

Embodiment 3

[0063] Synthesis method of 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide p-toluenesulfonate hydrate crystal form A

[0064] Add 100g of 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxyl, 750mL of ethanol, 250mL of water into the reaction flask and control the temperature to 20°C-30°C, nitrogen Slowly add 50% (mass fraction) of p-toluenesulfonic acid (75g) monohydrate solution under protection, after the addition is completed, stir at 20°C for 4 hours, filter, wash with water, and dry under vacuum at 40°C to obtain 110g of Form A.

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Abstract

The invention belongs to the field of chemical pharmaceuticals and particularly relates to the crystal form A of niraparib (2-[4-((3S)-3-piperidyl)phenyl]-2H-indazole-7-formamide) p-toluene sulfonateand a preparation method of the crystal form A. The X-ray powder diffraction diagram of the crystal form A has feature peaks at the 2theta values of 9.5+ / -0.2 degrees, 15.1+ / -0.2 degrees, 18.4+ / -0.2 degrees, 19.4+ / -0.2 degrees, 21.0+ / -0.2 degrees, 24.6+ / -0.2 degrees and 30.0+ / -0.2 degrees. The crystal form A which is free of or hardly has hygroscopicity is extremely high in stability, stable in properties, less prone to deterioration and beneficial to medicine effect maintaining.

Description

technical field [0001] The invention belongs to the field of chemical medicine and relates to 2-[4-((3S)-3-piperidinyl)phenyl]-2H-indazole-7-carboxamide (niraparib) p-toluenesulfonate hydrate Crystal form A and its preparation method. Background technique [0002] DNA damage is always accompanied by mammalian cells. External causes include ionizing radiation and chemical poisons, and internal causes include the stimulation of the cell's own metabolites and the breakage of DNA's own chemical bonds. The average number of damages per cell per day can reach tens of thousands. Failure to repair DNA damage in a timely and precise manner can lead to genome instability, and genome instability is an important feature of carcinogenesis. The DNA damage repair mechanism plays a very important role in maintaining the stability of the genome. Radiotherapy and many anti-tumor drugs achieve the purpose of killing tumor cells by damaging DNA, but tumor cells can activate their own DNA dama...

Claims

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Application Information

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IPC IPC(8): C07D401/10A61K31/454A61P35/00
CPCA61P35/00C07B2200/13C07D401/10
Inventor 王勇俞金泉
Owner GUANGZHOU BIO CURRENT BIOLOGICAL TECH LTD
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