Solvate crystal of PARP inhibitor and preparation method of solvate crystal

A solvate and crystal technology, applied in the field of solvate crystals of PARP inhibitors and their preparation, can solve problems such as poor fluidity and stability of compounds

Active Publication Date: 2019-10-29
SHANGHAI DE NOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The preparation method of the compound of the above formula is a

Method used

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  • Solvate crystal of PARP inhibitor and preparation method of solvate crystal
  • Solvate crystal of PARP inhibitor and preparation method of solvate crystal
  • Solvate crystal of PARP inhibitor and preparation method of solvate crystal

Examples

Experimental program
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Effect test

Embodiment 1

[0112] 1-cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl) -2,5-diazabicyclo[2,2,1]heptane-2-yl)ethane-1,2-dione (formula I) preparation

[0113] 1) 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (400mg, 1.32mmol), 2,5-diazabicyclo[2 , 2,1] Heptane-2-carboxylic acid (1S, 4S)-tert-butyl ester (665mg, 3.35mmol), 2-(7-azobenzotriazole)-N,N,N',N' -Tetramethylurea hexafluorophosphate (1.02g, 2.68mmol) and diisopropylethylamine (1.2ml, 6.7mmol) were dissolved in N,N-dimethylformamide (25ml), stirred at room temperature for 72 hours . The reaction solution was diluted with dichloromethane and water (50ml each), and the organic phase was washed with aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, filtered, and concentrated to give the crude product (1.23g) as a brown oil.

[0114] 2) Add trifluoroacetic acid (4 ml) to a solution of the crude product obtained in the previous step in dichloro...

Embodiment 2

[0118] Take 100g of the target product obtained in Example 1 and add 600ml of 100% (w / w) ethyl acetate to dissolve completely, and control the temperature at 10°C to stir and crystallize. Filter and rinse with an appropriate amount of ethyl acetate. The filter cake was dried under reduced pressure at 55° C. to constant weight to obtain 92.0 g of ethyl acetate solvate crystal A of formula I, with a yield of 92.0%.

Embodiment 3

[0120] Take 100 g of the target product obtained in Example 1 and add 2000 ml of ethyl acetate solution (95% (w / w) ethyl acetate, 5% (w / w) tetrahydrofuran) to dissolve completely, and control the temperature at 20° C. to stir and crystallize. Filter and rinse with an appropriate amount of ethyl acetate. The filter cake was dried under reduced pressure at 40° C. to constant weight to obtain 91.5 g of ethyl acetate solvate crystal A of formula I, with a yield of 91.5%.

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PUM

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Abstract

The invention discloses a solvate crystal of a PARP inhibitor, a preparation method, a pharmaceutical composition and application. The disclosed solvate crystal of a compound in a formula I includes an ethyl acetate solvate crystal A, an ethyl formate solvate crystal B, a methyl acetate solvate crystal C and an n-propyl formate solvate crystal D.

Description

[0001] field of invention [0002] The present invention relates to solvate crystals, preparation methods, pharmaceutical compositions and applications of PARP inhibitors. Background technique [0003] PARP is an abbreviation for "poly(ADP-ribose) polymerase". Tumor cells use the PARP enzyme to repair DNA damage, including that caused by chemotherapy. The researchers are investigating whether drugs that inhibit the PARP enzyme also weaken this self-repair mechanism and make tumor cells more sensitive to treatment, accelerating tumor cell death. [0004] PARP inhibitors are a family of pharmacological inhibitors of poly ADP ribose polymerase, which are important for promoting DNA repair, controlling RNA transcription, regulating cell death and immune response. Therefore, there are various indications for the development of PARP inhibitors, the most important indication being for the treatment of tumors. Several forms of BRCA-deficient tumor cells are more dependent on PARP f...

Claims

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Application Information

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IPC IPC(8): C07D487/08A61P35/00A61P9/00A61P29/00A61P37/06A61P3/10A61P25/16A61P25/00A61P31/12A61P31/00A61K31/502
CPCC07D487/08A61P35/00A61P9/00A61P29/00A61P37/06A61P3/10A61P25/16A61P25/00A61P31/12A61P31/00C07B2200/13
Inventor 焦育红蔡鸿飞赵坤蔡群芳汪晶翁玉芳
Owner SHANGHAI DE NOVO PHARMA
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