Crystal form b of abt-888 and its preparation method and application

Abstract

A B crystal form of 2-[(2R)-2-methyl-2-pyrrolidinyl]-1H-benzimidazole-7-carboxamide (ABT-888), a preparation method thereof and use are provided. The X-ray powder diffraction pattern (CuKα radiation) of B crystal form at 25 ℃ has characteristic peaks at 2 theta values of 9.40 ° ± 0.20 °, 17.30 ° ± 0.20 °, 22.80 ° ± 0.2 °. The B crystal form is prepared by dissolving ABT-888 free alkali in methanol and volatilizing the same at room temperature into a B crystal form. Compared with existing crystal forms, the B crystal form has a higher solubility and a simpler preparation process, and has good stability. The B crystal form is of great significance for improving the efficacy of and for reducing the drug load for treating metastatic breast cancer, colon cancer, metastatic melanoma and brain tumor.

Description

Technical field [0001] The invention relates to the crystal form B of 2-[(2R)-2-methyl-2-pyrrolidinyl]-1H-benzimidazole-7-carboxamide and a preparation method thereof. Background technique [0002] 2-[(2R)-2-Methyl-2-pyrrolidinyl]-1H-benzimidazole-7-carboxamide (compound of formula I), also known as ABT-888 (veliparib), is produced by Abbott ( Abbvie) a new type of high-selectivity PARP inhibitor developed by the company. In vivo and in vitro experiments have shown that ABT-888 has a significant inhibitory effect on PARP activity, and has achieved significant effects in the treatment of metastatic breast cancer, colon cancer, metastatic melanoma and brain tumors. At present, the combined application of ABT-888 and whole brain radiotherapy for the treatment of metastatic brain tumors has entered the phase I clinical stage, and the treatment of metastatic breast cancer, colon cancer and metastatic melanoma has also entered the phase II clinical stage, and is used in combination wi...

AI Technical Summary

Problems solved by technology

Among the two crystal forms, the solubility of crystal form 1 is relatively good, but crystal form 1 needs to react with the acid or diacid salt of ABT-888 with a base, and the crystal form 1 mixed with one or more than one solvent can be made by deprotonation reaction. ABT-888 is obtained by crystallization or recrystallization in the form of solid, semi-solid, wax or oil. The preparation process is relatively complicated and the requirements for operation are also high.

Although the preparation of crystal form 2 is relatively simple, it can be obtained by completely dissolving ABT-888 in methanol, then concentrating at 35°C, and drying to constant weight, but its solubility is poor

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