Imidazoquinazoline derivatives and their application in anti-tumor and anti-inflammation

Abstract

The invention provides an imidazo quinazoline derivative serving as a PI3K inhibitor. Compounds include analogues and pharmaceutically acceptable salts, stereoisomers and solvates. By adoption of a cyclization strategy, the left side portion of original Copanlisib is subjected to loop closing and structural modification, or a fluorine-containing fragment Rf is introduced to Copanlisib left atoms to optimize physicochemical properties of molecules. According to experiments, pharmacokinetic properties of the compounds are evidently improved as compared with those of Copanlisib, volume of distribution is remarkably reduced, and accordingly risks of in-vivo accumulation of medicines are reduced. The compounds have great pharmacokinetic properties, low toxic and side effects and a promising anti-tumor anti-inflammation application prospect and can be applied to preparation of anti-tumor anti-inflammation medicines. A formula a and a formula b of the compounds are structurally as shown in the specification.

Description

technical field [0001] The invention relates to the field of medicine, in particular to an imidazoquinazoline derivative as a PI3K inhibitor, a pharmaceutical composition containing it and its application in the preparation of anti-tumor and anti-inflammatory drugs. Background technique [0002] The PI3K / Akt / mTOR pathway is an abnormally activated signal transduction pathway in human cancer, which is closely related to the occurrence and development of malignant tumors. PI3K is a key kinase in this signaling pathway. At present, two PI3K inhibitors have been successfully approved for marketing, and nearly 30 PI3K inhibitors have entered clinical research successively. They are popular targets for anti-tumor drug development. [0003] In 2015, Idelalisib, an oral PI3Kδ selective inhibitor developed by Gilead, was approved for the treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma, but it was also found that idelalisib may in...

AI Technical Summary

Problems solved by technology

[0003] In 2015, Idelalisib, an oral PI3Kδ selective inhibitor developed by Gilead, was approved for the treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma, but it was also found that idelalisib may induce liver toxicity, side effects such as pneumonia, severe diarrhea, enteritis, and intestinal perforation. In addition, Copanlisib, a PI3K inhibitor developed by Bayer, also received accelerated approval from the US Food and Drug Administration in September 2017 for the treatment of patients with recurrent follicular lymphoid adult patients with tumors who have received at least two systemic therapies

However, clinical studies have shown that the drug has poor pharmacokinetic properties and a large volume of distribution, reaching 32.6L / kg, which is easy to store in the patient's body and cause corresponding toxic and side effects. Therefore, the clinical medication is within 28 days of treatment cycle. Injected on days 1, 8 and 15

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