Alkoxy benzo five-membered (six-membered) heterocyclic amine compound and medicinal application thereof

Abstract

The invention belongs to the field of medicinal chemistry and relates to an alkoxy benzo five-membered (six-membered) heterocyclic amine compound shown by a formula I or a pharmaceutically acceptablesalt thereof and medicinal application thereof, wherein R1, R2 and R3 are consistent with the detailed description in the summary of the invention. The compound can selectively inhibit the activity ofsphingomyelin synthase 2 and can be used for treating diseases caused by abnormally increased sphingomyelin level. The invention further provides application of the compound, the pharmaceutically acceptable salt thereof or the pharmaceutical composition taking the compound as an effective active ingredient in the preparation of medicines for preventing and treating diseases caused by abnormal increase of sphingomyelin level, including atherosclerosis, type II diabetes, fatty liver and obesity, metabolic syndrome thereof and inflammatory diseases including enteritis.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to alkoxybenzo five-membered (six-membered) heterocyclic amine compounds and their medicinal uses, in particular to alkoxybenzo five-membered (six-membered) heterocyclic amine compounds or their pharmaceutical use Acceptable salts and their use in the preparation of sphingomyelin synthase inhibitors and in the preparation of drugs for the prevention or treatment of atherosclerosis, type II diabetes, fatty liver and obesity and their metabolic syndrome and inflammatory diseases including enteritis Uses in medicine. Background technique [0002] According to reports, in my country, the morbidity and mortality of cardiovascular and cerebrovascular diseases have increased significantly in recent years to the second place in the total cause of death except tumors, and have become one of the major diseases that endanger human health. Studies have shown that atherosclerosis (AS) is one of...

AI Technical Summary

Problems solved by technology

[0011] One of the sphingomyelin synthase inhibitors currently reported in the literature is D609 (Aimin Meng; Chiara Luberto; et al. Experimental Cell Research, 2004, 292, 385–392.), which has a weak inhibitory effect on sphingomyelin synthase ( IC 50 =375μM), and its chemical structure contains orthosulfonate which makes the structure highly unstable (Bai, A. et al. J. Pharmacol. Exp. Ther. 2004, 309, 1051-1059), and the half-life is short; based on the same The virtual screening of the three-dimensional structure model of sphingomyelin synthase based on source modeling found the small molecule inhibitor compound D2 of sphingomyelin synthase (XiaodongDeng, Fu Lin, et al. European Journal of Medicinal Chemistry, 2014, 73, 1-7) , although its inhibitory activity against SMS2 in vitro is stronger than that of D609, it still has the following defects: the inhibitory activity against SMS2 needs to be improved, it contains a cyano group with a potential toxicity risk, and its physical and chemical properties such as water solubility and stability are not good. good

The 293 cell line was used to highly express human SMS2, and then the supernatant of its cell homogenate was used as the enzyme source to measure the inhibitory activity IC of 2-quinolinone derivatives 50 The value is 6.5nM (R.Adachi et al.European Journal of Medicinal Chemistry,2017,136,283-293); its activity and selectivity are high, but due to its relatively large molecular weight and high cLogP (MW 625.57; cLogP6.47) , so that there may be certain druggability problems

It has been reported in the literature that 2-benzyloxyphenyl oxazolopyridines possess micromolar-level SMS2 activity and good selectivity, and the inhibitor activity against pure SMS1 and SMS2 has been reported for the first time (Qi et al.Bioorg Med Chem Lett, 2017, 27(15), 3511-3515), but its activity needs to be further improved

Hokkaido University in Japan announced the inhibitory activity IC of homogenate cells with high expression of human protein 50 An SMS2 inhibitor with a value of 130nM, but its human SMS1 activity has not been reported (JP2017128518A)

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