Novel glutaminyl cyclase inhibitors and the use thereof in treatment of various diseases

Abstract

The invention relates to chemistry of organic substances, pharmacology and medicine, and concerns treating diseases associated and with aberrant activity of cells of the immune system, more particularly for treating lung, respiratory tract and abdominal diseases, radiation sickness, pain syndrome and other diseases by using compounds of formula (A), wherein R1 is a -C(O)-R2-C(O)- or -R2-C(O)- group, where R2 is a -(CH2)n- group optionally substituted with one or two C1-C6 alkyls, or phenyl, and n is an integer from 0 to 4; wherein the compounds are selected from a group consisting of the compounds as set out in the description. These compounds, as well as pharmaceutically acceptable salts thereof, are highly effective in inhibiting glutaminyl cyclase, which is involved, in particular, in post-translational modification of chemokines and chemotaxis of monocytes, macrophages and other cells of the immune system. This invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula (A) as defined above.

Description

technical field [0001] The present invention relates to the chemistry, pharmacology and medicine of organic compounds, and to the treatment of diseases associated with abnormal activity of cells of the immune system, especially the treatment of lung, respiratory and abdominal diseases. The invention also relates to the treatment of radiation sickness and pain syndrome, among other diseases, by the use of compounds that effectively inhibit the enzyme glutaminyl cyclase, which is particularly involved in the post-translational modification of chemokines and cells of the immune system chemotaxis. Background technique [0002] Chemotaxis or directed movement of cells of the immune system with concentration gradients of some endogenous and exogenous substances (chemoattractants) is one of the main components of the functional cells of the immune system. Excessive influx of immune system cells often leads to overactivity of immune system cells and damage to surrounding organs and...

AI Technical Summary

Problems solved by technology

The introduction of aliphatic substituents reduces the metabolic stability of the compound

Furthermore, the introduction of aliphatic substituents increases the hydrophobicity of the compounds and facilitates the penetration of the compounds across the blood-brain barrier, which is apparently undesirable for suppressing abnormal activity of immune system cells and could potentially cause side effects

[0016] So far, there are no drugs available as glutaminyl cyclase inhibitors for the treatment of diseases associated with abnormal activity of immune system cells, and therefore there is still a need for new effective drugs based on glutaminyl cyclase inhibitors development and practical application

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