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Use of a bisamide derivative of malonic acid for treating allergic diseases and other diseases in humans and animals

A technology for allergic rhinitis, use, applied in the field of organic chemistry, which can solve the problems such as the absence of antagonists of type 3 and type 4 histamine receptors

Active Publication Date: 2021-02-05
OBSHCHESTVO S OGRANICHENNOJ OTVETABTVENNOSTJU VALENTA INTELLEKT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Thus, to date there are no known drugs acting as antagonists of the type 3 and type 4 histamine receptors for the treatment of allergic diseases in humans

Method used

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  • Use of a bisamide derivative of malonic acid for treating allergic diseases and other diseases in humans and animals
  • Use of a bisamide derivative of malonic acid for treating allergic diseases and other diseases in humans and animals
  • Use of a bisamide derivative of malonic acid for treating allergic diseases and other diseases in humans and animals

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] Example 1. Study on the Effect of Compound I on Type 3 Histamine Receptor Activity

[0154] Compound I was dissolved in DMSO to a concentration of 100 mM; the stock solution was then serially diluted with DMSO. The maximum starting concentration of substances is 100 μM. Effects were determined at 8 concentrations of test compound; each concentration was tested in duplicate. The cells used in the experiments were CHO cells expressing the human type 3 histamine receptor, which were incubated with compound I after pre-incubation with histamine. The activity of the receptor was determined by intracellular cAMP concentration using fluorescence spectroscopy (Lim, H.D. et al. (2005) J. Pharmacol. Exp. Ther., 314:1310-1321).

[0155] In this study, compound I was found to be an antagonist of the type 3 histamine receptor and the IC 50 = 20 μM.

Embodiment 2

[0156] Example 2. Study of the Effect of Compound I on the Binding of Radiolabeled Ligands to Histamine Receptor Type 3

[0157] Compound I was dissolved in DMSO to a concentration of 300 mM; the stock solution was then serially diluted with DMSO. The maximum starting concentration of substances is 300 μM. Effects were determined at 10 concentrations of test compound; each concentration was tested in duplicate. Cells used in the experiments were CHO cells expressing the human type 3 histamine receptor, which were incubated with compound I after pre-incubation with [3H]Nα-methylhistamine (1 nM). The activity of Compound I was determined by the concentration of displaced radiolabeled ligand (Lovenberg, T.W. et al. (1999), Mol. Pharmacol., 55:1101-1107).

[0158] In this study, compound I was found to bind to the type 3 histamine receptor with a Ki value of 2.7 μΜ.

Embodiment 3

[0159] Example 3. Study of the Effect of Compound I on the Binding of Radiolabeled Ligands to Histamine Receptor Type 4

[0160] Compound I was dissolved in DMSO to a concentration of 300 mM; the stock solution was then serially diluted with DMSO. The maximum starting concentration of substances is 300 μM. Effects were determined at 10 different concentrations of test compound; each concentration was tested in duplicate. The cells used in the experiment were HEK-293 cells expressing the human histamine receptor type 4, which were incubated with compound I after pre-incubation with [3H]histamine (10 nM). The activity of compound I was determined by the concentration of displaced radiolabeled ligand (Liu, C. et al. (2001), J. Pharmacol. Exp. Ther., 299:121-130).

[0161] In this study, compound I was found to bind to the type 4 histamine receptor with a Ki value of 16 μΜ.

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PUM

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Abstract

The invention relates to therapy of diseases associated with the activity of histamine receptors, in particular therapy of allergic diseases, preferably therapy of perennial and persistent allergic rhinitis, pruritus, and also a series of other diseases associated with the activity of histamine receptors of type three and / or four, by means of the use of the compound NN'-bis(2-(1H-imidazol-5-yl)ethyl)malonamide (I). Said compound, and also the pharmaceutically acceptable salts, hydrates and solvates thereof, are antagonists of histamine receptors of type three and / or four. The present inventionalso relates to pharmaceutical compositions comprising a therapeutically effective amount of compound I.

Description

technical field [0001] The present invention relates to organic compound chemistry, pharmacology and medicine, and to the use of compounds that effectively inhibit the activity of type 3 (H3) and type 4 (H4) histamine receptors for the treatment of diseases associated with overactivation of histamine receptors, in particular For the treatment of perennial and persistent allergic rhinitis, type 3 (H3) and type 4 (H4) histamine receptors are specifically involved in the processes of vasodilation, edema and inflammation in the nasal cavity, and pain symptoms. Background technique [0002] Histamine receptors represent a class of G protein-coupled receptors that bind histamine as their major endogenous ligand. Histamine receptors are involved in many physiological processes associated with the development of various pathological conditions. In particular, histamine H1 or H2 receptor antagonists are widely used in the treatment of allergic and gastrointestinal disorders (Br J Ph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/12A61K31/4178A61P11/00A61P37/00
CPCA61K31/4178A61P37/08C07D403/12A61K45/06A61P17/04A61P11/00A61P37/00
Inventor 弗拉迪米尔·叶夫根尼耶维奇·涅博利辛
Owner OBSHCHESTVO S OGRANICHENNOJ OTVETABTVENNOSTJU VALENTA INTELLEKT