Therapeutic agent for trpv1-mediated disease

Abstract

An object of the present invention is to find a novel pharmacological action of a urea compound having a structure represented by the general formula [I]. The urea compound having a structure represented by the general formula [I] or a salt thereof has an excellent therapeutic effect on a TRPV1-mediated disease. In the formula, A represents a lower alkylene group or a lower alkenylene group; R1 represents a hydrogen atom, an alkyl group which may have a substituent or an alkenyl group which may have a substituent; and R2 and R3 are the same or different and represent a hydrogen atom or a lower alkyl group which may be substituted by a monocyclic cycloalkyl group, a polycyclic cycloalkyl group, or an aryl group.

Description

TECHNICAL FIELD[0001]The present invention relates to a therapeutic agent for a TRPV1-mediated disease containing a urea derivative as an active ingredient.BACKGROUND ART[0002]TRPV1 is a nonselective cation channel which belongs to the transient receptor potential (TRP) superfamily, contains six transmembrane domains, and has high permeability of calcium ions, and is also called vanilloid receptor 1 (VR1) or capsaicin receptor. As agonists for TRPV1, vanilloids such as capsaicin which is a pungent component in hot chili peppers and resiniferatoxin which is a capsaicin derivative are known. On the other hand, as antagonists for TRPV1, compounds such as iodoresiniferatoxin and capsazepine are known.[0003]TRPV1 is mainly located in sensory neurons, however, it is also expressed in non-neuronal tissues as well as neuronal tissues of epithelium, bone, bladder, gastrointestinal tract, lung, and many other visceral organs.[0004]It is known that TRPV1 is activated by a noxious stimulus such...

AI Technical Summary

Benefits of technology

[0025]As a result, these urea derivatives are found to be a TRPV1 agonist. Further, these urea derivatives are found to be useful as a therapeutic agent for TRPV1-mediated disease, particularly pain, overactive bladder, or gastrointestinal dysfunction because the derivatives have a therapeutic effect in experimental models of pain, overactive bladder, and gastrointestinal dysfunction, thereby accomplishing the present invention.

[0075]The activity of the present compound as a therapeutic agent for gastrointestinal dysfunction was studied using rat models for gastrointestinal mucosal blood flow rate and gastrointestinal dysfunction. As will be described in detail below, the present compound is a TRPV1 agonist and exhibited an excellent action of increasing the mucosal blood flow and an excellent therapeutic effect on gastric mucosal injury. Therefore, the present compound is useful as a therapeutic agent for gastrointestinal dysfunction, particularly upper gastrointestinal dysfunction such as gastric ulcer, duodenal ulcer, anastomotic ulcer, reflux esophagitis, non-erosive gastroesophageal reflux disease, upper gastrointestinal hemorrhage, acute gastritis, or chronic gastritis.

[0114]As is apparent from FIG. 4, the present compound suppressed the number of writhes in a dose-dependent manner in the acetic acid writhing model.

[0125]As is apparent from FIGS. 5 and 6, the present compound exhibited an excellent action of prolonging the micturition interval at an extremely low dose and the potency was higher than that of oxybutynin hydrochloride which is clinically used as a therapeutic agent for overactive bladder.

[0139]As is apparent from FIG. 8 and Table 3, the present compound exhibited a remarkable effect that it exhibited an action of inhibiting gastric mucosal injury with a potency comparable to that of omeprazole which is a therapeutic agent for peptic ulcer at a lower dose than that of omeprazole.

Problems solved by technology

However, most cases are idiopathic and the cause of overactive bladder cannot be identified, and it is inferred that several factors are involved in the onset of overactive bladder in combination.

However, a satisfactory therapeutic effect cannot be obtained in some patients, and medication compliance sometimes decreases due to discomfort such as dry mouth.

In the treatment of gastrointestinal dysfunction such as gastric ulcer, a compound which suppresses gastric acid secretion such as an H2 receptor inhibitor is used, however, a problem that ulcer relapse occurs when administration is discontinued and the like may sometimes arise (see Non-patent document 5).

In light of such circumstances, studies have been conducted as to whether compounds having various activities can be applied to a therapeutic agent for a TRPV1-mediated disease, however, the results are not always satisfactory, and further searches for a therapeutic agent for a TRPV1-mediated disease have been demanded.

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