Colonic motor dysfunction remedies comprising aminothiazole...

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills

Reexamination Certificate

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C424S451000, C424S485000, C514S365000, C514S370000, C548S195000, C548S122000

Reexamination Certificate

active

06673368

ABSTRACT:

TECHNICAL FIELD
This invention relates to remedies for colonic motor dysfunction, and more specifically to colonic motor dysfunction remedies comprising aminothiazole derivatives as active ingredients. This invention is also concerned with a treatment method for colonic motor dysfunction.
BACKGROUND ART
From the anatomical viewpoint, the digestive tract is divided roughly into an upper digestive tract and a lower digestive tract. The upper digestive tract includes the esoplagus, the stomach and the duodenum, while the lower digestive tract includes the small intestine, the large intestine and the rectal. To diseases and symptoms which occur in the respective regions, treatments are applied correspondingly.
Illustrative of diseases of the upper digestive tract are diseases in the esophageal region, such as esophageal carcinoma, esophagostenosis and reflux esophagitis; diseases in the gastric region, such as gastric ulcer, gastritis and gastric cancer; diseases in the duodenal region, such as duodenal ulcer and duodenal cancer; and as diseases occurring commonly in the gastric region and duodenal region, NUD (Non-Ulcer Dyspepsia) and gastroduodenal motor dysfunction. Examples of symptoms of such diseases of the upper digestive tract with which gastroduodenal motor dysfunction is associated include epigastric malaise, nausea, vomitting, brash, anorexia, bellyache, and dilatation of the stomach.
Illustrative of diseases of the lower digestive tract are colon cancer, colon polyp, ulcerative collitis, Crohn's disease, irritable bowel syndromes, constipation, intestinal atony, and drug-induced motor dysfunction. Of these, irritable bowel syndromes, constipation, intestinal atony and drug-induced motor dysfunction are diseases attributable to motor dysfunction of the large intestine, and are known to develop a cathartic disorder, such as constipation or diarrhea, and/or bellyache. Drug-induced motor dysfunction, on the other hand, is known to occur as a result of use of a calcium antagonist, a psychotropic or an antidepressant [Cardiology, 89(suppl. 1), 10-15, 1998; J. Clin. Psychopharmacol., 19, 401-406, 1999; Pharmacotherapy, 11, 179-195, 1991].
As improvers for irritable bowel syndromes, trimebutine maleate, allosetron hydrochloride and tegaseroid maleate are known. Of these, trimebutine maleate has been found to give side effects on the central nerve system (sleep, dizziness and the like) via opioid receptors. With respect to allosetron hydrochloride and tegaseroid maleate which are effective for diarrheal IBS and constipated IBS, respectively, there is an outstanding concern about side effect of constipation as an excess effect because drug efficacy is developed via serotonin receptors.
As gastroprokinetic agents for the upper digestive tract, cisapride, metoclopramide, itopride hydrochloride, mosapride citrate and the like are known (Gastroenterology, 118, S32-S47, 2000). However, these improvers have been reported to be ineffective for constipation associated with irritable bowel syndromes which are diseases caused by colonic motor dysfunction (J. Clin. Pharmacol., 19, 617-625, 1979; Scand. J. Gastroenterol., 33, 128-131, 1998;Aliment. Pharmacol. Ther., 11, 387-394, 1997).
PCT International Publications WO96/36619 and WO98/17654 disclose that aminothiazole derivatives enhance gastric motor activity and improve epigastric malaise, nausea, vomitting, brash, anorexia, bellyache, and dilatation of the stomach. These publications, however, make no mention about improving effects on diseases of the lower digestive tract caused by colonic motor dysfunction.
There is, accordingly, an outstanding desire for the development of improvers for colonic motor dysfunction, which are free of such side effects as those observed on the conventional irritable bowel syndrome improvers and caused via opioid receptors or serotonin receptors.
DISCLOSURE OF THE INVENTION
The present invention provides a colonic motor dysfunction remedy comprising, as an active ingredient, an aminothiazole derivative represented by the following formula (I) or a salt or hydrate thereof:
wherein R
1
, R
2
and R
3
may be the same or different and each independently represent a hydrogen atom or a hydroxyl, lower alkyl, lower alkoxy, amino, nitro or cyano group, R
4
and R
5
may be the same or different and each independently represent a hydrogen atom or a lower alkyl group, and n stands for an integer of from 2 to 4.
The present invention also provides use of an amino-thiazole derivative represented by the formula (I) or a salt or hydrate thereof for the production of a colonic motor dysfunction remedy.
The present invention also provides a treatment method for colonic motor dysfunction, which comprises administering an effective amount of an aminothiazole derivative represented by the formula (I) or a salt or hydrate thereof.
BEST MODES FOR CARRYING OUT THE INVENTION
In the aminothiazole derivative (I) useful in the practice of the present invention, the term “lower alkyl” means a linear, branched or cyclic, saturated hydrocarbon group which preferably has 1 to 6 carbon atoms. On the other hand, the term “lower alkoxy” means a group formed of a linear, branched or cyclic, saturated hydrocarbon, which preferably has 1 to 6 carbon atoms, and an oxygen atom bonded to the hydrocarbon.
Accordingly, illustrative of the “lower alkyl group” as R
1
, R
2
, R
3
, R
4
and R
5
are linear, branched or cyclic alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl, hexyl, 1-methylpentyl, 2-methyl-pentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, and cyclohexyl. Among these, more preferred lower alkyl groups are linear or branched alkyl groups having 1 to 4 carbon atoms. Particularly preferred as R
4
and R
5
is isopropyl. Particularly preferred as R
1
, R
2
and R
3
are H, hydroxy, methoxy, amino, nitro and cyano.
Illustrative of the “lower alkoxy group” as R
1
, R
2
and R
3
are linear, branched or cyclic alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, isopentoxy, tert-pentoxy, 1,2-dimethylpropoxy, neopentoxy, 1-ethylpropoxy, cyclopentoxy, hexyloxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, isohexyloxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-methyl-1-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethyl-propoxy, and cyclohexyloxy. Among these, more preferred lower alkoxy groups are linear or branched alkoxy groups having 1 to 4 carbon atoms. Particularly preferred is methoxy.
As n, 2 is particularly preferred.
Preferred examples of the aminothiazole derivative (I) useful in the practice of the present invention can include compounds in which R
1
, R
2
and R
3
are the same or different and each independently represent a hydroxyl group or a linear, branched or cyclic alkoxy group having 1 to 6 carbon atoms, specifically a methoxy group or one of R
1
, R
2
and R
3
is an amino, nitro or cyano group and the remaining two substituents are hydrogen atoms; R
4
and R
5
are the same and each represent an alkyl group having 1 to 6 carbon atoms, specifically an isopropyl group; and n is 2. Illustrative of particularly preferred compounds are
N-(N′,N′-diisopropylaminoethyl)-[2-(2-hydroxy-4,5-dimethoxy benzoylamino)-1,3-thiazol-4-yl] carboxamide,
N-(N′,N′-diisopropylaminoethyl)-[2-(3-cyano-benzoylamino)-1,3-thiazol-4-yl]carboxamide, and
N-(N′,N′-

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