Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-20
2003-07-22
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S456000, C514S459000
Reexamination Certificate
active
06596759
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a medicament useful for therapeutic and/or preventive treatment of irritable bowel syndrome which comprises a particular class of alkylenedioxybenzene derivative as an active ingredient.
2. Discussion of Background Information
Irritable bowel syndrome is caused by factors such as stress, and its main symptoms include somatic symptoms in the digestive system such as abdominal pain and diarrhea. The disease was previously called spastic colon, nervous colitis, mucous colitis, functional colitis, or colonic neurosis. However, the term “bowel” has been used rather than “colon”, because the disease is not localized in the large intestine, but the disease is considered as functional disorders of the digestive tract including the small intestine as well. It has been suggested that the disease is caused by physiological factors such as hormones, external stimulations such as food and stress, emotional factors, hereditary body constitutions and the like.
In general, it is difficult to completely eliminate symptoms in the treatment of irritable bowel syndrome. Typically, purposes of therapeutic treatment is to reduce a variety of complaints and to improve conditions so as to be sufficient for daily life. Applicable therapeutic treatments include psychotherapy, life guidance and diet therapy, as well as drug therapy as symptomatic therapy against the patient's complaints (see, references mentioned herein). As drug therapy for irritable bowel syndrome, opioid agonists such as loperamide or anticholinergic agents such as mepenzolate bromide and timepidium bromide have been used to control hypermotility of the digestive tract, and benzodiazepine drugs such as diazepam have been prescribed for anxiety, insomnia and the like. However, no drug therapy that enables causal therapy has been established.
Alkylenedioxybenzene derivatives represented by the following general formula (I) are known:
wherein m represents an integer of from 2 to 5, and n represents an integer of from 1 to 3 (Japanese Patent Unexamined Publication (Kokai) Nos. 3-264528/1991 and 4-288072/1992). These publications disclose that the alkylenedioxybenzene derivatives represented by the general formula bind to a serotonin-lA receptor subtype to exhibit an anti-conflict action, and that the derivatives are useful for therapeutic treatment of anxiety disorders, schizophrenia, circulatory psychosis and the like.
More specifically, affinities (Ki values) for the serotonin 1A receptor subtype are disclosed as for the meta-substituted compound wherein m is 3 and n is 2 (No. 1), the meta-substituted compound wherein m is 3 and n is 2 (No. 2), the meta-substituted compound wherein m is 3 and n is 3 (No. 3), the meta-substituted compound wherein m is 4 and n is 1 (No. 4), the meta-substituted compound wherein m is 4 and n is 3 (No. 6), the meta-substituted compound wherein m is 5 and n is 1 (No. 7), and the ortho-substituted compound wherein m is 3 and n is 1 (No. 13). These patent documents also disclose that the compounds of Nos. 1 to 3 have an anti-conflict action, and are useful for the treatment of anxiety disorders, schizophrenia, manic-depressive illness and the like.
Serotonin was revealed to participate in the regulation of intestinal motility, and effectiveness of serotonin-3 receptor subtype antagonists in inhibition of the intestinal motility has been suggested (Miyata et. al., J. Pharmacol. Exp. Ther., 261, pp.297-303, 1992). Serotonin-1A receptor subtype agonists are also known to inhibit rat defecation induced by the load of forced swimming stress (Foreman et. al., Drug Dev. Res., 34, pp.66-85, 1995). However, although the forced swimming test has been established as a screening method for antidepressants, its adequacy as an animal model for irritable bowel syndrome has not yet been clarified. Further, tandospirone, one of the serotonin-1A receptor agonists, revealed to have improving effect on patients with irritable bowel syndrome in a double-blind test, but failed to give a significant difference in therapeutic efficacy compared with a placebo (Kimura et. al., Clinical Evaluation (Rinsho Hyoka), 20, pp.225-257, 1992). Japanese Patent Unexamined Publication (Kokai) Nos. 3-264528/1991 and 4-288072/1992 neither suggest nor teach that the aforementioned compounds have therapeutic efficacy for irritable bowel syndrome.
SUMMARY OF THE INVENTION
The present invention provides a medicament useful for preventive and/or therapeutic treatment of irritable bowel syndrome. The inventors of the present invention found that a particular class of alkylenedioxybenzene derivatives were effective in a pathologic model of irritable bowel syndrome and useful for preventive and/or therapeutic treatment of irritable bowel syndrome. The present invention was achieved on the basis of the above findings.
The present invention thus provides a medicament for preventive and/or therapeutic treatment of irritable bowel syndrome which comprises as an active ingredient a substance selected from the group consisting of alkylenedioxybenzene derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof, and hydrates thereof and solvates thereof:
wherein m represents an integer of from 2 to 5, and n represents an integer of from 1 to 3. As a preferred embodiment of the aforementioned medicament of the present invention, there is provided a medicament for preventive and/or therapeutic treatment of irritable bowel syndrome, which comprises as an active ingredient a substance selected from the group consisting of alkylenedioxybenzene derivatives represented by the aforementioned general formula (I) wherein n is 1 (most preferably 5-[3 [(2S)-(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzo-dioxol) and physiologically acceptable salts thereof, and hydrates thereof and solvates thereof.
According to another preferred embodiment, the aforementioned medicament for preventive and/or therapeutic treatment is provided as a pharmaceutical composition comprising a substance selected from the aforementioned group as an active ingredient together with a pharmaceutical additive.
From other aspects, there are provided use of a substance selected from the group consisting of the alkylenedioxybenzene derivatives represented by the aforementioned general formula (I) and pharmaceutically acceptable salts thereof, and hydrates thereof and solvates thereof for the manufacture of the aforementioned medicament for preventive and/or therapeutic treatment of irritable bowel syndrome; and a method for preventive and/or therapeutic treatment of irritable bowel syndrome, which comprises the step of administering to a mammal including a human an effective amount of a substance selected from the group consisting of the alkylenedioxybenzene derivatives represented by the aforementioned general formula (I) and pharmaceutically acceptable salts thereof, and hydrates thereof and solvates thereof.
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Abe et al., “Reduction of Wrap Restraint Stress-Induced Defecation by MKC-242, a Novel Benzodioxan Derivative, via HT1A-Receptor Agonist Action in Rats”, Jpn. J. Pharmacol., vol. 77, pp 211-217 (1998).
Miyata et al., “Role of the Serotonin3Receptor in Stress-Induced Defecation”, J. Pharmacol. Exp. Ther., vol. 261, pp 297-303, (1998).
Foreman et al., “Pharmacological Characterization of Enantiomers of 8-Thiomethyl-2-(di-n-propylamino)tetralin, Potent and Selective 5-HT1AReceptor Agonists”, Drug Dev. Res., vol. 34, pp 66-85
Abe Michikazu
Saito Ken-Ichi
Greenblum & Bernstein P.L.C.
Krass Frederick
Mitsubishi Chemical Corporation
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