Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-09
2003-03-04
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S550000
Reexamination Certificate
active
06528504
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to 5,11-dihydrodibenzo [b,e][1,4]oxazepine derivatives antagonistic to calcium channel and useful for treating or preventing abnormal motor functions of gastrointestinal tracts, particularly intestinal diseases such as irritable bowel syndrome, stereoisomers thereof, pharmacologically acceptable salts thereof or hydrates thereof, and pharmaceutical compositions containing them as active ingredients.
It is disclosed in, for example, European Patent No. 0404359A1 that 5,11-dihydrodibenzo[b,e][1,4]thiazepine derivatives are usable as calcium channel antagonists selectively effective on gastrointestinal tracts. Quinn, P. et al., Brit. J. Pharmacol. 1994, 112 (Suppl.), Abst 573P and Wallis R. M. et al. Brit. J. Pharmacol. 1994, 112 (Suppl.), Abst. 574P disclose that (S)-5-[[1-(4-methoxyphenyl)ethyl]pyrrolidine-2-ylmethyl]-5,11-dihydrodibenzo[b,e][1,4]thiazepine maleate which is one of derivatives of those compounds has effects similar to the effects of them. Further, International Patent No. 9733885A1 discloses 5-(2-pyrrolidinyl-methyl)-5,11-dihydrodibenzo [b,e][1,4]oxazepine derivatives as medicines for improving motor insufficiency of gastrointestinal tracts. However, the activity and selectivity of these compounds toward gastrointestinal tracts are yet insufficient, and another defect of them is that they have an anticholinergic effect which causes side effects such as thirstiness and mydriasis.
As social environments have been complicated recently, many of people feel the severe stress and patients with irritative bowel syndrome having cardinal symptoms of irregular bowel movement and abdominal pain are increasing in number. Medicines used for improving these diseases are, for example, cholinergic blocking agents, laxatives, antidiarrheal agents, intestinal drugs, mucosal paralyzers, gastrointestinal function regulators, autonomic nerve regulators, Chinese medicines, anxiolytic agents, antidepressant agents, sleep promoting drugs and neurotropic agents. However, the clinical effects of these medicines are yet insufficient and, in addition, they are not always satisfactory from the viewpoint of side effects of them. Under these circumstances, the development of medicines of a new type for improving the gastrointestinal function regulators, which have no side effect, is demanded.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide new compounds having an excellent effect of improving the gastrointestinal function.
Another object of the present invention is to provide a pharmaceutical composition containing the new compound.
Calcium channel antagonists having an effect of inhibiting the smooth muscle contraction are effective against diseases caused by an abnormal acceleration of contraction of intestinal tracts such as intestinal diseases, e.g. irritative bowel syndrome. In fact, it was reported that calcium channel antagonists such as nicardipine and verapamil are effective against irritative bowel syndrome [Am. J. Gastroenterol., 80, 317 (1985), Gut, 28, 1609 (1987), J. Clin. Psychiatry, 48, 388 (1987) and Pharmacol. Ther., 60, 121 (1993)]. However, the calcium channel antagonists are scarcely used for the clinical treatment because of the main effect of them on the cardiovascular system. Under these circumstances, the inventors made intensive investigations on the development of calcium channel antagonists selective to the intestinal tracts but having only a low toxicity or in other words, ineffective on cardiovascular system for the purpose of obtaining therapeutic agents for intestinal diseases such as abnormal motor functions of gastrointestinal tracts, particularly irritable bowel syndrome. After the investigations, the inventors have found that compounds represented by following general formula [Ia], [Ib] or [Ic] have calcium channel antagonistic activity selective to the intestinal tracts and, therefore, they are effective as agents for regulating gastrointestinal function. The present invention has been completed on the basis of this finding. These compounds have excellent pharmacological effects and, in addition, they are highly soluble in water. It is expected, therefore, that when they are orally administered, they are rapidly absorbed well. It is also expected that when they are used in the form of a liquid preparation, the production of the preparation is easy.
Namely, the present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives of following general formula [Ia], [Ib] or [Ic], stereoisomers thereof, pharmacologically acceptable salts thereof or hydrates thereof, and pharmaceutical compositions containing them as active ingredients:
wherein R
1
to R
5
may be the same or different from each other and they each represent hydrogen atom, a halogen atom, cyano group, hydroxyl group, a lower alkyl group, a lower alkoxyl group, amino group or a lower alkylamino group, or R
1
and R
2
, R
2
and R
3
, R
3
and R
4
or R
4
and R
5
together represent —O(CH
2
)
n
O— group (n being 1, 2 or 3), R
6
represents hydrogen or a lower alkyl group, Y represents methylene group, oxygen atom, sulfur atom or an alkylamino group, A represents CH
2
, CHOH, CO or O, B represents CH
2
, CHOH or CO, or A-B represents CH═CH, and D represents CH
2
, CH
2
—CH
2
or CH
2
—CH
2
—CH
2
, or B-D represents CH
2
.
BEST MODE FOR CARRYING OUT THE INVENTION
In R
1
to R
5
in [Ia], [Ib] and [Ic] in the general formula, the halogen atoms include fluorine atom, chlorine atom, etc., the lower alkyl groups include those having 1 to 5 carbon atoms such as methyl group, ethyl group and n-propyl group, the lower alkoxyl groups include those having 1 to 5 carbon atoms such as methoxyl, ethoxyl and n-propoxyl group, the lower alkylamino groups include monoalkylamino groups and dialkylamino groups, and —O(CH
2
)
n
O— groups include methylenedioxy group, ethylenedioxy group and propylenedioxy group. Among them, the halogen atoms are preferably fluorine atom and chlorine atom, and the lower alkyl groups are preferably those having 1 to 3 carbon atoms. The lower alkoxyl groups are preferably those having 1 to 3 carbon atoms. The monoalkylamino groups and dialkylamino groups are preferably those wherein the alkyl groups have 1 to 5 carbon atoms, more preferably those wherein the alkyl groups have 1 to 3 carbon atoms.
A-B-D is preferably any of CH
2
—CH
2
, CO—CH
2
, CHOH—CH
2
, CHOH—CH
2
—CH
2
, CH
2
—CHOH—CH
2
, CH═CH—CH
2
, CO—CH
2
—CH
2
, O—CH
2
—CH
2
, CH
2
—CO—CH
2
or CH
2
—CH
2
—CH
2
.
In general formula [Ia] in the present invention, Y is preferably methylene group and R
1
to R
5
are not hydrogen atoms at the same time. In the present invention, one of R
1
to R
5
is preferably amino group or a lower alkylamino group and the others are hydrogen atom, or R
2
or R
3
is a halogen atom, a lower alkyl group or a lower alkoxyl group. It is also preferred that either R
2
or R
3
or both of R
2
and R
3
are methoxyl group, or R
2
and R
3
together form methylenedioxy group, and R
1
, R
4
and R
5
are hydrogen atom. It is further preferred that R
3
is methoxyl group, and R
1
, R
2
, R
3
, R
4
and R
5
are each hydrogen atom, Y is methylene group, and A and B-D are CH
2
. When Y is methylene group, preferably the absolute configuration at the 2-position of the piperidine ring is R-configuration, and when Y is not methylene group, the position thereof in the nitrogen-containing 6-membered ring has a configuration similar to it. In those compounds, examples of particularly preferred compounds are (R)-5,11-dihydro-5-[1-(4-methoxyphenethyl)piperidine-2-ylmethyl]dibenzo [b,e][1,4] oxazepine (Ia-1), (R)-5,11-dihydro-5-[1-(4-dimethylaminophenethyl) piperidine-2-ylmethyl]dibenzo[b,e][1,4]oxazepine (Ia-2), (R)-5,
Sakata Katsutoshi
Sasaki Noriko
Takahashi Kazuyoshi
Tsuji Takashi
Ajinomoto Co. Inc.
Coleman Brenda
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