Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-10
2003-05-13
Kifle, Bruck (Department: 1629)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S550000
Reexamination Certificate
active
06562808
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives, stereoisomers thereof, pharmacologically acceptable salts thereof and hydrates of them having a calcium channel-antagonistic effect and effective in treating and preventing intestinal diseases such as abnormal motor function of digestive tracts, particularly, irritable bowel syndrome, as well as pharmaceutical compositions containing them.
It is disclosed in, for example, European Patent No. 0404359A1 that 5,11-dihydrodibenzo[b,e][1,4]thiazepine derivatives are useful as calcium channel antagonists selectively effective on gastrointestinal tracts. In addition, Quinn P. et al and Wallis R. M. et al. also disclosed in Brit. J. Pharmacol. 1994, 112 (Suppl.), Abst 573P and Brit. Pharmacol. 1994, 112 (Suppl.) Abst 574P, respectively, that (S)-5-[1-(4-methoxyphenyl)ethyl]pyrrolidine-2-ylmethyl]-5,11-dihydrodibenzo[b,e][1,4]thiazepine maleate has the same effect as that described above. However, one of the defects of these compounds is that they have anticholinergic effect to cause side effects such as thirst and mydriasis.
As the social environment has become increasingly complicated, many people have been exposed to severe stress, and patients having irritable bowel syndrome mainly with irregular bowel movement and abdominal pain are increasing in number. Drugs given to the patients of such diseases include anticholinergics, laxatives, antidiarrheal drugs, intestinal drugs, mucosal paralyzing agents, drugs for controlling motor function of digestive tracts, autonomic drugs, Chinese orthodox medicines, antianxiety drugs, antidepressants, sleep promoting drugs and antipsychotic agents. However, the clinical effects of these drugs are yet insufficient and the drugs are not always satisfactory in view of their side effects. Under these circumstances, the development of a new-type drug having an excellent effect of improving the motor function of digestive tracts is demanded.
SUMMARY OF THE INVENTION
An object of the present invention is to provide new compounds having an excellent effect of improving the motor function of digestive tracts.
Another object of the present invention is to provide a pharmaceutical composition containing such new compounds.
Other objects of the present invention will be apparent from the following description and Examples given below.
It is generally considered that calcium channel antagonists are effective in treating intestinal diseases caused by abnormal acceleration of the contraction of intestinal tracts such as irritable bowel syndrome because they have a function of inhibiting the contraction of the smooth muscles. In fact, it was reported that calcium channel antagonists such as Nicardipine and Verapamil are effective on irritable bowel syndrome [Am. J. Gastroenterol., 80, 317 (1985); Gut. 28 1609 (1987); J. Clin. Psychiatry., 48, 388 (1987); an Pharmacol. Ther., 60, 121 (1993)]. However, these antagonists are rarely used clinically at present because of the main effects of the calcium channel antagonists on the cardiovascular system. Under these circumstances, the inventors made intensive investigations for the purpose of developing a calcium channel antagonist with low toxicity which is ineffective on the cardiovascular system but which is selectively effective on the intestinal tracts and is usable as a drug for abnormal motor function of intestinal tracts, particularly irritable bowel syndrome. After the investigations, the inventors have found that compounds represented by the following general formula [I-I] or [I-II] have calcium channel antagonistic activity selectively on the intestinal tracts and that they are usable as remedies for abnormal motor function of digestive tracts. The present invention has been completed on the basis of this finding.
Namely, the present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives represented by the following general formula [I-I] or [I-II], stereoisomers thereof, pharmacologically acceptable salts thereof and hydrates of them; and pharmaceutical compositions containing them as active ingredients, particularly pharmaceutical compositions for treating or preventing abnormal motor function of intestinal tracts:
wherein R
1
through R
5
may be the same or different from one another and they each represent a hydrogen atom, lower alkoxyl group, amino group or alkylamino group with the proviso that at least one of them represents the amino group or alkylamino group; R
6
and R
7
may be the same or different from one another and they each represent a hydrogen atom or hydroxyl group, or they together form ═O; and Y
1
represents a methylene group, sulfur atom or hydroxymethine group;
wherein R
11
through R
15
may be the same or different from one another and they each represent a hydrogen atom, halogen atom, cyano group, hydroxyl group, lower alkoxyl group, amino group or alkylamino group, or R
15
and R
11
, R
11
and R
12
, R
12
and R
13
or R
13
and R
14
together form —O(CH
2
)
n
O— group (n being 1, 2 or 3); Y
2
represents a methylene group, sulfur atom or hydroxymethine group; A represents CH
2
, CHOH, CO or O, B represents CH
2
or CHOH; or A—B represents CH═CH and D represents CH
2
, CH
2
—CH
2
or CH
2
—CH
2
—CH
2
.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The lower alkoxyl groups represented by R
1
through R
5
in above general formula [I-I] are preferably those having 1 to 5 carbon atoms, and more preferably those having 1 to 3 carbon atoms. The alkylamino groups represented by R
1
through R
5
include monoalkylamino groups and dialkylamino groups. The alkyl groups are preferably those having 1 to 5 carbon atoms and more preferably those having 1 to 3 carbon atoms.
In the present invention, it is preferred that one of R
1
through R
5
is an amino group or alkylamino group, and the balance is hydrogen atom. Further, in this case, R
6
and R
7
are each hydrogen atom. Y
1
is preferably methylene group.
R
1
and R
2
may be the same or different from each other and they each represent a hydrogen atom, amino group or alkylamino group in the present invention. It is preferred that R
1
and R
2
do not represent hydrogen atom at the same time and R
3
, R
4
and R
5
are each hydrogen atom. It is preferred in the present invention that both R
1
and R
2
represent an amino group or alkylamino group, and it is more preferred that one of R
1
and R
2
represents an amino group or alkylamino group and the other represents a hydrogen atom. It is also preferred that one of R
1
and R
2
represents an amino group or alkylamino group and the other represents a lower alkoxyl group. It is particularly preferred that R
2
represents an amino group or alkylamino group, and R
1
represents a hydrogen atom.
It is preferred in the present invention that R
6
and R
7
in general formula [I-I] each represent a hydrogen atom and Y
1
represents methylene group. In these compounds, particularly preferred compounds are those represented by the following formulae, i.e. (R)-5,11-dihydro-5-[1-[2-(4-dimethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-[2-(4-diethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-[2-(3-dimethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-[2-(3-methylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine and (R)-5,11-dihydro-5-[1-[2-(2-dimethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, as well as pharmaceutically acceptable salts thereof and hydrates of them.
Compounds [I-I] of the present invention can be produc
Sakata Katsutoshi
Sasaki Noriko
Takahashi Kazuyoshi
Tsuji Takashi
Ajinomoto Co. Inc.
Kifle Bruck
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