Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-12
2001-12-25
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S374000, C514S376000
Reexamination Certificate
active
06333328
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel and known benzoxazole derivatives, more particularly to a serotonin5-HT
3
receptor antagonist or a serotonin 5-HT
3
receptor partial activator, which has been developed on the basis of the effective and selective action of said derivatives upon serotonin 5-HT
3
receptors that are distributed in smooth muscles such as of digestive organs and the like and in central nervous system, intestinal nervous system and the like.
BACKGROUND OF THE INVENTION
It has been revealed that serotonin 5-HT
3
receptor antagonists can inhibit nausea and emesis as side effects caused by the use of cisplatin and the like carcinostatic agents and by radiation treatments, and several compounds thereof are now used in the clinical field. In addition to this, development on their use as digestive organ function controlling drugs has recently been examined.
The inventors of the present invention have already found that certain benzoxazole derivatives are possessed of serotonin 5-HT
3
receptor antagonism (JP-A-6-345744; the term “JP-A” as used herein means an “unexamined published Japanese patent application”).
When a compound having only serotonin 5-HT
3
receptor antagonism is administered as a digestive organ function controlling drug, it can inhibit diarrhea but poses a problem of frequently causing constipation as a side effect.
SUMMARY OF THE INVENTION
In view of the above, it therefore becomes an object of the present invention to provide a serotonin 5-HT
3
receptor partial activator which is possessed of not only serotonin 5-HT
3
receptor antagonism but also serotonin 5-HT
3
receptor activating action and is useful in getting rid of constipation side effect.
Using an evaluation test system in which serotonin 5-HT
3
receptor antagonizing and activating actions are judged by a guinea pig excised ileum contraction action which can be used as an index of the serotonin 5-HT
3
receptor activating action upon digestive organs, the inventors of the present invention have found that certain compounds among the benzoxazole derivatives disclosed in JP-A-345744 are possessed of serotonin 5-HT
3
receptor partial activity. As a result of subsequent synthesis and evaluation studies, it was found that certain novel or known benzoxazole derivatives are possessed of not only serotonin 5-HT
3
receptor antagonism but also serotonin 5-HT
3
receptor activating action and are useful as strong serotonin 5-HT
3
receptor partial activators. The present invention has been accomplished on the basis of these findings.
Accordingly, the gist of the present invention resides in the compounds of the following formulae (1) to (3):
wherein R
1
to R
4
may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or optional two groups of R
1
to R
4
may be linked together to form a ring structure which is a 5- or 6-membered ring composed of carbon atoms alone or carbon atoms and 1 to 2 hetero atoms, selected from a cyclohexane ring, a benzene ring, a pyridine ring, a piperidine ring and a pyrrolidine ring; and Y represents a saturated or unsaturated, substituted or unsubstituted 4- to 8-membered hetero ring containing 1 to 3 nitrogen atoms as the ring constituting atoms and carbon atoms as the remaining atoms, which is selected from the group consisting of an azetidine ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, an imidazole ring, a pyrazinyl ring, a pyridazinyl ring, a triazole ring, a homopiperidine ring, a 1,4-diazacyclooctanyl ring and a 1,5-diazacyclooctanyl ring;
wherein R
1
to R
4
may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R
1
and R
2
may be linked together to form a ring structure, namely a benzene ring, with the proviso that compounds in which all of R
1
to R
4
are hydrogen atoms are excluded; R
5
represents a hydrogen atom, a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; and m is an integer of 1 to 4; and
wherein R
1
to R
4
may be the same or different from one another and each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkenyl group or a substituted or unsubstituted amino group, or two groups of R
1
and R
2
may be linked together to form a ring structure, namely a benzene ring, with the proviso that compounds in which all of R
1
to R
4
are hydrogen atoms are excluded; R
5
and R
6
may be the same or different from each other and each represents a substituted or unsubstituted lower alkyl group or a substituted or unsubstituted lower alkenyl group; m is an integer of 1 to 4; and X
−
represents a halogen ion.
Further, the second aspect of the present invention resides in a serotonin 5-HT
3
receptor partial activator containing, as an active ingredient, the compounds of any one of the formulae (1) to (3) or a compound represented by the formula (4) shown hereinafter, for example, for use in the treatment and prevention of functional disorders of digestive organs and diarrhea.
Other objects and advantages of the present invention will be made apparent as the description progresses.
DETAILED DESCRIPTION OF THE INVENTION
In the aforementioned formula (1), examples of the ring structure represented by Y include an azetidine ring, a pyrrolidine ring, a piperidine ring, a pyridine ring, an imidazole ring, a pyrazinyl ring, a pyridazinyl ring, a triazole ring, a homopiperidine ring, a 1,4-diazacyclooctanyl ring and a 1,5-diazacyclooctanyl ring. Preferably, Y is 4-pyridinyl group, 4-piperidinyl group, 4-homopiperidinyl group, 3-pyrrolidinyl group, 1-(1,4-diazacyclooctanyl) group or 1-(1,5-diazacyclooctanyl) group.
The substituent of Y is a group which is linked to a nitrogen atom of Y and selected from the group consisting of a straight or branched C
1
-C
4
alkyl group and a straight or branched C
2
-C
4
alkenyl group, and at least one hydrogen atom of the alkyl or alkenyl group may be substituted with a substituent group which may be selected from the group consisting of a hydroxyl group, a halogen atoms, a carbamoyl group, an amino group and a cyano group.
Particularly preferred compounds of the formula (2) are those in which R
1
to R
4
may be the same or different from one another and each represents a hydrogen atom, a halogen atom or a substituted or unsubstituted lower alkyl group, or two groups of R
1
and R
2
may be linked together to form a benzene ring; R
5
is a substituted or unsubstituted lower alkyl group; and m is an integer of 2 or 3, with the proviso that compounds in which all of R
1
to R
4
are hydrogen atoms are excluded because such compounds are disclosed in JP-A-6-345744.
Definition
According to this specification, the alkyl or alkenyl as a group or a part of a group may be either straight chain or branched chain. Also in this specification, the term halogen atom means fluorine, chlorine, bromine or iodine atom.
Compounds of Formulae (1) to (3)
In the formulae (1) to (3), the lower alkyl group represented by any one of R
1
to R
6
is a C
1
-C
4
alkyl group, and at least one hydrogen atom of the alkyl group may be substituted with a substituent group which may be selected from the group consisting of a halogen atom, a hydroxyl group, a carbamoyl group, an amino group and a cyano group.
The lower alkenyl group represented by any one of R
1
to R
4
is a C
2
-C
4
alkenyl group, and at least one hydrogen atom of the alkenyl group may be substituted with a substituent group which may be selected from the group consisting of a hydroxyl group, a halogen atoms, a carbamoyl group, an amino group and a cyano group.
Examples of the substituent group of the amino
Iwamatsu Katsuyoshi
Kobayashi Kazuko
Konno Fukio
Sato Yasuo
Shudo Koichi
Meiji Seika Kaisha Ltd.
Sughrue & Mion, PLLC
Weddington Kevin E.
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