Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-02
2002-01-22
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S593000
Reexamination Certificate
active
06340678
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceuticals and, more particularly, it relates to 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivatives or salts thereof and also to a drug composition containing the same and a pharmaceutically acceptable carrier.
BACKGROUND OF THE INVENTION
Oxytocin is a peptide hormone which is mainly synthesized in hypothalamus and is secreted after an axonal transport in nerve cells to posterior pituitarity. It has been known already that an extract from posterior pituitarity has an activity of uterus contraction and of milk secretion, and two years after the elucidation of its amino acid structure in 1953, clinical application of synthetic oxytoxin started. As such, clinical application firstly proceeded for oxytocin, and it was used as a drug for controlling labor pains while analysis of physiological mechanism of oxytocin has not made so much progress. As the reasons therefor, it can be considered that since oxytocin is a small amino acid peptide, measurement of its concentration in blood was difficult, blood and tissues contain large amounts of oxytocin decomposition enzymes and that analysis of oxytocin receptor was difficult (cf.
Sanka to Fujinka,
10: 59-65, 1995).
It has been recently clarified that besides the above-mentioned two classic physiological actions, oxytocin has various physiological actions in addition to the area of delivery such as central action for maternal behavior and for memory, action to functional regulation of sexual glands, action as a neurotransmitter, and action in immune system (
Kusuri no Kaisetsu,
Vol. 30, No. 10: 1164-1167, 1994). Oxytocin receptor was cloned, too (Kimura, T. et al.,
Nature,
356: 526-529, 1992), and it is now possible to investigate the expression of the receptor in terms of molecular biology. It has been known that oxytocin receptor is mostly expressed in uterine muscle and endometrium in the cases of labor pain onset in term delivery.
Since the above-mentioned expression of oxytocin receptor in uterine muscle and endometrium increases in the cases of early delivery, the effect as a suppressor for uterine contraction at early delivery can be expected, and accordingly, investigation for oxytocin antagonist has started. As a drug which is the first runner in the clinical application, atosiban which is a peptidal oxytocin antagonist is available at present, and there is a report on the cases where it significantly lowers the frequency of uterine contraction without changes in heart rate and blood pressure during that time (Goodwin, T. M. et al.,
Am. J. Obstet. Gynecol.,
170: 474-478, 1994). It has been ascertained that atosiban has an antagonistic action not only to oxytocin receptor but also to vasopressin V
1
receptor.
Incidentally, oxytocin antagonists are mentioned in European Patent No. 450,761A and in Unexamined Published Japanese Patent Application No. 5-213,865. In addition, benzoheterocyclic derivatives represented by the following formula are mentioned in WO95/34540, and with respect to their vasopressin-acting/antagonizing action, specific pharmacological test methods, and the test results are mentioned therein. However, so far as an oxytocin-antagonizing action of these compounds is concerned, it is mentioned quite briefly only in one line, and any specific pharmacological test method and test results thereof are not disclosed at all:
R
2
is a hydrogen atom, . . . (omitted) . . . ; R
3
is a hydrogen atom, . . . (omitted) . . . ; or R
2
and R
3
are taken together to form an oxo group, a lower alkylidene group, a lower alkoxy-substituted lower alkylidene group, a lower alkoxycarbonyl-substituted lower alkylidene group, or a phenyl-substituted lower alkylidene group; X is a methylene group, a simple linkage, or a group represented by the formula, ═CH— or NR
14
; and for others, refer to the above-cited patent specifications.)
DISCLOSURE OF THE INVENTION
We, the present inventors conducted intensive studies for finding compounds having an antagonistic action to oxytocin. As a result, it has been found that novel 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivatives have a strong oxytoxin-antagonizing action, whereupon the present invention has been achieved.
Thus, the present invention relates to 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivatives or salts thereof having oxytoxin antagonism, as represented by the following formula (I). The present invention also relates to a drug composition, particularly an oxytocin antagonist, containing the 4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzoazepine derivative or its salt and a drug acceptable carrier:
(In the formula, each of the symbols has the following meaning:
ring A: a 5-membered heteroarylene group;
ring B: an optionally substituted aryl group or a 5- to 6-membered heteroaryl group;
D: a carbonyl group or a lower alkylene group;
R
1
: a group represented by formula, NR
3
R
4
, an —O-lower alkyl group, or OH;
R
2
: an optionally halogen atom-substituted lower alkyl group, an —O-lower alkyl group, an —S-lower alkyl group, or a —CO-lower alkyl group;
R
3
, R
4
: same or different and each is
1) a hydrogen atom,
2) a lower alkyl group (the lower alkyl group may be substituted with OH, an optionally protected amino group, an optionally protected mono-lower alkylamino group, a di-lower alkylamino group, an optionally lower alkyl group-substituted 5- to 7-membered saturated heterocyclic group, a 5- to 6-membered heteroaryl group, or an aryl group),
3) a cycloalkyl group,
4) an optionally lower alkyl group-substituted 5- to 7-membered saturated heterocyclic group,
5) a 5- to 6-membered heteroaryl group,
6) an aryl group, or
7) an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic group formed by integration of the formula, NR
3
R
4
(the 5- to 7-membered nitrogen-containing heterocyclic group may be fused with a benzene ring or with a 5- to 6-membered heteroaryl group); (in the 5- to 7-membered saturated heterocyclic group, the 5- to 7-membered nitrogen-containing heterocyclic group and the 5- to 6-membered heteroaryl group in the above 2), 4), 5) and 7), a group having a cyclic secondary amine may be one wherein the amine is protected); and
n: 0, 1 or 2).
The compounds of the present invention are characterized by having a chemical structure in which a difluoro group is present on a ring carbon atom adjacent to an azepine ring carbon atom substituted with a (substituted) methylidene group. Since the compounds of the present invention have a difluoro group, they are not isomerized but have good stability even in vivo.
Preferred compounds of the present invention are those in which R
1
is a group represented by the formula, NR
3
R
4
wherein R
3
and R
4
are an optionally lower alkyl-substituted 5- to 7-membered saturated heterocyclic group or a 5- to 6-membered heteroaryl group, or the formula, NR
3
R
4
may be integrated to form an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic group. More preferred compounds are those in which R
2
is an optionally halogen atom-substituted lower alkyl group.
The compounds (I) of the present invention will be further illustrated below. Unless otherwise mentioned in the definitions for the formula in this specification, the term “lower” means a carbon chain, either straight or branched, having from 1 to 6 carbon atoms. The “lower alkylene group” stands for an alkylene group having one to six carbon atoms, and its preferred examples are a methylene group, an ethylene group, a propylene group, a butylene group, etc.
The “5-membered heteroarylene group” is a cyclic group where two linkages are available from a 5-membered monocyclic heteroaryl group, and specific examples thereof are furandiyl, thiophendiyl, pyrroldiyl, imidazoldiyl, thiazoldiyl, oxazoldiyl, pyrazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, thiadiazoldiyl, triazoldiyl, tetrazoldiyl, etc. Preferred are furandiyl, thiophendiyl, imidazoldiyl, thiazoldiyl, oxazoldiyl, pyrazoldiyl, isoxazoldiyl, and triazoldiyl, with thiazoldiyl, imida
Kawano Noriyuki
Matsuhisa Akira
Murakami Takeshi
Sakuda Shuichi
Shibasaki Kumiko
Coleman Brenda
Finnegan Henderson Farabow Garrett & Dunner LLP
Yamanouchi Pharmaceutical Co. Ltd.
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