Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-01
2004-03-02
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S309000
Reexamination Certificate
active
06699891
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition for use as an NPY Y5 receptor antagonist, specifically, anti-obestic agent and novel compounds having an anti-obestic activity.
BACKGROUND ART
Neuropeptide Y (hereinafter referred to as NPY) is a peptide which consists of 36 amino acid residues and was isolated from porcine brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.
It has been reported that NPY possesses a stimulating activity of food intake, an anti-seizure activity, a learning-promoting activity, an anti-anxiety activity, an anti-stress activity etc. in central nervous system, and it may be pivotally involved in the central nervous system diseases such as depression, Alzheimer's disease and Parkinson's disease. NPY is thought to be associated with the cardiovascular diseases, since it induces a contraction of smooth muscles such as blood vessels or cardiac muscles in the peripheral tissues. Furthermore, NPY is also known to be involved in the metabolic diseases such as obesity, diabetes, and hormone abnormalities (Trends in Pharmacological Sciences, Vol.15, and 153 (1994)). Therefore, an NPY receptor antagonist is expected as a medicine for preventing or treating various diseases involved in the NPY receptor.
Subtypes of Y1, Y2, Y3, Y4, Y5, and Y6 have now been identified as the NPY receptor (Trends in Pharmacological Sciences, Vol.18, and 372 (1997)). It has been suggested that the Y5 receptor is at least involved in the feeding behavior and its antagonist is expected as an anti-obestic agent (Peptides, Vol.18, and 445 (1997)).
Quinazoline compounds having similar structures to those of the compounds of the present invention and exhibiting an NPY receptor antagonistic activity are described in WO97/20820, WO97/20821, WO97/20823 and the like. In addition, it is described that urea derivatives having a sulfonamide group and amide derivatives having a sulfonyl group in WO 99/64349 and benzyl sulfonamide derivatives in EP1010691-A, have an NPY antagonistic activity.
Compounds having similar structures to those of the compounds of the present invention are described in JP59-16871-A and WO97/15567. Their activities are quite different from that of the present invention and these documents do not suggest the present invention.
DISCLOSURE OF INVENTION
The object of the present invention is to provide a superior pharmaceutical composition for use as an NPY Y5 receptor antagonist and novel compounds having the activity.
The present invention provides
[1] A pharmaceutical composition for use as an NPY Y5 receptor antagonist comprising a compound of the formula (I):
wherein R
1
is optionally substituted lower alkyl, optionally substituted cycloalkyl or optionally substituted aryl,
R
2
is hydrogen or lower alkyl, and R
1
and R
2
taken together may form lower alkylene,
n is 1 or 2,
X is optionally substituted lower alkylene,
optionally substituted lower alkenylene,
optionally substituted —CO-lower alkylene,
optionally substituted —CO-lower alkenylene or
wherein R
3
, R
4
, R
5
and R
6
are each independently hydrogen or lower alkyl,
is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene, optionally substituted arylene or optionally substituted heterocyclediyl and p and q are each independently 0 or 1,
—NR
2
—X— may be
wherein
is piperidinediyl, piperazinediyl, pyridinediyl, pyrazinediyl, pyrrolidinediyl or pyrrolediyl and U is single bond, lower alkylene or lower alkenylene,
Y is OCONR
7
, CONR
7
, CSNR
7
, NR
7
CO or NR
7
CS,
R
7
is hydrogen or lower alkyl, and
Z is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted amino, optionally substituted lower alkoxy, optionally substituted carbocyclyle or optionally substituted heterocyclyl,
prodrug, pharmaceutically acceptable salt or solvate thereof,
[2] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in [1] wherein R
2
is hydrogen or lower alkyl and Z is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted carbocyclyl, optionally substituted heterocyclyl or optionally substituted amino, provided that R
1
is optionally substituted C3 to C10 alkyl when Z is optionally substituted amino,
[3] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in [1] wherein R
1
is optionally substituted lower alkyl or optionally substituted cycloalkyl, X is optionally substituted lower alkylene, optionally substituted lower alkenylene or
wherein
is the same as defined in [1], and Z is optionally substituted lower alkyl, optionally substituted carbocyclyl or optionally substituted heterocyclyl,
[4] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in any one of [1] to [3] wherein R
1
is optionally substituted C3 to C10 alkyl,
[5] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in any one of [1] to [4] which is an anti-obestic agent,
[6] The pharmaceutical composition for use as an NPY Y5 receptor antagonist described in any one of [1] to [4] which is an anorectic agent,
[7] A method for treating and/or preventing obesity comprising administering an effective dose of an NPY Y5 receptor antagonist described in any one of [1] to [4],
[8] A method for suppressing food intake comprising administering an effective dose of an NPY Y5 receptor antagonist described in any one of [1] to [4],
[9] Use of an NPY Y5 receptor antagonist described in any one of [1] to [4] for manufacturing a medicine for treating and/or preventing obesity,
[10] Use of an NPY Y5 receptor antagonist described in any one of [1] to [4] for manufacturing a medicine for suppressing food intake,
[11] A compound of the formula (I):
wherein X is C2 to C6 alkylene or C3 to C6 alkenylene, R
1
is optionally substituted C3 to C10 alkyl or optionally substituted C5 to C6 cycloalkyl and the other symbols are the same as defined in [1], provided that Z is not lower alkylphenylamino,
hydroxy(lower)alkylphenylamino and acylphenylamino when Y is NR
7
CO,
prodrug, pharmaceutically acceptable salt or solvate thereof,
[12] The compound described in [11] wherein Z is optionally substituted lower alkyl or optionally substituted phenyl, prodrug, pharmaceutically acceptable salt or solvate thereof,
[13] A compound of the formula (I):
wherein X is
is optionally substituted cycloalkylene, optionally substituted cycloalkenylene, optionally substituted bicycloalkylene or optionally substituted piperidinylene, R
1
is optionally substituted C3 to C10 alkyl or optionally substituted C5 to C6 cycloalkyl and the other symbols are the same as defined in [1], prodrug, pharmaceutically acceptable salt or solvate thereof,
[14] The compound described in [13] wherein is optionally substituted cyclohexylene or optionally substituted piperidinylene and p and q are simultaneously 0, prodrug, pharmaceutically acceptable salt or solvate thereof,
[15] The compound described in [13] or [14] wherein Y is CONH, prodrug, pharmaceutically acceptable salt or solvate thereof,
[16] The compound described in any one of [13] to [15] wherein Z is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted pyridyl or optionally substituted benzopyranyl, prodrug, pharmaceutically acceptable salt or solvate thereof,
[17] A compound of the formula (I):
wherein X is
R
1
is optionally substituted C3 to C10 alkyl or optionally substituted C5 to C6 cycloalkyl,
Z
Hanasaki Kohji
Kawanishi Yasuyuki
Okada Tetsuo
Takenaka Hideyuki
Chang Ceila
Shionogi & Co. Ltd.
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