Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-29
2002-11-05
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S281000
Reexamination Certificate
active
06476038
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain amino substituted pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazines, preferably those which selectively and/or potently bind mammalian neuropeptide Y (NPY) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating physiological disorders associated with an excess of neuropeptide Y, especially feeding disorders, some psychiatric disorders, and certain cardiovascular diseases.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982 and subsequently found to be largely conserved across species. It belongs to a large family of peptides that includes, among others, peptide YY (PYY) and pancreatic peptide (PP). NPY is believed to be the most abundant peptide in the mammalian brain. It is also found in sympathetic neurons, and NPY-containing fibers have been found in peripheral tissues, such as around the arteries in the heart, the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Central injection of NPY elicits a multitude of physiological responses, such as stimulation of feeding, increase in fat storage, elevation of blood sugar and insulin, anxiolytic behaviors, reduction in locomotor activity, hormone release, increase in blood pressure, reduction in body temperature, and catalepsy. In the cardiovascular system, NPY is believed to be involved in the regulation of coronary tone, while in the gastrointestinal tract, PYY is reported to cause inhibition of gastric acid secretion, pancreatic exocrine secretion, and gastroinestinal motility. These effects appear to be selectively mediated by various NPY receptors which currently include the Y
1
, Y
2
, Y
3
, Y
4
, Y
5
, and Y
6
subtypes, in addition to the hypothetical Y
1
-like subtype. Selective peptidic agonists and antagonists have been identified for most of the subtypes, but few selective non-peptidic antagonists have been reported. The Y
1
and Y
5
receptor subtypes appear to be involved in appetite regulation, but their relative contribution to the modulation of food intake and energy expenditure remains unclear. The discovery of non-peptidic antagonists of the Y
1
and/or Y
5
receptor provides novel therapeutic agents, that are less prone to the shortcomings of the peptide antagonists, namely, for example, poor metabolic stability, low oral bioavailability, and poor brain permeability, for the treatment of obesity and cardiovascular diseases. Recently, a few of such agents have been reported, some of which having demonstrated pharmacological efficacy in pre-clinical animal models. The present invention provides a novel class of potent non-peptidic antagonists of the NPY receptors, in particular, the Y
1
receptor.
Insofar as is known, aminoalkyl substituted pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazines have not been previously reported as NPY receptor antagonists useful in the treatment of feeding and cardiovascular disorders. However, this general class of compounds has been described for other uses by virtue of different mechanisms of action, e.g., as antagonists of the corticotropin releasing factor (CRF
1
). For example International Patent Publication WO 98/03510 describes certain pyraazolotriazines and pyrazolopyrimidines as being of use as corticotropin releasing factors.
SUMMARY OF THE INVENTION
Compounds that interact with the Y
1
receptor and inhibit the activity of neuropeptide Y at those receptors are useful in treating physiological disorders associated with an excess of neuropeptide Y, including eating disorders, such as, for example, obesity and bulimia, and certain cardiovascular diseases, for example, hypertension.
This invention relates to a method of treating a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of an amino substituted pyrazolo[1,5,-a]-1,5-pyrimidine or a pyrazolo[1,5-a]-1,3,5-triazine of the formula I:
or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound exhibits a K
i
of 5 micromolar or less in an assay of NPY receptor binding, and
X is N or CR
14
;
R
1
is selected from H, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cyano, halo, C
1
-C
6
haloalkyl, OR
7
, C
1
-C
6
alkyl-OR
7
, C
1
-C
6
cyanoalkyl, NR
8
R
9
, and C
1
-C
6
alkyl-NR
8
R
9
;
R
2
is
H,
C
1
-C
6
alkyl which optionally forms a C
3
-C
6
aminocarbocycle or a C
2
-C
5
aminoheterocycle with A or B, each of which is optionally substituted with R
7
,
C
3
-C
10
cycloalkyl, or
(C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl; or
R
2
and R
6
jointly form with the 2 nitrogen atoms to which they arc bound a C
2
-C
5
aminoheterocycle optionally substituted with R
7
;
A is (CH
2
)
m
where m is 1,2 or 3 and is optionally mono- or di-substituted at each carbon atom with C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
1
-C
6
alkynyl, cyano, halogen, C
1
-C
6
haloalkyl, OR
7
, C
1
C
6
alkyl-OR
7
; C
1
-C
6
cyanoalkyl, NR
8
R
9
, or C
1
-C
6
alkyl-NR
8
R
9
, or
A and B jointly form a C
3
-C
6
carbocycle, which is optionally substituted at each carbon atom with R
7
, or
A and R
2
jointly form a C
3
-C
6
aminocarbocycle , which is optionally substituted at each carbon atom with R
7
;
B is (CH
2
)
n
where n is 0, 1, 2, or 3 and is optionally substituted at each carbon atom with C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cyano, halogen, C
1
-C
6
haloalkyl, OR
7
, C
1
-C
6
alkyl-OR
7
; C
1
-C
6
cyanoalkyl, NR
8
R
9
, or C
1
-C
6
alkyl-NR
8
R
9
, or
B and R
2
jointly form a C
3
-C
6
aminocarbocycle , which is optionally substituted at each carbon atom with R
7
, or
B and R
6
jointly form a C
3
-C
6
aminocarbocycle, which is optionally substituted at each carbon atom with R
7
;
R
3
is selected from H, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, cyano, halo, C
1
-C
6
haloalkyl, OR
7
, C
1
-C
6
alkyl-OR
7
, C
1
-C
6
cyanoalkyl, NR
8
R
9
, and C
1
-C
6
alkyl-NR
8
R
9
;
R
4
is selected from aryl or heteroaryl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, C
3
-C
10
cycloalkenyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, halogen, C
1
-C
6
haloalkyl, trifluromethylsulfonyl, OR
7
, C
1
-C
6
alkyl-OR
7
, NR
8
R
9
, C
1
-C
6
alkyl-NR
8
R
9
, CONR
8
R
9
, C
1
-C
6
alkyl-CONR
8
R
9
, COOR
7
, C
1
-C
6
alkyl- COOR
7
, CN, C
1
C
6
alkyl-CN, SO
2
NR
8
R
9
, SO
2
R
7
, aryl, heteroaryl, heterocycloalkyl, and 3-, 4-, or 5-(2-oxy-1,3-oxazolidinyl), with the proviso that at least one of the positions ortho or para to the point of attachment of the aryl or heteroaryl ring to the pyrazole is substituted;
R
5
and R
6
are independently selected from H, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
2
-C
6
alkenyl, and C
2
-C
6
alkynyl;
R
7
is H, C
1
-C
6
alkyl, C
3
-C
10
cycloalkyl, C
3
-C
10
cycloalkenyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
1
-C
3
haloalkyl, or heterocycloalkyl, C
1
-C
8
alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C
1
-C
8
alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C
1
-C
6
arylalkyl or C
1
-C
6
heteroarylalkyl each of which is optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C
1
-C
6
haloalkyl, OR
13
, NR
8
R
9
, C
1
-C
6
alkyl-OR
13
, C
1
-C
6
alkyl-NR
8
R
9
, CONR
8
R
9
, COOR
13
, CN, SO
2
NR
8
R
9
, SO
2
R
13
, with the proviso that for SO
2
R
7
, R
7
cannot be H;
R
8
and R
9
are independently selected at each occurrence from H
Blum Charles
Carpino Philip Albert
Darrow James W.
De Lombaert Stephane
Giangiordano Mark
Berch Mark L.
Habte H Kahsay
Ladas & Parry
Neurogen Corporation
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