Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-29
2002-04-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S245000, C514S258100, C544S194000, C544S197000, C544S198000, C544S204000, C544S206000, C544S209000, C544S211000, C544S212000, C544S263000, C544S281000
Reexamination Certificate
active
06372743
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain alkylene diamine-substituted pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo [1,5-a]-1,3,5-triazines which selectively and 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 [K. Tatemoto, M. Carlquist, V. Mutt,
Nature
, 296, 659, (1982)] and subsequently found to be largely conserved across species. It belongs to a large family of peptides which includes, among others, peptide YY (PYY) and pancreatic peptide (PP). NPY is the most abundant peptide in the mammalian brain, but is also localized 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 are selectively mediated by various NPY receptors which currently include the Y
1
, Y
2
, Y
3
, Y
4
, and Y
6
subtypes, in addition to the hypothetical Y
1-like
subtype [C. Wahlestedt, D. Reis,
Ann. Rev. Pharmacol. Toxicol
., 33, 309 (1993); D. Gehlert, P. Hipskind,
Curr. Pharm. Design
, 1, 295 (1995); M. C. Michel et al.,
Pharmacol. Rev
., 50, 143 (1998)]. Selective peptidic agonists and antagonists have been identified for most of the subtypes, but few selective non-peptidic antagonists have been reported [B. A. Zimanyi, Z. Fathi, G. S. Pointdexter,
Curr. Pharm. Design
, 4, 349 (1998)]. 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 [D. R. Gehlert, P. A. Hipskind,
Exp. Opin. Invest. Drugs
, 6, 1827, (1997)]. The discovery of non-peptidic antagonists of the Y
1
and/or Y
5
receptor, would provide novel therapeutic agents, devoid of the shortcomings of the peptide antagonists, namely, for example, poor metabolic stability, low oral bioavailability, poor brain permeability, for the treatment of obesity and cardiovascular diseases. Recently, a few of those agents have been reported [D. R. Gehlert, P. A. Hipskind,
Exp. Opin. Invest. Drugs
, 6, 1827, (1997); P. Hipskind et al.,
J Med. Chem
., 40, 3712 (1997); M. Müiller et al.,
Arch. Pharm. Pharm. Med. Chem
., 330, 333 (1997); H. Zarrinmayeh, et al.,
J Med. Chem
., 41 2709 (1998); H. A. Wieland et al., Br.
J. Pharmacol
., 125, 549 (1998); Y. Shigeri et al.,
Pharmacol. Letters
, 63, PL 151 (1998); D. M Zimmerman et al.,
Bioorg. Med. Chem. Letters
, 8, 473, (1998); L. Criscione,
J Clin. Invest
., 102 12, 2136 (1998); Y. Murakami, et al.,
J. Med. Chem
., 42, 2621 (1999); T. C. Britton et al.,
Bioorg. Med. Chem. Letters
, 9, 475, (1999); H. Zarrinmayeh, et al.,
Bioorg. Med. Chem. Letters
, 9, 647, (1999)], 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 Y1 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(s) 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. For instance, WO 98/03510 and WO 99/38868 (Du Pont Pharmaceuticals) discloses pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazol[1,5-a]-1,3,5-triazines as antagonists of the corticotropin releasing factor (CRF). Therein, other prior art relative to pyrazolo[1,5,-a]-1,5-pyrimidines and pyrazolo[1,5-a]-1,3,5-triazines is also described. Similar compounds have also been described in WO 97/29109, 98/08847, and D. J. Wustrow et al.,
Bioorg. Med. Chem. Lett
. 8, 2067 (1998).
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 novel compounds, compositions, and methods for the treatment of physiological disorders associated with an excess of neuropeptide Y. The novel compounds encompassed by the present invention are those of formula I
wherein:
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
, 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 optionally substituted at each occurrence 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 are bound a C
2
-C
5
aminoheterocycle optionally substituted at each occurrence with R
7
;
A is (CH
2
)
m
where m is 1,2 or 3 and is optionally mono- or di-substituted on each occurrence 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, halo, C
1
-C
6
haloalkyl, OR
7
, C
1
-C
6
alkyl-OR
7
; C
1
-C
6
cyanoalkyl, NR
8
R
9
, C
1
-C
6
alkyl-NR
8
R
9
, or A and B jointly form a C
3
-C
6
carbocycle, optionally substituted at each occurrence with R
7
, or, as mentioned above, A and R
2
jointly form a C
3
-C
6
aminocarbocycle or a C
2
-C
5
aminoheterocycle optionally substituted at each occurrence with R
7
;
B is (CH
2
)
n
where n is 1,2 or 3 and is optionally mono- or di-substituted on each occurrence 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, halo, C
1
-C
6
haloalkyl, OR
7
, C
1
-C
6
alkyl-OR
7
; C
1
-C
6
cyanoalkyl, NR
8
R
9
, C
1
-C
6
alkyl-NR
8
R
9
, or, as mentioned above, B and A jointly form a C
3
-C
6
carbocycle, optionally substituted at each occurrence with R
7
or, as mentioned above, B and R
2
jointly form a C
3
-C
6
aminocarbocycle or a C
2
-C
5
aminoheterocycle optionally substituted at each occurrence 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
, 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
1
-C
6
alkenyl, C
1
-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
Blum Charles
Carpino Philip Albert
Darrow James W.
De Lombaert Stephane
Giangiordano Mark
Neurogen Corporation
Truong Tamthom N.
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