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
2003-01-14
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...
C544S080000, C544S278000, C544S262000, C544S276000, C544S277000, C544S254000, C544S281000, C544S282000, C544S236000, C544S256000, C544S257000, C544S279000, C514S259410, C514S263200, C514S263210, C514S263220, C514S263230, C514S263400, C514S264110, C514S265100
Reexamination Certificate
active
06506762
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to certain alkylene diamine-substituted heterocycles 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 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 gastrointestinal 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 disease.
SUMMARY OF THE INVENTION
The present invention also provides a general method to whereby mono-, bi-, or tricyclic heterocycles may be modified to obtain potent antagonists at the NPY
1
receptor.
The present invention provides novel, potent, non-peptidic antagonists of NPY receptors, particularly, the NPY
1
receptors, designed from a selection of mono- , bi-, or tri-cyclic heterocyclic cores.
The heterocyclic cores encompassed by the compounds of formula II-XV (shown below) have been previously described. The modifications made to these heterocyclic cores to obtain potent and selective NPY
1
antagonists are entirely novel.
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 the formula I-XV.
wherein
X is N or CR
14
;
W is S, O, or NR
15
;
Y is N or CR
3
;
E, F, and G are each, independently, CR
3
or N;
I and J are each, independently,
C═O, S, O, CR
3
R
16
or NR
15
when single bonded to both adjacent ring atoms, or
N, or CR
3
when double bonded to an adjacent ring atom;
K is
N or CR
3
when double bonded to L or J, or
O, S, C═O, CR
3
R
16
, or NR
15
when single bonded to both adjacent ring atoms, or
N or CR
3
when double bonded to an adjacent ring atom;
L is
N or CR
16
when single bonded to all atoms to which it is attached, or
C (carbon) when double bonded to K;
the 6- or 7-membered ring that contains I, J, K, and L may contain from 1 to 3 double bonds, from 0 to 2 heteroatoms, and from 0 to 2 C═O groups, wherein the carbon atom of such groups are part of the ring and the oxygen atom is a substituent on the ring;
Q is O or NR
15
;
R
1
in 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
4
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
and R
16
are selected independently at each occurrence 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, halogen, 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, 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, 3-, 4-, or 5-(2-oxo-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 heterocyclic core is substituted;
R
5
is selected from:
C
1
-C
6
alkyl, (C
3
-C
10
cycloalkyl) C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, each of which is substituted with 1 to 5 groups independently selected at each occurrence from halo, C
1
-C
2
haloalkyl, OR
7
, cyano, NR
8
R
9
, CONR
8
R
9
, COOR
7
, SO
2
NR
8
R
9
, SO
2
R
7
, NR
11
COR
12
, NR
11
SO
2
R
7
;
C
1
-C
6
arylalkyl, C
1
-C
6
heteroarylalkyl, C
5
-C
8
arylcycloalkyl, or C
5
-C
8
heteroarylcycloalkyl, where aryl is phenyl or naphthyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4-
Carpino Philip A.
De Lombaert Stephane
Griffith David A.
Hodgetts Kevin J.
Horvath Raymond F.
Berch Mark L.
Habte Kahsay
Ladas & Parry
Neurogen Corporation
LandOfFree
Certain alkylene diamine-substituted heterocycles does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Certain alkylene diamine-substituted heterocycles, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Certain alkylene diamine-substituted heterocycles will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3004874