Spiro[isobenzofuran-1,4′-piperidin]-3-ones...

Details Spiro[isobenzofuran-1,4′-piperidin]-3-ones... Spiro[isobenzofuran-1,4′-piperidin]-3-ones...

2001-12-11

2003-05-20

Seaman, D. Margaret (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S017000, C546S199000

Reexamination Certificate

active

06566367

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to substituted spiro[isobenzofuran-1,4′-piperidin]-3-ones and 3H-spiroisobenzofuran-1,4′-piperidines that are modulators of mammalian neuropeptide Y
5
(NPY5) receptors, and to the use of such compounds for treating a variety of physiological disorders associated with NPY5 receptor activation, such as feeding disorders, psychiatric disorders and cardiovascular diseases. The invention further relates to the use such compounds as probes for the detection and localization of NPY5 receptors.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) is a 36 amino acid peptide that mediates a variety of physiological effects in humans and other mammals. This is largely conserved across mammalian species, and belongs to a large family of peptides that includes, among others, peptide YY (PYY) and pancreatic peptide (PP). NPY is the most abundant peptide in the mammalian brain, and is also present in sympathetic neurons. In addition, 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 appears to be involved in the regulation of coronary tone. These effects are selectively mediated by various NPY receptors, which currently include the Y
1
, Y
2
, Y
3
, Y
4
, Y
5
and Y
6
subtypes, as well as the hypothetical Y
1-like
subtype (e.g., Wahlestedt and Reis (1993)
Ann. Rev. Pharmacol. Toxicol.
33:309; Gehlert and Hipskind (1995)
Curr. Pharm. Design,
1:295; Michel et al. (1998)
Pharmacol. Rev.
50:143).
The Y
5
receptor subtype (e.g. U.S. Pat. No. 5,602,024) appears to be involved in appetite regulation, including the modulation of food intake and energy expenditure. In addition, studies of seizure-prone mice have suggested that the NPY
5
receptor may have an anti-epileptic activity in the control of limbic seizures. NPY
5
-like receptors have also been implicated in attenuation of morphine withdrawal symptoms, enhancement of diuresis and natriuresis, lowering of blood glucose, inhibition of luteinizing hormone secretion, and reduction of acetylcholine release in the ileum.
Selective peptide agonists and antagonists have been identified for most of the NPY receptor subtypes. Peptides, however, generally have serious shortcomings for therapeutic use including, poor metabolic stability, low oral bioavailability and poor brain permeability. To date, few non-peptide antagonists have been reported. WO 01/14376 describes certain spiro NPY receptor antagonists, but additional antagonists with improved properties are needed as therapeutic agents for the treatment of physiological disorders associated with NPY5 receptor activation, such as feeding disorders (e.g., obesity and bulemia), psychiatric disorders, diabetes and cardiovascular diseases (such as hypertension). The present invention fulfills this need, and provides further related advantages.
SUMMARY OF THE INVENTION
The present invention provides NPY5 receptor modulators that inhibit or enhance NPY binding to NPY5 receptor. Such modulators generally comprise a substituted spiro[isobenzofuran-1,4′-piperidin]-3-one or 3H-spiroisobenzofuran-1,4′-piperidine characterized by one of the following formulas (or a pharmaceutically acceptable salt or prodrug thereof):
Within Formulas I and II, X is oxygen or H
2
; A, D, V, W, Y and Z are each independently N or CR
1
; B is N or CR
2
; and E is N or CR
3
. R
1
is independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, —C(═O)NH
2
, —COOH and groups of the formula L—R
A
—Q—G. Within the formula L—R
A
—Q—G, L is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)
n
—, —NR
B
—, —C(═O)NHR
B
—, —NHR
B
C(═O)—, —NR
B
S(O)
n
— or —S(O)
n
NR
B
—. n is independently chosen at each occurrence from 0, 1 or 2. R
A
is (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkenyl, (C
3
-C
8
)cycloalkynyl or (C
3
-C
8
)heterocycloalkyl, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C
1
-C
6
)alkyl and halo(C
1
-C
6
)alkyl. Q is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)n—, —CHR
B
—, —NR
B
—, —C(═O)NHR
B
—, —NHR
B
C(═O)—, —NR
B
S(O)
n
— or —S(O)
n
NR
B
. R
B
is independently selected at each occurrence from hydrogen, (C
1
-C
8
)alkyl, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkyl(C
1
-C
8
)alkyl and (C
1
-C
8
)alkyl(C
3
-C
8
)cycloalky. G is: (i) hydrogen; or (ii) (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, (C
3
-C
8
)cycloalkyl(C
1
-C
8
)alkyl, or a 3- to 10-membered carbocyclic or heterocyclic group, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C
1
-C
8
)alkyl, halo(C
1
-C
8
)alkyl, (C
1
-C
8
)alkoxy, —NH(C
1
-C
8
)alkyl, —N(C
1
-C
8
)alkyl)
2
, —NHC(═O)(C
1
-C
8
)alkyl, —N(C
1
-C
8
)alkylC(═O)(alkyl), —NHS(O)s(C
1
-C
8
)alkyl, —S(O)
s
(C
1
-C
8
)alkyl, —S(O)
s
NH(C
1
-C
8
)alkyl and —S(O)
s
N(C
1
-C
8
)alkyl)
2
, wherein s is 0, 1 or 2.
Within certain embodiments, R
1
is independently selected at each occurrence from hydrogen, halogen, hydroxy, nitro, cyano, amino, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
3
-C
7
)cycloalkyl, (C
3
-C
7
)cycloalkyl(C
1
-C
4
)alkyl, (C
2
-C
6
)alkenyl, (C
3
-C
7
)cycloalkenyl, (C
2
-C
6
)alkynyl, (C
3
-C
7
)cycloalkynyl, halo(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkoxy, mono and di(C
1
-C
6
)alkylamino, amino(C
1
-C
6
)alkyl, and mono- and di(C
1
-C
6
)alkylamino(C
1
-C
6
)alkyl.
R
2
and R
3
are independently selected at each occurrence from hydrogen, halogen, hydroxy, amino, nitro, cyano, —C(═O)NH
2
, —COOH; and groups of the formula T—R
C
—U—M. Within the formula T—R
C
—U—M, T is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)
n
—, —NR
D
—, —C(═O)NHR
D
—, —NHR
D
C(═O)—, —NR
D
S(O)
n
— or —S(O)
n
NR
D
—. n is independently chosen at each occurrence from 0, 1 or 2. R
c
is (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl or a 3- to 10-membered carbocyclic or heterocyclic group, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C
1
-C
6
)alkyl and halo(C
1
-C
6
)alkyl. U is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O—, —O—C(═O)O—, —S(O)
n
—, —CHR
D
—, —NR
D
—, —C(═O)NHR
D
—, —NHR
D
C(═O)—, —NR
D
S(O)
n
— or —S(O)
n
NR
D
—. R
D
is independently selected at each occurrence from hydrogen, (C
1
-C
8
)alkyl, (C
3
-C
8
)cycloalkyl, (C
3
-C
8
)cycloalkyl(C
1
-C
8
)alkyl and (C
1
-C
8
)alkyl(C
3
-C
8
)cycloalkyl. M is: (i) hydrogen; or (ii) (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl or a 3- to 10-membered carbocyclic or heterocyclic group, each of which is optionally substituted with from 1 to 5 substituents independently selected from hydroxy, halogen, amino, cyano, nitro, (C
1
-C
8
)alkyl, halo(C
1
-C
8
)alkyl, (C
1
-C
8
)alkoxy, —NH(C
1
-C
8
)alkyl, —N(C
1
-C
8
)alkyl)
2
, —NHC(═O)(C
1
-C
8
)alkyl, —N(C
1
-C
8
)alkylC(═O)(alkyl), —NHS(O)
s
(C
1
-C
8
)alkyl, —S(O)
s
(C
1
-C
8
)alkyl, —S(O)
s
NH(C
1
-C
8
)alkyl and —S(O)
s
N(C
1
-C
8
)alkyl)
2
, wherein s is 0, 1 or 2.
Within certain embodiments, R
2
and R
3
are independently selected from: (i) hydrogen and halogen; and (ii) T—R
c
, wherein T is a bond, —O—, —C(═O)—, —OC(═O)—, —C(═O)O— or —S(O)
2
—; and R
c
is (C
1
-C
6
)alkyl or a 5- to 6-membered carbocyclic or heterocyclic ring, each of which is

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