Substituted imidazole neuropeptide Y Y5 receptor antagonists

Details Substituted imidazole neuropeptide Y Y5 receptor antagonists Substituted imidazole neuropeptide Y Y5 receptor antagonists

2002-07-23

2003-10-14

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S341000, C514S326000, C514S318000, C514S252140, C514S253090, C514S254020, C514S254050, C546S194000, C546S210000, C546S256000, C546S274100, C544S295000, C544S360000, C544S367000, C544S370000

Reexamination Certificate

active

06632828

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to selective 4-(phenyl or pyridyl)imidazole derivative neuropeptide Y Y5 receptor antagonists useful in the treatment of eating disorders, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
Neuropeptide Y is a 36 amino acid peptide that is widely distributed in the central and peripheral nervous systems. This peptide mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that activation of neuropeptide Y Y5 receptors results in hyperphagia and decreased thermogenesis. Therefore compounds that antagonize neuropeptide Y at the Y5 receptor subtype represent an approach to the treatment of eating disorders such as obesity and hyperphagia, and diabetes.
Substituted imidazoles are used in various pharmaceutical and non-pharmaceutical applications. WO 99/01128 discloses substituted diarylimidazoles as NPY Y5 receptor antagonists.
SUMMARY OF THE INVENTION
The present invention relates to compounds represented by the structural formula I:
or a pharmaceutically acceptable salt, solvate or N-oxide thereof, wherein
X is ═CH— or ═N—;
Y is 1 to 3 substituents independently selected from the group consisting of H, halogen, trihaloalkyl, C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
3
-C
7
-cycloalkyl, C
1
-C
6
alkyl substituted by C
3
-C
7
-cycloalkyl, —OH, —O(C
1
-C
6
)alkyl, —SH, —S(C
1
-C
6
)alkyl, or —CN.
R is R
1
-phenyl, R
1
-pyridyl, adamantyl, —(CH
2
)
n
—O—(R
9
-phenyl), —(CH
2
)
n
—S—(R
9
-phenyl), —CF
3
, C
1
-C
6
alkyl, C
3
-C
7
-cycloalkyl, or heterocycloalkyl selected from the group consisting of 4 to 6 membered rings comprising 3 to 5 carbon ring members and 1 to 3 ring members selected from the group consisting of —NR
8
—, —O— and —S—, heterocycloalkyl(C
1
-C
6
)alkyl wherein heterocycloalkyl is as defined above, heteroaryl(C
1
-C
6
)alkyl,
 provided that when R is R
1
-phenyl, R
1
-pyridyl, adamantyl, —(CH
2
)
n
—O—(R
9
-phenyl, —(CH
2
)
n
—S—(R
9
-phenyl), —CF
3
, C
1
-C
6
alkyl, or C
3
-C
7
-cycloalkyl, Y is 3-CF
3
;
n is 0, 1, 2 or 3;
R
1
is 1-3 substituents independently selected from the group consisting of hydroxy(C
1
-C
6
)alkyl; NO
2
; —CHO, —C(O)O(C
1
-C
6
)alkyl; —C(O)NR
4
R
5
; —(CH
2
)
p
NR
4
R
5
; —(CH
2
)
p
NR
4
R
6
; —NR
4
SO
2
R
7
; —NHCOH; —NR
4
COR
5
; —NHC(O)NR
4
R
5
; aryl; and heteroaryl;
p is 0, 1, 2 or 3;
R
4
is hydrogen or C
1
-C
6
alkyl;
R
5
is C
1
-C
6
alkyl, aryl or heteroaryl; provided R
4
and R
5
are not both C
1
-C
6
alkyl, and provided that when R
4
is hydrogen, R
5
is not C
1
-C
6
alkyl; or R
4
and R
5
together are C
3
-C
6
alkylene and together with the nitrogen to which they are attached form a 4-7 membered ring; or R
4
and R
5
, together with the nitrogen to which they are attached, form a 5, 6 or 7-membered ring, wherein 1 or 2 ring members are independently selected from the group consisting of —O—, —S— and —NR
12
—;
R
6
is C
3
-C
7
cycloalkyl, benzyl, diphenylmethyl or
 or R
4
and R
6
, together with the nitrogen to which they are attached form a group of the formula
R
7
is C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, benzyl, aryl, or heteroaryl;
R
8
is hydrogen, C
1
-C
6
alkyl, —C(O)—(C
1
-C
6
alkyl), —C(O)—(C
3
-C
7
cycloalkyl), —C(O)-aryl, —C(O)-heteroaryl, —SO
2
—R
7
, aryl, heteroaryl, —CONR
4
R
5
or —C(O)—O—(C
1
-C
6
)alkyl;
R
9
is 1 to 3 substituents independently selected from the group consisting of hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, halogeno and —CF
3
;
R
10
and R
11
are independently selected from the group consisting of hydrogen and C
1
-C
6
alkyl, or R
10
and R
11
, together with the carbon to which they are attached, form a C
3
-C
7
ring; and
R
12
is hydrogen, C
1
-C
6
alkyl, —C(O)—(C
1
-C
6
alkyl), —SO
2
—R
7
, R
9
-phenyl, —CONR
4
R
5
, —C(O)—O—(C
1
-C
6
)alkyl, —CHO, C
3
-C
7
cycloalkyl, (C
3
-C
7
)cycloalkyl(C
1
-C
6
)alkyl, benzyl, benzoyl, —C(O)(C
3
-C
7
)cycloalkyl, —C(O)(C
1
-C
6
)alkylphenyl, pyridylmethyl, —C(O)pyridyl, —C(O)N(di-(C
1
-C
6
)-alkyl) or 4-tetrahydropyranyl.
One group of preferred compounds is that wherein R is as defined above; R
1
is 1-3 substituents selected from the group consisting of hydroxy(C
1
-C
6
)alkyl, NO
2
, —CHO, —C(O)O(C
1
-C
6
)alkyl, —(CH
2
)
p
NR
4
R
5
, —(CH
2
)
p
NR
4
R
6
, —NR
4
SO
2
R
7
, —NHCOH, —NHCOR
5
, —NR
4
COR
5
—, NHC(O)NR
4
R
5
, aryl and heteroaryl; and p is 0, 1 or 2.
Another group of preferred compounds is that wherein R is adamantyl, —(CH
2
)
n
—O—(R
9
-phenyl), —(CH
2
)
n
—S—(R
9
-phenyl), —CF
3
, C
1
-C
6
alkyl, C
3
-C
7
-cycloalkyl, heteroaryl-(C
1
-C
6
)alkyl, heterocycloalkyl-(C
1
-C
6
)alkyl, or
Another group of preferred compounds is that wherein R is heterocycloalkyl,
wherein heterocycloalkyl is defined as
and R
8
is preferably C(O)—(C
1
-C
6
alkyl), —C(O)—(C
3
-C
7
cycloalkyl), —C(O)-aryl, —C(O)-heteroaryl, —SO
2
—R
7
, aryl, heteroaryl, and —CONR
4
R
5
.
In another group of preferred compounds of formula I, R is R
1
-phenyl or R
1
-pyridyl of the formula
R
1
is preferably —NR
4
SO
2
R
7
, wherein R
4
is H or straight or branched C
1
-C
6
alkyl, and R
7
is straight or branched C
1
-C
6
alkyl.
Preferred compounds of this invention include those of formula I wherein X is ═CH—, Y is 3-CF
3
, and R is selected from the group consisting of:
Another group of preferred compounds of this invention include those of formula 1 wherein X is ═CH—, and R is selected from the group consisting of:
Still another group of preferred compounds of this invention include those selected from the group consisting of:
Yet one more group of preferred compounds of this invention include those selected from the group consisting of:
The present invention also relates to a method of treating eating disorders, such as obesity and hyperphagia, and diabetes comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.
Another aspect of the invention is a pharmaceutical composition for treating eating disorders and diabetes which comprises a compound of formula I in combination with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “alkoxy”, etc.
Alkyl represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. If the number of carbon atoms is not specified, e.g., if the term lower alkyl is used, chain lengths of 1 to 6 carbons are intended.
Aryl-(including the aryl portion of arylalkyl and heteroarylalkyl)-represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl is a phenyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment, said carbocyclic group being optionally substituted with one or more (e.g., 1 to 3) of halo, alkyl, hydroxy, alkoxy, phenoxy, CF
3
, —C(O)N(R
18
)
2
, —SO
2
R
18
, —SO
2
N(R
18
)
2
, amino, alkylamino, dialkylamino, —COOR
23
or —NO
2
, wherein R
18
represents H, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl and R
23
represents alkyl or aryl;
Cycloalkyl represents a saturated carbocyclic ring having 3 to 7 carbon atoms.
Halogeno represents fluoro, chloro, bromo or iodo.
As defined above, heterocycloalkyl represents 4 to 6 membered rings comprising 3 to 5 carbon ring members and 1 to 3 ring members selected from the group consisting of —NR
12
—, —O— and —S—. Where a heterocycloalkyl ring comprises more than one heteroatom, no rings are formed where there are adjacent oxygen atoms, adjacent sulfur atoms, or three consecutive heteroatoms. Examples of heterocycloalkyl rings are piperazinyl, tetrahydro

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