Neuropeptide Y5 receptor antagonists

Details Neuropeptide Y5 receptor antagonists Neuropeptide Y5 receptor antagonists

1999-06-07

2001-12-11

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S319000, C546S205000, C546S224000

Reexamination Certificate

active

06329395

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to selective neuropeptide Y Y5 receptor antagonists useful in the treatment of eating disorders and diabetes, 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.
Phenyl amides and ureas are known as antiatherosclerotic agents, see for example U.S. Pat. No. 4,623,662, and benzoic acid amides are disclosed as antidiabetic agents in U.S. Pat. No. 5,378,728. N,N-alkylenebis-(benzamides) are known as endocrinological agents, see U.S. Pat. No. 4,009,208. WO 98/35957, published Aug. 20, 1998, discloses amide derivatives as selective neuropeptide Y receptor antagonists.
SUMMARY OF THE INVENTION
The present invention relates to compounds represented by the structural formula I
or a pharmaceutically acceptable salt thereof, wherein
a and b are independently 0, 1 or 2, provided that the sum of a and b is 0 to 3;
X is —O—, —S—, —SO—, —SO
2
—, —CH(OR
8
)—, —C(O)—, —C(R
23
)
2
—, —C(R
25
)═C(R
25
)—, —C≡C— or
R
1
is R
15
-aryl, R
24
-heteroaryl, —NHR
12
, —N(R
12
)
2
, —(C
1
-C
9
)alkyl-OC(O)R
8
, aryloxy(C
1
-C
9
)alkyl,
 wherein m is 1-4, or
 wherein d and e are independently 0, 1 or 2;
R
2
, R
3
, R
4
and R
5
are independently selected from the group consisting of H, C
1
-C
5
straight or branched alkyl, (C
3
-C
12
)cycloalkyl, R
14
-(C
3
-C
12
)cycloalkyl, halogen, —OR
8
, —N(R
8
)
2
, —CO
2
R
8
and CF
3
;
R
6
and R
7
are independently selected from the group consisting of H, (C
1
-C
9
)alkyl, (C
1
-C
9
)alkenyl, hydroxy-(C
1
-C
9
)alkyl, amino-(C
1
-C
9
)-alkyl, (C
1
-C
9
)alkoxy-(C
1
-C
9
)alkyl, (C
3
-C
12
)cycloalkyl and (C
3
-C
12
)-cycloalkyl-(C
1
-C
6
)alkyl, or R
6
and R
7
, together with the carbon to which they are attached, form a 3, 4, 5, 6 or 7-membered carbocyclic ring, or a 4, 5, 6 or 7-membered heterocyclic ring, wherein 1, 2 or 3 ring members are independently selected from the group consisting of O, S and N;
R
8
is independently selected from the group consisting of H, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, R
15
-aryl and R
24
-heteroaryl;
R
9
is (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, R
15
-aryl or R
24
-heteroaryl;
R
11
is independently selected from the group consisting of H, (C
1
-C
6
)alkyl and (C
3
-C
12
)cycloalkyl;
R
12
is independently selected from the group consisting of straight or branched (C
1
-C
9
)alkyl, hydroxy(C
2
-C
9
)alkyl, (C
1
-C
9
)alkoxy-(C
2
-C
9
)-alkyl, N(R
11
)(R
19
)-(C
2
-C
9
)-alkyl, HS(C
2
-C
9
)-alkyl, (C
1
-C
9
)-alkylthio-(C
2
-C
9
)-alkyl, (C
3
-C
12
)-cycloalkyl, R
14
-(C
3
-C
12
) cycloalkyl, R
15
-aryl, R
24
-heteroaryl, R
15
-aryl(C
1
-C
6
)-alkyl, R
24
-heteroaryl(C
1
-C
6
)-alkyl,
 wherein j and k are independently 0, 1 or 2, and
 wherein q is 1 or 2, and s is 0, 1 or 2; or two R
12
groups, together with the nitrogen to which they are attached, form a ring of the formula
 wherein p is 0, 1 or 2;
R
10
is —NR
18
—, —O— or —S—;
R
13
is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, halogen, (C
1
-C
6
)alkoxy and CF
3
;
R
14
is 1 to 3 substituents independently selected from the group consisting of (C
1
-C
6
)alkyl, benzyl, R
13
-aryl and R
13
-heteroaryl;
R
15
is 1 to 3 substituents independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, halo, polyhalo(C
1
-C
6
)alkyl, R
17
O—, —N(R
17
)
2
, —S(R
17
), R
17
O—(C
1
-C
6
)alkyl, (R
17
)
2
N—(C
1
-C
6
)alkyl formyl, —C(O)R
17
, —COOR
17
, —CON(R
17
)
2
, —OC(O)N(R
17
)
2
, —N(R
17
)C(O)N(R
17
)
2
, —NR
17
C(O)R
17
, —NR
17
C(O)OR
14
, R
17
S(O)—, R
17
SO
2
—, R
17
SO
2
NR
17
— and tri(C
1
-C
6
)-alkylsilyl;
R
16
is 1-3 substituents independently selected from the group consisting of H, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, (C
3
-C
12
)spirocycloalkyl, (C
3
-C
4
)spiro-alkylenedioxy, R
15
-aryl, R
24
-heteroaryl, benzyl, N-piperidinyl, —COR
8
, —C(O)NR
8
R
9
, —NR
8
R
9
and —NR
8
C(O)R
9
, or when two R
16
groups are attached to adjacent ring carbon atoms, together with said carbon atoms, they can form a (C
5
-C
7
)cycloalkyl ring;
R
17
is independently selected from the group consisting of H, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, (C
3
-C
12
)cycloalkyl(C
1
-C
6
)alkyl, R
13
-aryl and R
13
-heteroaryl;
R
18
is independently selected from the group consisting of H, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, (C
3
-C
12
)cycloalkyl-(C
1
-C
6
)alkyl, R
15
-aryl, R
24
-heteroaryl, —CO
2
R
9
, —C(O)N(R
8
)
2
, —COR
8
and —SO
2
R
9
;
R
19
is H, (C
3
-C
12
)cycloalkyl-(C
1
-C
6
)alkyl, R
15
-aryl, R
24
-heteroaryl, —CO
2
R
9
, —C(O)N(R
8
)
2
, —COR
8
or —SO
2
R
9
;
R
20
is (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, (C
3
-C
12
)cycloalkyl-(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, oxo(C
1
-C
6
)alkyl or polyhalo(C
1
-C
6
)alkyl;
R
21
and R
22
are independently selected from the group consisting of H, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl-(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, R
15
-aryl, R
24
-heteroaryl, R
15
-aryl(C
1
-C
6
)alkyl or R
24
-heteroaryl(C
1
-C
6
)-alkyl;
R
23
is independently selected from the group consisting of H, halogen, (C
1
-C
6
)alkyl, (C
3
-C
12
)cycloalkyl, R
15
-aryl, and R
24
-heteroaryl;
R
24
is 1 to 2 substituents independently selected from the group consisting of hydrogen, (C
1
-C
6
)alkyl, halo, polyhalo(C
1
-C
6
)alkyl, R
17
O—, —N(R
17
)
2
, —S(R
17
), R
17
O—(C
1
-C
6
)alkyl, (R
17
)
2
N—(C
1
-C
6
)alkyl, formyl, —C(O)R
17
, —COOR
17
, —CON(R
17
)
2
, —OC(O)N(R
17
)
2
, —N(R
17
)C(O)N(R
17
)
2
, —NR
17
C(O)R
17
, —NR
17
C(O)OR
14
, R
17
S(O)—, R
17
SO
2
—, R
17
SO
2
NR
17
— and tri(C
1
-C
6
)-alkylsilyl; and
R
25
is independently selected from the group consisting of hydrogen, halogen, (C
1
-C
6
)-alkyl and polyhalo(C
1
-C
6
)alkyl.
In a preferred group of compounds of formula I, Q is
wherein R
4
is H. Also preferred are compounds wherein R
3
is H, and wherein R
2
and R
5
are independently H or halogen. R
6
and R
7
are preferably (C
1
-C
9
)alkyl, especially methyl, or R
6
and R
7
, together with the carbon to which they are attached, form a C
3
-C
6
carbocyclic ring.
In compounds of formula I, X is preferably —S—; —C(O)—; or —C(R
8
)
2
, especially wherein R
8
is H. More preferably, X is —C(R
8
)
2
—, and compounds wherein X is —CH
2
— are especially preferred.
In compounds of formula I, a is preferably 1 or 2 and b is preferably 0.
In compounds of formula I, R
1
is preferably —NHR
12
or —N(R
12
)
2
, especially
wherein R
18
is (C
1
-C
6
)alkyl or —SO
2
R
9
; R
9
is (C
1
-C
6
)alkyl or aryl; and R
22
is (C
1
-C
6
)alkyl or (C
3
-C
12
)cycloalkyl(C
1
-C
6
)alkyl.
Another aspect of the invention is a pharmaceutical composition for treating eating disorders or diabetes which comprises an effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier.
Yet another aspect of this invention is a method of treating an eating disorder or diabetes comprising administering an effective amount of a compound of formula I to a patient in need of such treatment.
Also claimed are novel compounds similar to those of formula I wherein b is 0, X is —O— or —S—and the substituent corresponding to R
1
is optionally substituted alkyl.
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.

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