Neuropeptide Y Y5 receptor antagonists

Details Neuropeptide Y Y5 receptor antagonists Neuropeptide Y Y5 receptor antagonists

2002-07-24

2003-12-23

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S224000, C548S557000, C548S950000, C540S605000, C514S426000, C514S330000, C514S212010, C514S210030

Reexamination Certificate

active

06667319

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to neuropeptide Y Y5 receptor antagonists useful in the treatment of obesity and eating disorders, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) is a 36 amino acid neuropeptide that is widely distributed in the central and peripheral nervous systems. NPY is a member of the pancreatic polypeptide family that also includes peptide YY and pancreatic polypeptide (Wahlestedt, C., and Reis, D., Ann. Rev. Toxicol., 32, 309, 1993). NPY elicits its physiological effects by activation of at least six receptor subtypes designated Y1, Y2, Y3, Y4, Y5 and Y6 (Gehlert, D., Proc. Soc. Exp. Biol. Med., 218, 7, 1998; Michel, M. et al., Pharmacol. Rev., 50,143,1998). Central administration of NPY to animals causes dramatically increased food intake and decreased energy expenditure (Stanley, B. and Leibowitz, S., Proc. Natl. Acad. Sci. USA 82: 3940, 1985; Billington et al., Am J. Physiol., 260, R321, 1991). These effects are believed to be mediated at least in part by activation of the NPY Y5 receptor subtype. The isolation and characterization of the NPY Y5 receptor subtype has been reported (Gerald, C. et al., Nature, 1996, 382, 168; Gerald, C. et al. WO 96/16542). Additionally, it has been reported that activation of the NPY Y5 receptor by administration of the Y5-selective agonist [D-Trp
32
]NPY to rats stimulates feeding and decreases energy expenditure (Gerald, C. et al., Nature, 1996, 382,168; Hwa, J. et al., Am. J. Physiol., 217 (46), R1428, 1999). Hence, compounds that block binding of NPY to the NPY Y5 receptor subtype should have utility in the treatment of obesity, disorders such as, bulimia nervosa, anorexia nervosa, and in the treatment of disorders associated with obesity such as type 11 diabetes, insulin resistance, hyperlipidemia, and hypertension.
PCT patent application WO 00/27845 describes a class of compounds, characterized therein as spiro-indolines, said to be selective neuropeptide Y Y5 receptor antagonists and useful for the treatment of obesity and the complications associated therewith. Urea derivatives indicated as possessing therapeutic activity are described in U.S. Pat. No. 4,623,662 (antiatherosclerotic agents) and U.S. Pat. No. 4,405,644 (treatment of lipometabolism).
Provisional application, U.S. Serial No. 60/232,255 describes a class of substituted urea neuropeptide Y Y5 receptor antagonists.
SUMMARY OF THE INVENTION
In one embodiment, this invention provides novel urea compounds having NPY Y5 receptor antagonist activity. In an embodiment of the invention is a compound represented by the structural formula
or a pharmaceutically acceptable salt or solvent thereof, wherein:
X is independently N or C;
z is independently NR
8
or CR
3
R
9
;
D is independently H, —OH, -alkyl or substituted -alkyl with the proviso that when X is N, D and the X—D bond are absent;
E is independently H, -alkyl or substituted -alkyl or D and E can independently be joined together via a —(CH
2
)
p
— bridge;
Q is independently H, -alkyl or substituted -alkyl, or D, X, Q and the carbon to which Q is shown attached can jointly form a 3 to 7-membered ring;
g, j, k, m and n can be the same or different and are independently selected;
g is 0 to 3 and when g is 0, the carbons to which (CH
2
)
g
is shown connected are no more linked;
j and k are independently 0 to 3 such that the sum of j and k is 0, 1, 2 or 3;
m and n are independently 0 to 3 such that the sum of m and n is 1, 2,3, 4 or 5;
p is 1 to 3;
R
1
is 1 to 5 substituents which can be the same or different, each R
1
being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —NR
5
R
6
, —NO
2
, —CONR
5
R
6
, —NR
5
COR
6
, —NR
5
CONR
5
R
6
where the two R
5
moieties can be the same or different, —NR
6
C(O)OR
7
, —C(O)OR
6
, —SOR
7
, —SO
2
R
7
, —SO
2
NR
5
R
6
, aryl and heteroaryl;
R
2
is 1 to 6 substituents which can be the same or different, each R
2
being independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, alkoxy, and hydroxy, with the proviso that when X is N and R
2
is hydroxy or alkoxy, R
2
is not directly attached to a carbon adjacent to X;
R
3
is independently hydrogen, -alkyl or substituted -alkyl;
R
4
is 1 to 6 substituents which can be the same or different, each R
4
being independently selected from hydrogen, -alkyl, substituted -alkyl, alkoxy, and hydroxy, with the proviso that when Z is NR
8
and R
4
is hydroxy or alkoxy, R
4
is not directly attached to a carbon adjacent to the NR
8
;
R
5
and R
6
are independently hydrogen, -alkyl, substituted -alkyl or -cycloalkyl;
R
7
is independently -alkyl, substituted -alkyl or -cycloalkyl;
R
8
is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —SO
2
R
5
O, —SO
2
NR
5
R
11
, —C(O)R
11
, —C(O)NR
5
R
11
and —C(O)OR
10
;
R
9
is independently hydrogen, -alkyl, substituted -alkyl, hydroxy, alkoxy, —NR
5
R
11
, aryl, or heteroaryl; or R
3
and R
9
can be joined together and with the carbon to which they are attached form a carbocyclic or heterocyclic ring having 3 to 7 ring atoms;
R
10
is -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl; aryl or heteroaryl; and
R
11
is independently hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, aryl or heteroaryl.
The above statement “when g is 0, the carbons to which (CH
2
)
g
is shown connected are no more linked” means that when g is 0, then the structural component:
shown in formula I above becomes:
Ureas of formula I or formula III are highly selective, high affinity NPY Y5 receptor antagonists useful for the treatment of obesity.
This invention is also directed to pharmaceutical compositions for the treatment of metabolic disorders such as obesity, and eating disorders such as hyperphagia. In one aspect, this invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula I or formula III thereof, or a pharmaceutically acceptable salt or solvate of said compound, and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
The present invention relates to compounds that are represented by structural formula I or formula III or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above. The compounds of formula I or formula III can be administered as racemic mixtures or enantiomerically pure compounds.
In a preferred embodiment of the invention is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, wherein:
R
1
is 1 to 5 substituents which can be the same or different, each R
1
being independently selected from the group consisting of Cl, Br, I or F;
X is N;
D is absent and the X—D bond is absent;
E is H;
g is 0;
j is 1;
k is 1;
m is 2;
n is 2;
R
2
is H;
R
3
is methyl;
R
4
is H; and
Z is NR
8
, where R
8
is independently selected from the group consisting of hydrogen, -alkyl, substituted -alkyl, -cycloalkyl, -alkylcycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, —SO
2
R
10
, —SO
2
NR
5
R
11
, —C(O)R
11
, —C(O)NR
5
R
11
and —C(O)OR
10
.
A preferred embodiment of the present invention is a compound of formula II or a pharmaceutically acceptable salt or solvate thereof, wherein:
wherein R
8
is defined as herein in the Detailed Description in Table 1.
An additional preferred embodiment of the present invention is a compound of formula III or a pharmaceutically acceptable salt or solvate thereof, wherein:
wherein
R
1
is 1 to 5 substituents which can be the same or different, each R
1
being independently selected from the group consisting of hydrogen, hydroxy, halogen, haloalkyl, -alkyl, substituted -alkyl, -cycloalkyl, CN, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, —NR
5
R
6
, —NO
2
, —CO

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