Fused heterocyclic compounds

Details Fused heterocyclic compounds Fused heterocyclic compounds

2002-11-06

2004-10-26

Berch, Mark C. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S070000

Reexamination Certificate

active

06809104

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds, compositions and methods useful in the treatment or prevention of conditions and disorders associated with eating behavior, energy homeostasis and anxiety.
BACKGROUND OF THE INVENTION
G-protein coupled receptors play important roles in diverse signaling processes, including those involved with sensory and hormonal signal transduction. Eating disorders, which represent a major health concern throughout the world, have been linked to GPCR regulation. On the one hand, disorders such as obesity, the excess deposition of fat in the subcutaneous tissues, manifest themselves by an increase in body weight. Individuals who are obese often have, or are susceptible to, medical abnormalities including respiratory difficulties, cardiovascular disease, diabetes and hypertension. On the other hand, disorders like cachexia, the general lack of nutrition and wasting associated with chronic disease and/or emotional disturbance, are associated with a decrease in body weight.
The neuropeptide melanin-concentrating hormone (MCH), a cyclic hypothalamic peptide involved in the regulation of several functions in the brain, has previously been found to be a major regulator of eating behavior and energy homeostasis. It has previously been determined that MCH is the natural ligand for the 353-amino acid orphan G-protein-coupled-receptor (GPCR) termed SLC-1 (also known as GPR24). Subsequent to this determination, SLC-1, which is sequentially homologous to the somatostatin receptors, is frequently referred to as melanin-concentrating hormone receptor (MCH receptor, MCHR or MCHR1) (see Chambers et al.,
Nature
400:261-65 (1999); Saito et al.,
Nature
400:265-69 (1999); and Saito et al.,
TEM
11(8):299-303 (2000)).
Compelling evidence exists that MCH is involved in regulation of eating behavior. First, intracerebral administration of MCH in rats resulted in stimulation of feeding. Next, mRNA corresponding to the MCH precursor is up-regulated in the hypothalamus of genetically obese mice and of fasted animals. Finally, mice deficient in MCH are leaner and have a decreased food intake relative to normal mice. MCH is believed to exert its activity by binding to MCHR, resulting in the mobilization of intracellular calcium and a concomitant reduction in cAMP levels (see Chambers et al.,
Nature
400:261-65 (1999); Shimada et al.
Nature
396:670-74 (1998)). MCH also activates inwardly rectifying potassium channels, and MCHR has been found to interact with both Gai protein and Gaq protein (Saito et al.,
TEM
11(8):299-303 (2000)). Moreover, analysis of the tissue localization of MCHR indicates that it is expressed in those regions of the brain involved in olfactory learning and reinforcement. The cumulative data suggest that modulators of MCHR should have an effect on neuronal regulation of food intake (see Saito et al.,
Nature
400:265-69 (1999)).
MCH has been shown to modulate behaviors other than feeding, such as anxiety (Gonzales et al. (1996)
Peptides
17:171-177; Monzon et al. (1999)
Physiol. Behav.
67:813-817).
The identification of MCHR modulators is useful for the study of physiological processes mediated by MCHR and the development of therapeutic agents for the treatment or prevention of conditions and disorders associated with weight regulation, learning, anxiety and other neuronal-related functions.
SUMMARY OF THE INVENTION
The present invention provides fused heterocyclic compounds and compositions, and methods of use thereof to treat or prevent conditions and disorders mediated by MCHR. In particular, the present invention provides compounds, compositions and methods for treating or preventing conditions and disorders associated with eating behavior, energy homeostasis and anxiety.
The compounds provided herein have the formula (I):
wherein
L is a bond or (C
1
-C
4
)alkylene;
R and R′ are independently selected from the group consisting of hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, CO
2
R
13
, SO
2
R
13
, C(O)NR
13
R
14
, SO
2
NR
13
R
14
and (C
1
-C
4
)alkylene-CO
2
R
13
;
optionally, R and R′ may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
R″ is hydrogen or (C
1
-C
9
)alkyl;
each R
1
is independently selected from the group consisting of halogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, fluoro(C
1
-C
4
)alkyl, —OR
5
, —SR
5
, fluoro(C
1
-C
4
)alkoxy, aryl, aryl(C
1
-C
4
)alkyl, —NO
2
, —NR
5
R
6
, —C(O)R
5
, —CO
2
R
5
, —C(O)NR
5
R
6
, —N(R
6
)C(O)R
5
, —N(R
6
)CO
2
R
5
, —N(R
7
)C(O)NR
5
R
6
, —S(O)
m
NR
5
R
6
, —S(O)
m
R
5
, —CN and —N(R
6
)S(O)
m
R
5
;
R
2
is selected from the group consisting of halogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, fluoro(C
1
-C
4
)alkyl, —OR
8
, —SR
8
, fluoro(C
1
-C
4
)alkoxy, aryl, aryl(C
1
-C
4
)alkyl, —NO
2
, —NR
8
R
9
, ═O, —C(O)R
8
, —CO
2
R
8
, —C(O)NR
8
R
9
, —N(R
9
)C(O)R
8
, —N(R
9
)CO
2
R
8
, —N(R
10
)C(O)NR
8
R
9
, —S(O)
m
NR
8
R
9
, —S(O)
m
R
8
, —CN and —N(R
9
)S(O)
m
R
8
;
R
4
is selected from the group consisting of hydrogen —OR
11
, —C(O)R
11
, —CO
2
R
11
, —C(O)NR
11
R
12
, —CN, (C
1
-C
4
)alkyl and aryl;
R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
16
and R
17
are independently selected from the group consisting of hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, fluoro(C
1
-C
4
)alkyl, hetero(C
1
-C
4
)alkyl, aryl and aryl(C
1
-C
4
)alkyl;
optionally, when two R groups selected from the group consisting of R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
the subscript m is 1 or 2; and
the subscript n is 0, 1 or 2.
Also provided herein are compounds of formula (II):
wherein
R and R′ are independently selected from the group consisting of hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, CO
2
R
13
, SO
2
R
13
, C(O)NR
13
R
14
, SO
2
NR
13
R
4
and (C
1
-C
4
)alkylene-CO
2
R
13
;
R″ is hydrogen or (C
1
-C
8
)alkyl;
each R
1
is independently selected from the group consisting of halogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, fluoro(C
1
-C
4
)alkyl, —OR
5
, —SR
5
, fluoro(C
1
-C
4
)alkoxy, aryl, aryl(C
1
-C
4
)alkyl, —NO
2
, —NR
5
R
6
, —C(O)R
5
, —CO
2
R
5
, —C(O)NR
5
R
6
, —N(R
6
)C(O)R
5
, —N(R
6
)CO
2
R
5
, —N(R
7
)C(O)NR
5
R
6
, —S(O)
m
NR
5
R
6
, —S(O)
m
R
5
, —CN and —N(R
6
)S(O)
m
R
5
;
R
2
is selected from the group consisting of halogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, fluoro(C
1
-C
4
)alkyl, —OR
8
, —SR
8
, fluoro(C
1
-C
4
)alkoxy, aryl, aryl(C
1
-C
4
)alkyl, —NO
2
, —NR
8
R
9
, ═O, —C(O)R
8
, —CO
2
R
8
, —C(O)NR
8
R
9
, —N(R
9
)C(O)R
8
, —N(R
9
)CO
2
R
8
, —N(R
10
)C(O)NR
8
R
9
, —S(O)
m
NR
8
R
9
, —S(O)
m
R
8
, —CN and —N(R
9
)S(O)
m
R
8
;
R
4
is selected from the group consisting of hydrogen —OR
1
, —C(O)R
11
, —CO
2
R
11
, —C(O)NR
11
R
12
, —CN, (C
1
-C
4
)alkyl and aryl;
R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
are independently selected from the group consisting of hydrogen, (C
1
-C
8
)alkyl, (C
2
-C
8
)alkenyl, (C
2
-C
8
)alkynyl, fluoro(C
1
-C
4
)alkyl, hetero(C
1
-C
4
)alkyl, aryl and aryl(C
1
-C
4
)alkyl;
optionally, when two R groups selected from the group consisting of R
5
, R
6
, R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
and R
14
are attached to the same nitrogen atom, the R groups may be combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing the nitrogen atom and from 0 to 2 additional heteroatoms selected from the group consisting of N, O and S;
the subscript m is 1 or 2; and
the subscript n is 0, 1 or 2; and
the subscript p is an integer of from 1 to 4.
Also provided herein are compounds of formula (III):
wherein
R and R&prim

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