Compounds for the treatment of obesity

Details Compounds for the treatment of obesity Compounds for the treatment of obesity

2001-01-04

2003-02-04

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S396000, C514S397000, C514S399000, C514S341000, C546S001000, C546S274100, C546S276400, C546S278400, C548S335100, C548S335500, C548S341500, C548S343500

Reexamination Certificate

active

06514966

ABSTRACT:

BACKGROUND OF INVENTION
This invention relates to NPY antagonists, particularly NPY-5 antagonists, and pharmaceutical compositions containing such antagonists and the use of such antagonists to treat, for example, obesity, feeding disorders, as well as other NPY mediated diseases/conditions in mammals, including humans, dogs, cats and horses.
Neuropeptide Y (NPY), a 36 amino acid peptide neurotransmitter, is a member of the pancreatic polypeptide class of neurotransmitters
eurohormones which has been shown to be present in both the periphery and central nervous system. NPY is one of the most potent orexogenic agents known and has been shown to play a major role in the regulation of food intake in animals. At least 6 NPY receptor subclasses have been identified and cloned to date, with two of these subclasses, NPY-1 and NPY-5, thought to be the most important receptor subtypes modulating food intake and energy expenditure.
Various animal studies have shown that activation of neuropeptide Y receptors is related to stimulation of consummatory behavior, Food and Morley
Peptides
, 10:963-966 (1989), Leibowitz and Alexander,
Peptides
, 12:1251-1260 (1991), and Stanley et al.
Peptides
, 13:581-587 (1992), and to vasoconstriction, Wahlestedt et al. Regul.
Peptides
, 13:307-318 (1986), McCauley and Westfall
J. Pharmacol. Exp. Ther
. 261:863-868 (1992), and Grundemar et al.
Br. J. Pharmacol
. 105:45-50 (1992).
Further, Grundemar and Hakanson
TiPS
, May 1994 [Vol. 15], 153-159, state that in animals, neuropeptide Y is a powerful stimulus of food intake and inducer of vasoconstriction leading to hypertension. They also point out that low levels of neuropeptide Y (NPY) are associated with loss of appetite. The reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
Hence, agents capable of blocking NPY binding at these receptor subtype(s) should have utility in a number of feeding disorders including obesity, anorexia nervosa, bulimia nervosa; obesity-related disorders including but not limited to insulin resistance, diabetes, hyperlipidemia, and hypertension, as well other indications for treatment where blockade of NPY activity is beneficial.
EP0759441 and U.S. Pat. No. 5,576,337 report physiological disorders related to any excess of neuropeptide Y.
In addition, a variety of publications have disclosed the use of imidazole and benzylamine derivatives for various utilities including the treatment of obesity.
WO 99/01128 discloses certain NPY5 receptor mediators useful for treating feeding disorders such as obesity and bulima as well as certain cardiovascular diseases such as essential hypertension.
WO 96/14307 describes substituted benzylamine derivatives which selectively bind to human neuropeptide Y1 receptors.
U.S. Pat. Nos. 4,440,774 and 4,853,383 disclose certain substituted imidazoles and their use as &bgr;-adrenergic blockers for the treatment of, for example, hypertension.
EP 0354549 discloses certain imidazoles which are cyan couplers useful in the photography industry.
Thus, there is clearly a need and a continuing search in this field of art for treatments for obesity.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula I
a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug;
wherein Y is an aromatic five to eight membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen or an aromatic bicyclic ring consisting of two fused three to six membered rings, taken independently, optionally having one to four heteratoms selected independently from nitrogen, sulfur and oxygen;
wherein said Y ring has a maximum of three substituents selected independently from Group I, Group II and Group III:
Group I: said Y ring is optionally mono-, di-, or tri-substituted independently with nitro, amino, hydroxy, (C
2
-C
6
)alkenyl, (C
1
-C
4
)alkylthio, halo, cyano, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyloxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy or (C
3
-C
6
)cycloalkoxy, said (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyloxy, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy and (C
3
-C
6
)cycloalkoxy moieties optionally substituted with one to nine fluorines;
Group II: said Y ring is optionally mono-substituted with a four to seven membered saturated nitrogen containing ring optionally having one to two additional heteroatoms selected independently from sulfur, oxygen or nitrogen, said four to seven membered ring optionally mono- or di-substituted independently with (C
1
-C
5
)alkyl, said (C
1
-C
5
)alkyl optionally substituted with one to nine fluorines; or
Group III: said Y ring is optionally mono-, or di-substituted independently with mono-N- or di-N,N-(C
1
-C
6
)alkylamino, mono-N- or di-N,N-(C
3
-C
6
)cycloalkylamino or N-(C
1
-C
6
)alkyl-N-(C
3
-C
6
)cycloalkylamino, said mono-N- or di-N,N-(C
1
-C
6
)alkylamino, mono-N- or di-N,N-(C
3
-C
6
)cycloalkylamino or N-(C
1
-C
6
)alkyl-N-(C
3
-C
6
)cycloalkylamino optionally mono-, di-, or tri-substituted independently on each (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl with (C
3
-C
6
)cycloalkyl, hydroxy, (C
1
-C
3
)alkoxy, (C
3
-C
6
)cycloalkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
3
)alkoxy, cyano or fluoro;
L and M are each independently carbon or nitrogen, with the proviso that L and M are not the same, wherein said carbon is bonded to an R
3
ring through an R
3
ring nitrogen;
wherein R
3
is a four to eight membered saturated or partially saturated nitrogen containing ring optionally having one additional heteratom selected independently from sulfur, oxygen or nitrogen;
wherein said additional optional R
3
ring nitrogen is optionally mono-substituted with:
1) H or a T ring, optionally linked through (C
1
-C
8
)alkyl or carbonyl wherein said T ring is a partially saturated or fully unsaturated five to eight membered ring optionally having one to two heteroatoms selected independently from oxygen, sulfur and nitrogen or said T ring is a four to seven membered saturated ring having one to two heteroatoms selected independently from sulfur, oxygen or nitrogen or said T ring is an aromatic bicyclic ring consisting of two fused three to six membered rings, taken independently, optionally having one to four heteratoms selected independently from nitrogen, sulfur and oxygen;
wherein said T ring is substituted with a maximum of three substituents selected independently from Group IV, Group V and Group VI (this phase and analogous phrases used herein is exemplified as follows: there may be 3 substituents from Group IV for a total of 3 substituents, there may be 2 substituents from Group V and 1 substituent from group IV for a total of 3 substituents, etc.):
Group IV: said T ring is optionally mono-, di- or tri-substituted independently with nitro, amino, hydroxy, (C
2
-C
6
)alkenyl, (C
1
-C
4
)alkylthio, halo, cyano, (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyloxy, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkoxy, said (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
6
)alkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyloxy and (C
3
-C
6
)cycloalkoxy moieties optionally substituted with one to nine fluorines;
Group V: said T ring optionally mono- or di-substituted independently with mono-N- or di-N,N-(C
1
-C
6
)alkylamino, mono-N- or di-N,N-(C
3
-C
6
)cycloalkylamino or N-(C
1
-C
6
)alkyl-N-(C
3
-C
6
)cycloalkylamino wherein said mono-N- or di-N,N-(C
1
-C
6
)alkylamino, mono-N- or di-N,N-(C
3
-C
6
)cycloalkylamino or N-(C
1
-C
6
)alkyl-N-(C
3
-C
6
)cycloalkylamino is optionally mono-, di-, or tri-substituted independently on each of said (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl with (C
3
-C
6
)cycloalkyl, hydroxy, (C
1
-C
3
)alkoxy, (C
3
-C
6
)cycloalkoxy, (C
3
-C
6
)cycloalkyl(C
1
-C
3
)alkoxy, cyano or fluoro;
Group VI: said T ring is optionally mono-subst

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