PPAR agonists

Details PPAR agonists PPAR agonists

2002-02-14

2004-03-02

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S539000, C514S561000, C514S562000, C514S564000, C514S567000, C514S596000, C514S618000, C514S361000, C514S378000, C514S381000, C562S426000, C562S455000, C562S451000, C564S047000, C564S053000, C564S054000, C564S161000, C564S182000, C564S084000, C564S092000, C564S095000, C564S184000, C564S194000, C548S131000, C548S245000, C548S253000, C548S254000, C560S037000, C560S045000, C560S048000, C558S404000, C558S408000

Reexamination Certificate

active

06699904

ABSTRACT:

BACKGROUND OF INVENTION
This invention relates to peroxisome proliferator activator receptor (PPAR) agonists, in particular, PPAR&agr; agonists, pharmaceutical compositions containing such agonists and the use of such agonists to treat atherosclerosis, hypercholesterolemia, hypertriglyceridemia, diabetes and obesity in mammals, including humans.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of “fatty streaks” in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, gives rise to development of the “fibrous plaque,” which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. These cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the “complicated lesion,” which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of “normal” are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particularly high risk. Additional independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes could be improved. The use of insulin typically requires multiple daily doses. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy.
U.S. Pat. No. 5,658,944, WO92/10468, WO97/36579, WO98/05331 and WO 00/23407 disclose agents for the treatment of atherosclerosis, obesity and diabetes.
Thus, although there are a variety of anti-atherosclerosis and diabetes therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.
SUMMARY OF THE INVENTION
This invention is directed to compounds of Formula I:
prodrugs thereof, and pharmaceutically acceptable salt of said compound and of said prodrugs;
wherein
E is carbonyl or sulfonyl;
B is methylene or —N(H)—;
Z is carboxyl, carboxaldehyde, hydroxymethyl, (C
1
-C
4
)alkoxycarbonyl, cyano, hydroxyaminocarbonyl, tetrazolyl, tetrazolylaminocarbonyl, 4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 3-oxoisoxazolidin-4-yl-aminocarbonyl, or —C(O)N(H)SO
2
R
4
;
where R
4
is (C
1
-C
6
)alkyl, amino or mono-N— or di-N,N—(C
1
-C
6
)alkylamino, said (C
1
-C
6
)alkyl substituents are optionally substituted independently with from one to nine fluorines; W is a bond, —N(H)—, —N((C
1
-C
4
)alkyl)—, (C
1
-C
4
)alkylamino or (C
1
-C
8
)alkylene;
wherein said (C
1
-C
8
)alkylene may optionally be mono- or di-substituted independently with oxo, halo, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkyl, (C
2
-C
6
)alkenyl, (C
3
-C
7
)cycloalkyl, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
4
)alkylthio, amino, cyano, nitro, or mono-N— or di-N,N—(C
1
-C
6
)alkylamino or
wherein W is CR
7
R
8
wherein R
7
and R
8
are linked together to form a three to six membered fully saturated carbocyclic ring;
R
1
is H, (C
1
-C
6
)alkyl or (C
3
-C
6
)cycloalkyl;
R
2
is H, a (C
3
-C
6
)cycloalkyl or a fully saturated, partially unsaturated or fully unsaturated one to four membered straight or branched carbon chain wherein the carbon(s) may optionally be replaced with one or two heteroatoms selected independently from oxygen and sulfur and wherein said carbon(s) is optionally mono-, di- or tri-substituted independently with halo, said carbon(s) is optionally mono-substituted with hydroxy, said carbon(s) is optionally mono-substituted with oxo, said sulfur is optionally mono- or di-substituted with oxo, and said chain is optionally mono-substituted with Y;
wherein Y is a partially saturated, fully saturated or fully unsaturated three to eight membered ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, said bicyclic ring optionally having one to four heteroatoms selected independently from oxygen, sulfur and nitrogen;
wherein said Y ring is optionally mono-, di- or tri-substituted independently with halo, (C
2
-C
6
)alkenyl, (C
1
-C
6
) alkyl, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
4
)alkylthio, amino, nitro, cyano, oxo, carboxy, (C
1
-C
6
)alkyloxycarbonyl, mono-N— or di-N,N—(C
1
-C
6
)alkylamino wherein said (C
1
-C
6
)alkyl substituent is optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
4
)alkylthio, amino, nitro, cyano, oxo, carboxy, (C
1
-C
6
)alkyloxycarbonyl, mono-N— or di-N,N—(C
1
-C
6
)alkylamino, said (C
1
-C
6
)alkyl substituent is also optionally substituted with from one to nine fluorines; or
R
1
and R
2
are linked together to form a three to six membered fully saturated carbocyclic ring optionally having one heteroatom selected from oxygen, sulfur and nitrogen;
R
3
is (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl or (C
2
-C
10
)alkynyl, said (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl or (C
2
-C
10
)alkynyl substituents are optionally mono-, di- or tri-substituted independently with halo, hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
4
)alkylthio, amino, nitro, cyano, oxo, carboxy, (C
1
-C
6
)alkyloxycarbonyl, mono-N— or di-N,N—(C
1
-C
6
)alkylamino or optionally
said (C
1
-C
10
)alkyl, (C
2
-C
10
)alkenyl or (C
2
-C
10
)alkynyl substituents are mono-substituted with a partially saturated, fully saturated or fully unsaturated five to six membered ring optionally having one to two heteroatoms selected from nitrogen, oxygen and sulfur, or a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, said bicyclic ring optionally having one to four heteroatoms selected independently fr

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