Activators of PPAR delta

Details Activators of PPAR delta Activators of PPAR delta

2001-12-19

2004-03-23

Rotman, Alan L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S374000, C548S204000, C548S236000

Reexamination Certificate

active

06710063

ABSTRACT:

This application is filed pursuant to 35 U.S.C. §371 as a United States National Phase Application of International Application No. PCT/EP00/05720 filed Jun. 22, 2000, which claims priority from GB9914977.5 filed Jun. 25, 1999 in the United Kingdom.
The present invention relates to certain novel compounds. In particular, the present invention relates to compounds that activate the delta subtype of the human peroxisome proliferator activated receptor (“hPPAR&dgr;”). The present invention also relates to method for preparing and using the novel compounds and to methods for using activators of hPPAR&dgr;.
Several independent risk factors have been associated with cardiovascular disease. These include hypertension, increased fibrinogen levels, high levels of triglycerides, elevated LDL cholesterol, elevated total cholesterol, and low levels of HDL cholesterol. HMG CoA reductase inhibitors (“statins”) are useful for treating conditions characterized by high LDL-c levels. It has been shown that lowering LDL-c is not sufficient for reducing the risk of cardiovascular disease in some patients, particularly those with normal LDL-c levels. This population pool is identified by the independent risk factor of low HDL-c. The increased risk of cardiovascular disease associated with low HDL-c levels has not yet been successfully addressed by drug therapy (i.e. currently there are no drugs on the market that are useful for raising HDL-c). (Bisgaier, C. L.; Pape, M. E.
Curr. Pharm. Des
. 1998, 4, 53-70).
Syndrome X (including metabolic syndrome) is loosely defined as a collection of abnormalities including hyperinsulinemia, obesity, elevated levels of trigycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
NIDDM (non insulin dependent or Type 2 diabetes mellitus) is described as insulin resistance which in turn causes anomalous glucose output and a decrease in glucose uptake by skeletal muscle. These factors eventually lead to impaired glucose tolerance (IGT) and hyperinsulinemia.
Three mammalian Peroxisome Proliferator-Activated Receptors have been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also known as NUC1 or PPAR-beta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H. Keller and W. Wahli,
Trends Endoodn. Met
291-296, 4 (1993)).
It has now been reported that thiazolidinediones are potent and selective activators of PPAR-gamma and bind directly to the PPAR-gamma receptor (J. M. Lehmann et. al.,
J. Biol. Chem
. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones.
Activators of the nuclear receptor PPAR&ggr; gamma, for example troglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levelsin patients with Type 2 diabetes. See, for example, D. E. Kelly et al.,
Curr. Opin. Endocrinol. Diabetes
, 90-96, 5 (2), (1998); M. D. Johnson et al.,
Ann. Pharinacother
., 337-348, 32. (3), (1997); and M. Leutenegger et al.,
Curr. Ther. Res
., 403-416, 58 (7), (1997).
The mechanism for this triglyceride lowering effect appears to be predominantly increased clearance of very low density lipoproteins (VLDL) through induction of liporotein lipase (LPL) gene expression. See, for example, B. Staels et al.,
Aerieoscler. Thromb., Vasc. Biol
., 1756-1764, 17 (9), (1997).
Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10-15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and increase HDLc 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPAR&agr;. See, for example, B. Staels et al.,
Curr. Pharm. Des
., 1-14, 3 (1), (1997). Activation of PPAR alpha results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion. In addition, PPAR alpha activation decreases production of apoC-III. Reduction in apoC-III, an inhibitor of LPL activity, increases clearance of VLDL. See, for example, J. Auwerx et al.,
Atherosclerosis
, (
Shannon, Irel
.), S29-S37, 124 (Suppl), (1996).
Certain compounds that activate or otherwise interact with one or more of the PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models. See, for example, U.S. Pat. No. 5,847,008 (Doebber et al.) and U.S. Pat. No. 5,859,051 (Adams et al.) and PCT publications WO 97/28149 (Leibowitz et al.) and WO 99/04815 (Shimokawa et al.). In a recent report (Berger et al.,
J. Biol. Chem
. 1999), vol. 274, pp. 6718-6725) it was stated that PPAR delta activation does not appear to modulate glucose or triglyceride levels.
Briefly, in one aspect, the present invention. provides compounds of formula (I), and pharmaceutically acceptable salts and, solvates thereof, wherein
X represents a COOH (or a hydrolysable ester thereof) or tetrazole group;
X
1
represents NH, NCH
3
, O, S, a bond (i.e., is absent), CH
2
, or CH where the dashed line indicates that when X
1
is CH the depicted bond is a double bond;
X
2
represents O or S;
R
1
and R
2
independently represent H, CH
3
, OCH
3
, or halogen;
n is 1 or 2;
one of Y and Z is N and the other is S or O:
y is0 1, 2, 3, 4 or 5;
Each R
3
independently represents CF
3
or halogen.
In another aspect, the present invention discloses a method for prevention or treatment of a human PPAR delta (“hPPAR&dgr;”) mediated disease or condition comprising administration of a therapeutically effective amount of a compound of this invention. hPPAR&dgr; mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, Type 2 diabetes mellitus, Type 1 diabetes, insulin resistance, hyperlipidemia, and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the compounds of this invention are useful in the treatment and prevention of cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a hPPAR&dgr; mediated disease or condition.
In another aspect, the present invention provides a method for lowering triglycerides by administration of a hPPAR&dgr; agonist. Preferably the hPPAR&dgr; agonist is a selective agonist.
In another aspect the present invention provides the use of a hPPAR&dgr; agonist for the manufacture of a medicament for lowering triglyceride. levels. Preferably the hPPAR&dgr; agonist is a selective agonist.
In a further aspect the present invention provides a method for treating Type 2 diabetes, decreasing insulin resistance or lowering blood pressure comprising administering a hPPAR&dgr; agonist. Preferably the hPPAR&dgr; agonist is a selective agonist.
In a further aspect there is provided the use of a hPPAR&dgr; agoni

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