Alkynyl-substituted propionic acid derivatives, their...

Details Alkynyl-substituted propionic acid derivatives, their... Alkynyl-substituted propionic acid derivatives, their...

2001-01-26

2003-05-27

Richter, Johann (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S539000, C514S535000, C514S537000, C514S538000, C514S568000, C560S055000, C560S056000, C560S078000, C560S080000, C560S081000, C562S465000, C562S470000

Reexamination Certificate

active

06569901

ABSTRACT:

FIELD OF INVENTION
The present invention relates to novel compounds, pharmaceutical compositions containing them, methods for preparing the compounds and their use as medicaments. More specifically, compounds of the invention can be utilised in the treatment and/or prevention of conditions mediated by nuclear receptors, in particular the Peroxisome Proliferator-Activated Receptors (PPAR).
BACKGROUND OF THE INVENTION
Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the ‘deadly quartet’ category of impaired glucose tolerance (IGT), insulin resistance, hypertriglyceridaemia and/or obesity).
The hypolipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidaemia often observed in Type 2 diabetic or metabolic syndrome patients. The thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans. However, the fibrate class of compounds are without beneficial effects on glycaemia. Studies on the molecular actions of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apolipoproteins respectively, both key-players in regulation of plasma triglyceride content. Fibrates, on the one hand, are PPAR&agr; activators, acting primarily in the liver. Thiazolidinediones, on the other hand, are high affinity ligands for PPAR&ggr; acting primarily on adipose tissue.
Adipose tissue plays a central role in lipid homeostasis and the maintenance of energy balance in vertebrates. Adipocytes store energy in the form of triglycerides during periods of nutritional affluence and release it in the form of free fatty acids at times of nutritional deprivation. The development of white adipose tissue is the result of a continuous differentiation process throughout life. Much evidence points to the central role of PPAR&ggr; activation in initiating and regulating this cell differentiation. Several highly specialised proteins are induced during adipocyte differentiation, most of them being involved in lipid storage and metabolism. The exact link from activation of PPAR&ggr; to changes in glucose metabolism, most notably a decrease in insulin resistance in muscle, has not yet been clarified. A possible link is via free fatty acids such that activation of PPAR&ggr; induces Lipoprotein Lipase (LPL), Fatty Acid Transport Protein (FATP) and Acyl-CoA Synthetase (ACS) in adipose tissue but not in muscle tissue. This, in turn, reduces the concentration of free fatty acids in plasma dramatically, and due to substrate competition at the cellular level, skeletal muscle and other tissues with high metabolic rates eventually switch from fatty acid oxidation to glucose oxidation with decreased insulin resistance as a consequence.
PPAR&agr; is involved in stimulating &bgr;-oxidation of fatty acids. In rodents, a PPAR&agr;-mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis in rodents. The phenomenon of peroxisome proliferation is not seen in man. In addition to its role in peroxisome proliferation in rodents, PPAR&agr; is also involved in the control of HDL cholesterol levels in, rodents and humans. This effect is, at least partially, based on a PPAR&agr;-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic action of fibrates and fatty acids also involves PPAR&agr; and can be summarised as follows: (I) an increased lipolysis and clearance of remnant particles, due to changes in lipoprotein lipase and apo C-III levels, (II) a stimulation of cellular fatty acid uptake and their subsequent conversion to acyl-CoA derivatives by the induction of fatty acid binding protein and acyl-CoA synthase, (III) an induction of fatty acid &bgr;-oxidation pathways, (IV) a reduction in fatty acid and triglyceride synthesis, and finally (V) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles constitutes mechanisms that contribute to the hypolipidemic effect of fibrates.
A number of compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (U.S. Pat. No. 5,306,726, PCT Publications nos. WO 91/19702, WO 95/03038, WO 96/04260, WO 94/13650, WO 94101420, WO 97/36579, WO 97/25042, WO 95/17394, WO 99/08501, WO 99/19313 and WO 99/16758).
SUMMARY OF THE INVENTION
Glucose lowering as a single approach does not overcome the macrovascular complications associated with Type 2 diabetes and metabolic syndrome. Novel treatments of Type 2 diabetes and metabolic syndrome must therefore aim at lowering both the overt hypertriglyceridaemia associated with these syndromes as well as alleviation of hyperglycaemia.
The clinical activity of fibrates and thiazolidinediones indicates that research for compounds displaying combined PPAR&agr; and PPAR&ggr; activation should lead to the discovery of efficacious glucose and triglyceride lowering drugs that have great potential in the treatment of Type 2 diabetes and the metabolic syndrome (i.e. impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity).
DETAILED DESCRIPTION OF THE INVENTION
Accordings, the present invention relates to compounds of the general formula (I):
wherein
X is hydrogen or
X is C
1-12
-alkyl, C
2-12
-alkenyl, C
2-12
-alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl or heterocyclyl each of which is optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkynyl, hydroxy, C
1-6
-alkoxy, C
1-6
-alkylthio, aryl, aryloxy, arylthio, acyl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, C
1-6
-alkylthio, cyano, amino, C
1-6
-alkylamino, C
1-6
-dialkylamino, carboxy or C
1-6
-alkylester; and
Y is hydrogen or
Y is C
1-12
-alkyl, C
2-12
-alkenyl, C
2-12
-alkynyl, C
4-12
-alkenynyl, aryl, heteroaryl, aralkyl or heteroaralkyl each of which is optionally substituted with one or more substituents selected from halogen, C
1-6
-alkyl, perhalomethyl, hydroxy, aryl, heteroaryl, amino, carboxy or C
1-6
-alkylester; and
Z is hydrogen, halogen, hydroxy or
Z is C
1-6
-alkyl or C
1-6
-alkoxy each of which is optionally substituted with one or more substituents selected from C
1-6
-alkoxy, halogen, hydroxy, carboxy, amino or cyano; and
Q is O, S or NR
5
, wherein R
5
is hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkynyl, C
4-6
-alkenynyl, aralkyl or heteroaralkyl and wherein R
5
is optionally substituted with one or more substituents selected from halogen, hydroxy, C
1-6
-alkoxy, amino or carboxy; and
Ar is arylene, heteroarylene or a divalent heterocyclic group each of which can be optionally substituted with one or more substituents selected from C
1-6
-alkyl, aryl or C
1-6
-alkoxy each of which can be optionally substituted with halogen, hydroxy, carboxy or C
1-6
-alkylester; and
R
1
is hydrogen, hydroxy or halogen; or R
1
forms a bond together with R
2
; and
R
2
is hydrogen or C
1-6
-alkyl; or R
2
forms a bond together with R
1
; and
R
3
is hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkynyl, C
4-6
-alkenynyl, aryl, aralkyl, C
1-6
-alkoxyC
1-6
-alkyl, acyl, heterocyclyl, heteroaryl or heteroaralkyl groups optionally substituted with one or more substituents selected from halogen, perhalomethyl, hydroxy, cyano, carboxy or C
1-6
alkylester; and
R
4
is hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkynyl, C
4-6
-alkenynyl or aryl;
n is an integer rang

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