Oxazole derivatives

Details Oxazole derivatives Oxazole derivatives

2003-07-01

2004-06-08

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S235000, C548S236000

Reexamination Certificate

active

06747049

ABSTRACT:

BACKGROUND OF THE INVENTION
Peroxisome Proliferator Activated Receptors (PPAR's) are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Various subtypes thereof have been identified and cloned. These include PPAR&agr;, PPAR&bgr; (also known as PPAR&dgr;), and PPAR&ggr;. There exist at least two major isoforms of PPAR&ggr;. While PPAR&ggr;1 is ubiquitously expressed in most tissues, the longer isoform PPAR&ggr;2 is almost exclusively found in adipocytes. In contrast, PPAR&agr; is predominantly expressed in the liver, kidney and heart. PPAR's modulate a variety of body responses including glucose- and lipid-homeostasis, cell differentiation, inflammatory responses and cardiovascular events.
Diabetes is a disease in which a patient's ability to control glucose levels in blood is impaired, because he has partially lost the ability to respond properly to the action of insulin. In type II diabetes (T2D), often referred to as non-insulin dependent diabetes mellitus (NIDDM), which afflicts 80-90% of all diabetic patients in developed countries, the Isles of Langerhans in the pancreas still produce insulin. However, the target organs, mainly muscle, liver and adipose tissue, exhibit a profound resistance to insulin stimulation, and the body compensates by producing unphysiologically high levels of insulin. In later stage of disease, however, insulin secretion decreases due to exhaustion of the pancreas. In addition to that T2D is a metabolic-cardiovascular disease syndrome. Among the comorbidities associated with T2D are for example insulin resistance, dyslipidemia, hypertension, endothelial dysfunction and inflammatory atherosclerosis.
Current first line treatment for diabetes generally involves low fat—and glucose—diet and exercise. However, compliance can be moderate and as the disease progresses, treatment with hypoglycemic drugs, e.g. sulfonylureas or metformin, becomes necessary. A promising new class of drugs has recently been introduced that resensitizes patients to their own insulin (insulin sensitizers), thereby reverting blood glucose and triglyceride levels to normal, and thus abolishing, or at least reducing, the requirement for exogenous insulin. Pioglitazone (Actos™) and rosiglitazone (Avandia™) belong to the thiazolidinediones (TZD) class of PPAR&ggr;-agonists and were the first representatives who had been approved for NIDDM in several countries. These compounds, however, suffer from side effects including rare but severe liver toxicity (as seen with troglitazone), and they increase body weight in humans. Therefore, new, better and more efficacious drugs for the treatment of NIDDM are urgently needed. Recent studies provide evidence that a coagonism on PPAR&agr; and PPAR&ggr; would result in compounds with enhanced therapeutic potential, i.e. with an improved lipid profile effect on top of the normalization of glucose- and insulin-levels (Keller and Wahli: Trends Endocrin. Metab. 1993; 4:291-296, Macdonald and Lane: Current Biology Vol.5 pp.618-621 (1995)).
SUMMARY OF THE INVENTION
The invention provides compounds of formula I
and pharmaceutically acceptable salts and esters thereof, wherein
R
1
is aryl;
R
2
is hydrogen, alkyl or cycloalkyl;
R
3
is hydrogen, alkyl, aralkyl, aryl, alkylcarbonyl, arylcarbonyl, alkyl-S(O)
2
— or aryl-S(O)
2
—;
R
4
is aralkyl;
R
5
, R
6
, R
7
and R
8
are independently selected from hydrogen, alkyl or cycloalkyl; and
n is 1, 2, 3, 4 or 5.
The compounds of formula I and their pharmaceutically acceptable salts and esters are insulin sensitizers, particularly PPAR activators.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is concerned with oxazole derivatives useful as insulin sensitizers, particularly PPAR activators.
The invention provides compounds of formula I
and pharmaceutically acceptable salts and esters thereof, wherein
R
1
is aryl;
R
2
is hydrogen, alkyl or cycloalkyl;
R
3
is hydrogen, alkyl, aralkyl, aryl, alkylcarbonyl, arylcarbonyl, alkyl-S(O)
2
— or aryl-S(O)
2
—;
R
4
is aralkyl;
R
5
, R
6
, R
7
and R
8
are independently selected from hydrogen, alkyl or cycloalkyl; and
n is 1, 2, 3, 4 or 5.
The compounds of formula I and their pharmaceutically acceptable salts and esters are insulin sensitizers, particularly PPAR activators.
The compounds of the present invention bind to and activate both PPAR&agr; and PPAR&ggr;, simultaneously and very efficiently. Therefore, these compounds combine the anti-glycemic effect of PPAR&ggr; activation with the anti-dyslipidemic effect of PPAR&agr; activation. Consequently, plasma glucose and insulin are reduced (=insulin sensitization), triglycerides lowered and HDL cholesterol increased (=improved lipid profile). In addition, such compounds may also lower LDL cholesterol, decrease blood pressure and counteract inflammatory atherosclerosis. Since multiple facets of the T2D disease syndrome are addressed by PPAR&agr; and &ggr; coagonists, they are expected to have an enhanced therapeutic potential.
Accordingly, the compounds of formula I can be used in the prophylaxis and/or treatment of diabetes, particularly non-insulin dependent diabetes mellitus, elevated blood pressure, increased lipid and cholesterol levels, atherosclerotic diseases or metabolic syndrome.
In the present description the term “alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms Examples of straight-chain and branched C
1
-C
8
alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl and ethyl and most preferred methyl.
The term “cycloalkyl”, alone or in combination, signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C
3
-C
8
cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethyl-cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.
The term “alkoxy”, alone or in combination, signifies a group of the formula alkyl-O— in which the term “alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert.butoxy, 2-hydroxyethoxy, 2-methoxyethoxy preferably methoxy and ethoxy, and most preferred methoxy.
The term “aryloxy”, alone or in combination, signifies a group of the formula aryl-O— in which the term “aryl” has the previously given significance, such as phenyloxy.
The term “aryl”, alone or in combination, signifies a phenyl or naphthyl group, preferably a phenyl group which optionally carries one or more substituents each independently selected from halogen, trifluoromethyl, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy, or nitro. Examples of aryl include phenyl, chlorophenyl, trifluoromethylphenyl, chlorofluorophenyl, aminophenyl, methylcarbonylphenyl, methoxyphenyl, methylendioxyphenyl, 1-naphthyl and 2-naphthyl.
Preferred is phenyl, 3-chlorophenyl, 3-trifluoromethylphenyl, 3-aminophenyl, 4-methylcarbonylphenyl, 4-methoxyphenyl and particularly phenyl.
The term “aralkyl”, alone or in combination, signifies an alkyl or cycloalkyl group as previously defined in which one or more, preferably one hydrogen atom has been replaced by an aryl group as previously defined. Preferred are benzyl, benzyl substituted with hydroxy, alkoxy or halogen, preferably fluorine. Particularly preferred is benzyl.
The term “amino”, alone or in combination, signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino gr

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