Oxazole derivatives

Details Oxazole derivatives Oxazole derivatives

2002-05-09

2003-11-04

Lambkin, Deborah C. (Department: 1713)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06642389

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 sysndrome. 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 present invention comprises novel oxazole derivatives, their manufacture and their use as medicaments. In particular, the invention relates to compounds of the formula (I)
and pharmaceutically acceptable salts and esters thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises compounds of the formula
and pharmaceutically acceptable salts and esters thereof, wherein
R
1
is aryl or heteroaryl;
R
2
, R
3
, R
4
and R
6
are independently selected from the group consisting of hydrogen, hydroxy, lower-alkenyl, halogen, lower-alkyl and lower-alkoxy, wherein at least one of R
2
, R
3
, R
4
and R
6
is not hydrogen, or
R
2
and R
6
are independently selected from the group consisting of hydrogen, hydroxy, lower-alkenyl, halogen, lower-alkyl and lower-alkoxy, and R
3
and R
4
are bonded to each other to form a ring together with the carbon atoms to which they are attached, and R
3
and R
4
together are —CH═CH—S—, —S—CH═CH—, —CH═CH—O—, —O—CH═CH—, —CH═CH—CH═CH—, —(CH
2
)
3-5
—, —O—(CH
2
)
2-3
— or —(CH
2
)
2-3
—O—;
R
5
is lower-alkoxy, lower-alkenyloxy,
R
7
is hydrogen or lower-alkyl;
R
8
is hydrogen or lower-alkyl;
R
9
is hydrogen or lower-alkyl;
R
10
is aryl;
n is 1, 2 or 3;
wherein the bond between the carbon atom C
a
and the carbon atom C
b
is a carbon carbon single or double bond.
The novel compounds of the present bind to and activate both, PPAR&agr; and PPAR&ggr;, simultaneously and very efficiently. Therefore, these compounds combine the anti-gylcemic 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 compared to the compounds already known in the art.
The compounds of the present invention further exhibit improved pharmacological properties compared to known compounds.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term “lower” is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term “halogen” refers to fluorine, chlorine, bromine and iodine.
The term “protecting group” refers to groups such as e.g. acyl, alkoxycarbonyl, aryloxycarbonyl, silyl, or imine-derivatives, which are used to temporarily block the reactivity of functional groups. Well known protecting groups are e.g. t-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl or diphenylmethylene which can be used for the protection of amino groups, or lower-alkyl-, &bgr;-trimethylsilylethyl- and &bgr;-trichloroethyl-esters, which can be used for the protection of carboxy groups.
The term “alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Alkyl groups can be substituted e.g. with halogen, hydroxy, lower-alkoxy, lower-alkoxy-carbonyl, NH
2
, N(H, lower-alkyl) and/or N(lower-alkyl)
2
.
The term “lower-alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. A lower-alkyl group may have a substitution pattern as described earlier in connection with the term “alkyl”.
The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl. The term “lower-alkoxy” refers to the group R′—O—, wherein R′ is lower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy.
The term “lower-alkenyl”, alone or in combination signifies a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 8, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl.
The term “lower-alkenyloxy” means a group R″—O—, wherein R″ is lower-alkenyl. Examples of lower-alkenyloxy groups are butenyloxy, particularly but-3-enyloxy.
The term “aryl” relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted, particularly mono- or

Affiliated with

Also associated with

Rating

Oxazole derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Oxazole derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oxazole derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3142722