Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-29
2004-09-07
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S340000, C514S341000, C514S375000, C514S381000
Reexamination Certificate
active
06787556
ABSTRACT:
The present invention relates to the use of certain benzoic acid derivatives which act as peroxisome proliferator activated receptor (PPAR) agonists, in particular gamma receptors (PPAR&ggr;), and so are useful in the treatment of states of insulin resistance, including type 2 diabetes mellitus. Novel pharmaceutical compositions and novel compounds are also defined, together with methods of their production.
Traditionally, therapeutic intervention in type 2 diabetes has had a ‘glucocentric focus’ dominated by the use of insulin secretogogues e.g. the sulphonylureas and the measurement of glycated haemoglobin (HbA1c) or fasting blood sugar level (FPG) as indices of diabetic control. In the USA, patients with type 2 diabetes are usually treated with diet and, when needed, a sulphonylurea compound. However, it is estimated that approximately 30% of patients initially treated with sulphonylurea agents have a poor response and in the remaining 70%, the subsequent failure rate is approximately 45% per annum. Other estimates put failure rates higher with few patients responding after 10 years therapy. A treatment-related increase in body weight is also experienced with these agents. Prior to the FDA approval of metformin in 1995, the only therapeutic option for type 2 diabetic patients, in whom sulphonylurea therapy had failed, was insulin.
Despite the introduction of newer agents both the incidence and prevalence of type 2 diabetes continues to increase on a global basis. Approximately 16 million people in the USA have diabetes mellitus, 90-95% of whom have type 2 disease. This represents an enormous healthcare burden; estimated in 1998 to be some $98 billion per annum in direct and indirect healthcare costs. Recently, both the ADA and WHO have revised guidelines for the diagnosis of diabetes and classified diabetes more according to aetiology. The threshold for diagnosis (FPG>126 mg/dl) has been lowered and the term ‘type 2’ is now used to describe mature onset diabetics who have not progressed to insulin therapy. After the ADA implemented these new criteria in 1997, the prevalence of the type 2 disease sector increased by nearly 6 million people in the seven major pharmaceutical markets (France, Germany, Italy, Japan, Spain, UK and USA).
Apart from often mild acute symptoms, type 2 diabetics are also at a considerable risk of developing long term complications of the disease. These include a 4-5 fold higher risk, (compared with non-diabetics), of developing macrovasular disease including CHD and PVD and microvascular complications including retinopathy, nephropathy and neuropathy. In many individuals, overt type 2 diabetes is preceded by a period of reduced insulin sensitivity (insulin resistance), accompanied by a cluster of other cardiovascular risk factors, collectively termed as insulin resistance syndrome (IRS).
It has been estimated that approximately 80% of type 2 diabetics are obese and other co-morbidities of the IRS include: dyslipidemia, hyperinsulineria, raised arterial blood pressure, uricemia and a reduced fibrinolysis. Given the increased global prevalence and incidence of type 2 diabetes and the very high costs of treating the long term complications of the disease there is tremendous interest in the development of agents that delay or prevent the onset of type 2 diabetes and in those that reduce the risk of cardiovascular complications associated with IRS. These activities have lead to the introduction of the thiazolidinedione (TZD) class of insulin sensitisers that improved the dyslipidemia and thus restored the insulin sensitivity leading to improved glycemic control and lower HbA1c levels.
Although the complex interplay between lipids and carbohydrates as metabolic fuels has been recognised for many decades it is only recently, that researchers and clinicians have begun to focus on the importance of dyslipidemia seen in type 2 diabetes. Much has been made of the relative sensitivities of muscle, liver and adipose tissues to insulin and a case for the primacy of insulin resistance in adipose tissue leading to the IRS has been debated. A typical dyslipidemic atherogenic lipoprotein phenotype (referred to as type B) is seen in IRS including frequently in type 2 diabetics, characterised by a modestly raised LDL-C, a more significant increase in VLDL-TG and reduced HDL. Apparently, changes in the physicochemical properties of VLDL-TG particles result in slower plasma clearance rates and in the generation of small dense LDL particles. The latter permeate the vascular endothelium more readily and are more prone to oxidation and glyration and are considered to play a critical role in atherogenesis in large vessels. Although more difficult to measure, improved free fatty acid (IFFA) flux is increasingly considered to play an important role in the IRS affecting metabolic events in muscle, liver, adipose tissue and pancreas.
The first generation TZDs e.g. troglitazone, pioglitazone, rosiglitazone were in clinical development before the putative mechanism of action was discovered and published in 1995 (PPAR&ggr; activation). It is clear from experience with these first generation agents that it is difficult to predict from animal pharmacology the safety and efficacy profile these agents will have in the clinic. Thus, knowledge of the putative mechanism of action of this class coupled with concerns regarding safety, offers the opportunity to identify non-TZD activators of PPAR for the treatment of type 2 diabetes and is the subject of this invention. Furthermore, we recognise that agents with a dual action at both &agr; and g PPAR may have additional benefits in reducing diabetic co-morbidities, particularly raised triglycerides. Such agents may be useful in the treatment of type 2 diabetes, the IRS, dyslipidemia and in reducing risk of cardiovascular disease.
Certain heterocyclic amides and their use as leukotriene antagonists is described in EP-A-179619. Additional phenyltetrazole leukotriene D
4
receptor antagonists have been described by Sawyer et al., J. Med. Chem. 1992, 35, 7, 1200-1209.
The present invention provides the use of a compound of formula (I)
or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for use in the activation of PPAR,
where Q, X, Y and Z are either —CR
a
═, —CR
b
═CR
c
— or —N═; where R
a
, R
b
and R
c
are independently selected from hydrogen, halo or a bond, such that together with the nitrogen atom to which Y and Z are attached, they form a five or six-membered aromatic ring;
R
1
and R
3
are independently selected from C
1-3
alkyl, halo, haloC
1-3
alkyl, C
1-3
alkoxy, or haloC
1-3
alkoxy;
n and m are independently selected from 0, 1 or 2;
A is an alkylene, alkenylene or alkynylene chain optionally interposed by a heteroatom; and
R
2
is an optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted cycloalkyl moiety.
As used herein, the term “hydrocarbyl” refers to alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl groups.
As used herein the term “heterocyclyl” refers to single or fused ring structures which, unless stated otherwise, may be aromatic or non-aromatic in nature and which suitably contain from 2 to 20 ring atoms, suitably from 5 to 8 ring atoms, at least one of which and suitably up to four of which are heteroatoms. The term “heteroatom” includes oxygen, sulphur and nitrogen. Where a heteroatom is nitrogen, it will be further substituted for example by hydrogen or an alkyl group.
In this specification the term “aryl” refers to phenyl, biphenyl and naphthyl.
The term “heterocyclyl” includes aromatic or non-aromatic rings, for example containing from 4 to 20, Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl.
“Heteroaryl” refers to those groups described above
Hargreaves Rodney Brian
Whittamore Paul Robert Owen
AstraZeneca AB
Powers Fiona T.
White & Case LLP
LandOfFree
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