3-aryl-2-hydroxypropionic acid derivative III

Details 3-aryl-2-hydroxypropionic acid derivative III 3-aryl-2-hydroxypropionic acid derivative III

1999-07-20

2002-03-26

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S060000, C562S470000

Reexamination Certificate

active

06362360

ABSTRACT:

FIELD OF INVENTION
The present invention releates to a novel 3-aryl-2-hydroxypropionic acid derivative, to a process and intermediate for preparing such a compound, having the utility in clinical conditions associated with insulin resistance, to methods for its therapeutic use and to pharmaceutical compositions containing it.
BACKGROUND OF THE INVENTION
Insulin resistance, defined as reduced sensitivity to the actions of insulin in the whole body or individual tissues such as skeletal muscle, myocardium, fat and liver prevail in many individuals with or without diabetes mellitus. The insulin resistance syndrome, IRS, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinemia, possibly non insulin dependent diabetes mellitus (NIDDM); arterial hypertension; central (visceral) obesity; dyslipidemia observed as deranged lipoprotein levels typically characterized by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations and reduced fibrinolysis.
Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In non-insulin dependent diabetes mellitus these atherosclerosis related conditions cause up to 80% of all deaths.
In clinical medicine there is at present only limited awareness of the need to increase the insulin sensitivity in IRS and thus to correct the dyslipidemia which is considered to cause the accelerated progress of atherosclerosis.
Furthermore there is at present no pharmacotherapy available to adequately correct the metabolic derangements associated with IRS. To date, the treatment of NIDDM has been focused on correction of the deranged control of carbohydrate metabolism associated with the disease. Stimulation of endogenous insulin secretion by means of secretagogues, like sulphonylureas, and if necessary administration of exogenous insulin are methods frequently used to normalize blood sugar but that will, if anything, further enhance insulin resistance and will not correct the other manifestations of IRS or reduce cardiovascular morbidity and mortality. In addition such treatment involves a significant risk of hypoglycemia with associated complications.
Other therapeutic strategies have focused on aberrations in glucose metabolism or absorption, including biguanides, such as methformin, or glucosidase inhibitors, such as acarbose. Although these agents have been efficacious to a degree, their limited clinical effect is associated with side effects.
A novel therapeutic strategy involves the use of insulin sensitizing agents, such as the thiazolidinediones, which, at least in part, mediate their effects via an agonistic action on nuclear receptors. Ciglitazone is the prototype in this class. In animal models of IRS these compounds seem to correct insulin resistance and the associated hypertriglyceridaemia and hyperinsulinemia, as well as hyperglycemia in diabetes, by improving insulin sensitivity via an effect on lipid transport and handling, leading to enhanced insulin action in skeletal muscle, liver and adipose tissue.
Ciglitazone as well as later described thiazolidinediones in clinical development either have been discontinued reportedly due to unacceptable toxicity or show inadequate potency. Therefore there is a need for new and better compounds with insulin sensitizing properties.
PRIOR ART
Compounds of the formula
and certain derivatives thereof disclosed in U.S. Pat. No. 5,306,726 and WO 91/19702 are said to be useful as hypoglycemic and hypocholesterolemic agents, and in U.S. Pat. No. 5,232,945 said to be useful in the treatment of hypertension.
AU 650 429 discloses structurally related compounds, but claimed to have different properties: diuretic, antihypertensive, platelet anti-aggregating and anti-lipoxygenase properties.
EP 139 421 discloses compounds having the ability to lower blood lipid and blood sugar levels. Among these compounds is troglitazone, a compound that has reached the market for treatment of NIDDM or decreased glucose tolerance.
DESCRIPTION OF THE INVENTION
It has now surprisingly been found that the novel compound 3-{4-[2-(4-tert-Butoxycarbonylaminophenyl)ethoxy]phenyl}-(S)-2-ethoxy propanoic acid having the formula I
is effective in conditions associated with insulin resistance.
The invention also relates to pharmaceutically acceptable salts, solvates, such as hydrates, and crystalline forms of the compound of the formula I.
In the present specification the expression “pharmaceutically acceptable salts” is intended to define but is not limited to such salts as the alkali metal salts (e.g. sodium, lithium and potassium), alkaline earth metal salts (e.g. calcium, barium and magnesium), aluminum, zinc and bismuth salts, ammonium salts, salts with basic amino acids, such as arginine, lysine, and salts with organic amines such as ethanolamine, ethylenediamine, triethanoleamine, benzylphenethylamine, diethylamine, tromethamine, benzathine, chloroprocaine, choline, meglumine, procaine, clemizole and piperazine.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all pharmaceutically acceptable salts thereof, crystalline forms and solvates thereof such as for instance hydrates.
Methods of Preparation
The compound of the invention may be prepared as outlined below according to any of methods A-H. However, the invention is not limited to these methods, the compound may also be prepared as described for structurally related compounds in the prior art.
A. The compound of the formula I of the invention can be prepared by converting a compound of formula II
wherein A is —OR
p
, wherein R
p
is a protective group, e.g. ethyl, or A is a chiral auxiliary group, such as a chiral amine, e.g. (R)-phenylglycinol, a chiral alcohol, such as menthol or a chiral oxazolidinone, such as (S)-4-benzyl-2-oxazolidinone. The convertion can be performed as a hydrolysis which can be either acidic or basic and performed according to standard methods known to anyone skilled in the art or as described in the experimental part.
B. The compound of the formula I or the formula II wherein A is a chiral auxiliary group or —OR
p
and R
p
is as defined above, can be prepared by reacting a compound of the formula III
wherein X is —OH or a leaving group such as a sulfonate or a halogen, with a compound of the formula IV
wherein Q is H and A is a chiral auxiliary group, —OH or —OR
p
, and R
p
is as defined above. The reaction can be performed either by an alkylation reaction or a Mitsunobu reaction.
In an alkylation reaction the leaving group X can be a sulfonate such as mesylate, nosylate, tosylate, or a halogen, such as bromine or iodine. The compounds of formula III and IV, in approximately equimolar amounts or with an excess of either compound, are heated to reflux temperature in an inert solvent, such as isopropanol or acetonitrile, in the presence of a base, such as potassium carbonate or cesium carbonate.
The mixture is refluxed for the necessary time, typically between 0.5 h to 24 h, the work-up procedure usually includes filtration, for removal of solid salt, evaporation, neutralization (when A=—OH) and extraction with water and an organic solvent such as dichloromethane, ethyl acetate, or diethyl ether. The crude product is purified if desired e.g. by recrystallization or by standard chromatographic methods.
The Mitsunobu reaction can be carried out according to standard methods or as described in for example Tsunoda T., Yamamiaya Y., Ito S., Tetrahedron Letters, 34, 1639-1642 (1993) or O. Mitsunobu, Synthesis, 1981, p.1. When using a Mitsunobu reaction A can not be —OH.
In a typical Mitsunobu reaction a compound of formula III, wherein the group X is a hydroxyl group, and a compound of formula IV are mixed, in approximately equimolar amounts or with an excess of either compound, in an inert solvent, such as chloroform, dichloromethane, or tet

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