3-aryl propionic acid derivatives and analogs

Details 3-aryl propionic acid derivatives and analogs 3-aryl propionic acid derivatives and analogs

1999-07-20

2003-10-07

Killos, Paul J. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S011000, C560S023000, C560S041000, C562S429000, C562S465000, C564S162000, C558S335000, 57, 57, 57, 57, 57, 57

Reexamination Certificate

active

06630600

ABSTRACT:

FIELD OF INVENTION
The present invention relates to certain novel 3-aryl-2-hydroxypropionic acid derivatives and analogs, to a process for preparing such compounds, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.
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, prevails 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 nor 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, platelets 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. WO 97/31907 discloses compounds which are claimed to show good goblood-glucose lowering activity and therefore to be of use in the treatment and/or prophylaxis of hyperglycaemia, dyslipidemia, and are of particular use in the treatment of Type II diabetes.
These compounds are also claimed to be of use for the treatment and/or prophylaxis of other diseases including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension and cardiovascular disease, especially atherosclerosis.
Description of the Invention
The invention relates to compounds of the general formula (I)
and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and crystalline forms thereof, in which formula
A is situated in the ortho, meta or para position and represents
R is hydrogen;
—OR
a
, wherein R
a
represents hydrogen, alkyl, aryl or alkylaryl;
—NR
a
R
b
, wherein R
a
and R
b
are the same or different and R
a
is as defined above and R
b
represents hydrogen, alkyl, aryl, alkylaryl, cyano, —OH, —Oalkyl, —Oaryl, —Oalkylaryl, —COR
c
or —SO
2
R
d
, wherein R
c
represents hydrogen, alkyl, aryl or alkylaryl and R
d
represents alkyl, aryl or alkylaryl;
R
1
is alkyl, aryl, alkene, alkyne, cyano;
—OR
e
, wherein R
e
is alkyl, acyl, aryl or alkylaryl;
—O—[CH
2
]
m
—OR
f
, wherein R
f
represents hydrogen, alkyl, acyl, aryl or alkylaryl and m represents an integer 1-8;
—OCONR
a
R
c
, wherein R
a
and R
c
are as defined above;
—SR
d
, wherein R
d
is as defined above;
—SO
2
NR
a
R
f
, wherein R
f
and R
a
are as defined above;
—SO
2
OR
a
, wherein R
a
is as defined above;
—COOR
d
, wherein R
d
is as defined above;
R
2
is hydrogen, halogen, alkyl, aryl, or alkylaryl,
R
3
and R
4
are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl,
n is an integer 1-6,
D is situated in the ortho, meta or para position and represents
—OSO
2
R
d
, wherein R
d
is as defined above;
—OCONR
f
R
a
, wherein R
f
and R
a
are as defined above;
—NR
c
COOR
d
, wherein R
c
and R
d
are as defined above;
—NR
c
COR
a
, wherein R
c
and R
d
are as defined above;
—NR
c
COR
a
, wherein R
c
and R
a
are as defined above;
—NR
c
R
d
, wherein R
c
and R
d
are as defined above;
—NR
c
SO
2
R
d
, wherein R
c
and R
d
are as defined above;
—NR
c
CONR
a
R
k
, wherein R
a
, R
c
and R
k
are the same or different and each represents hydrogen, alkyl, aryl, or alkylaryl;
—NR
c
CSNR
a
R
k
, wherein R
a
, R
c
and R
k
are the same or different and each represents hydrogen, alkyl, aryl or alkylaryl;
—SO
2
R
d
, wherein R
d
is as defined above;
—SOR
d
, wherein R
d
is as defined above;
—SR
c
, wherein R
c
is as defined above;
—SO
2
NR
a
R
f
, wherein R
f
and R
a
are as defined above;
—SO
2
OR
a
, wherein R
a
is as defined above;
—CN,
—CONR
c
R
a
, wherein R
c
and R
a
are as defined above;
D′ is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, —CN, —NO
2
, —NR
f
R
b
, wherein R
f
and R
b
are as defined above;
—OR
f
, wherein R
f
is as defined above;
—OSO
2
R
d
, wherein R
d
is as defined above;
D″ is situated in the ortho, meta or para position and represents hydrogen, alkyl, acyl, aryl, alkylaryl, halogen, —CN, —NO
2
, —NR
f
R
b
wherein R
f
and R
b
are as defined above;
—OR
f
, wherein R
f
is as defined above.
—OSO
2
R
d
, wherein R
d
is as defined above.
For ease of reference the definitions of formula I above are henceforth referred to as defined in Category A. Unless otherwise stated the definitions of the various substituents are as defined under Category A throughout the present application.
The compounds of the formula I are surprisingly effective in conditions associated with insulin resistance.
Category A2: In one embodiment the present invention

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