Phenalkyloxy-phenyl derivatives

Details Phenalkyloxy-phenyl derivatives Phenalkyloxy-phenyl derivatives

2002-06-03

2003-10-07

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C558S051000, C558S423000, C564S192000, C568S033000, C568S077000, C514S513000, C514S517000

Reexamination Certificate

active

06630509

ABSTRACT:

FIELD OF INVENTION
The present invention relates to certain phenalkyloxy-phenyl derivatives of formula I 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 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 type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidemia observed as deranged lipoprotein levels typically characterised by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations, the presence of small, dense LDL (Low Density Lipoprotein) particles 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 disorders associated with IRS. To date, the treatment of type 2 diabetes mellitus 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 normalise 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 sensitising 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 hyperglycaemia in diabetes, by improving insulin sensitivity via an effect on lipid transport and handling primarily in adipocytes, 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 sensitising properties.
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 sensitising 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 hypertriglyceridemia 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 sensitising properties.
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, prodrugs, solvates and crystalline forms thereof, in which formula
A is situated in the ortho, meta or para position and represents
R is cyano, when X is O, and when X is 1 then R is;
—BR
a
or SCOR
a
, wherein B is O, S, SO or SO, (preferably B is O or S), wherein R
a
represents hydrogen, alkyl, aryl or alkylaryl (preferably R
a
is selected from hydrogen, alkyl and alkyaryl) and wherein the alkyl, aryl or alkylaryl group is optionally substituted one or more times by R
b
, wherein R
b
represents alkyl, aryl, alkylaryl, cyano, —NR
c
R
c
, ═O, halogen, —OH, —SH, —Oalkyl, —Oaryl, —Oalkylaryl, —COR
c
, —SR
d
, —SOR
d
, or —SO
2
R
d
(preferably R
b
is selected from alkyl, aryl, alkylaryl, cyano, —NH
2
, ═O, halogen and —OH), wherein R
c
represents hydrogen, alkyl, aryl or alkylaryl and R
d
represents alkyl, aryl or alkylaryl;
—BB
1
R
a
, wherein B
1
is O when B is S, SO or SO
2
or B
1
is S, SO or SO
2
when B is O, and wherein B and R
a
are as defined above;
or alternatively R is —NR
a
R
a
, wherein each R
a
is the same or different and wherein R
a
is defined above;
R
2
represents alkyl, halogen (preferably bromo, chloro or iodo), aryl, alkylaryl, alkenyl, alkynyl, nitro or cyano and wherein the alky, aryl, alkenyl, alkylaryl and alkynyl group is optionally substituted by R
b
, wherein R
b
is as defined above;
—BR
a
wherein B and R
a
are as defined above;
—SO
2
NR
a
R
f
, wherein R
f
represents hydrogen, alkyl, acyl, aryl or alkylaryl and R
a
is as defined above;
—SO
2
OR
a
, wherein R
a
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;
—CONR
c
R
a
, wherein R
c
and R
a
are as defined above;
—NR
c
SO
2
R
d
, wherein R
a
and R
d
are as defined above;
—NR
c
CONR
a
R
k
, wherein R
a
and R
c
are as defined above and R
k
represents hydrogen, alkyl, aryl, or alkylaryl;
alternatively R
2
is —NR
c
R
a
, wherein R
c
and R
d
are as defined above;
R
1
, R
3
and R
4
are the same or different and each represents hydrogen, alkyl, aryl, alkenyl, alkynyl, cyano, halogen or alkylaryl (preferably R
1
, R
3
and R
4
are independently selected from hydrogen or alkyl, ideally R
1
, R
3
and R
4
are hydrogen) wherein the alkyl, aryl, alkenyl or alkynyl group is optionally substituted by R
b
;
n is an integer from 1 to 6 (preferably n is an integer from 1 to 3, ideally n is 1);
X is an integer 0 or 1 (preferably X is 1);
m is an integer 0 or 1 (preferably m is 1);
D is situated in the ortho, meta or para position (preferably D is situated in the para position) and represents alkyl, acyl, aryl, alkylaryl, halogen, —CN and NO
2
, wherein the alkyl, aryl, or alkylaryl group is optionally substituted by R
b
;
—NR
c
COOR
a
, wherein R
c
and R
a
are as defined above;
—NR
c
COR
a
, wherein R
c
and R
a
are as defined above;
—NR
c
R
a
, wherein R
c
and R
a
are as defined above;
—NR
c
SO
2
R
d
, wherein R
c
and R
d
are as defined above;
—NR
c
CONR
k
R
c
, wherein R
a
, R
c
and R
k
are as defined above;
—NR
c
CSNR
a
R
k
, wherein R
a
, R
c
and R
k
are as defined above;
—OR
a

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