Cyclic compounds useful in the treatment of dyslipidaemia,...

Details Cyclic compounds useful in the treatment of dyslipidaemia,... Cyclic compounds useful in the treatment of dyslipidaemia,...

2001-01-16

2003-03-04

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S326000, C514S414000, C546S207000, C568S811000, C568S812000, C549S336000, C549S290000, C549S373000, C549S374000, C549S375000

Reexamination Certificate

active

06528538

ABSTRACT:

The present invention relates to cyclic compounds which can be used in the treatment of dyslipidaemia, atherosclerosis and diabetes, to pharmaceutical compositions containing them and to processes for preparing these compounds.
The invention also relates to the use of these compounds for the production of medicinal products intended for the treatment of dyslipidaemia, atherosclerosis and diabetes.
In most countries, cardiovascular disease remains one of the main diseases and the main cause of mortality. About a third of men develop a major cardiovascular disease before the age of 60, women showing a lower risk (ratio of 1 to 10). This disease becomes even more prevalent with age (after the age of 65, women become just as vulnerable to cardiovascular disease as men). Vascular diseases such as coronary disease, cerebrovascular accidents, restenosis and peripheral vascular disease remain the main cause of mortality and handicap throughout the world.
Although the diet and the lifestyle can accelerate the development of cardiovascular diseases, a genetic predisposition leading to dyslipidaemia is a significant factor in cardiovascular attacks and death.
The development of atherosclerosis appears to be linked mainly to dyslipidaemia, which means abnormal levels of lipoproteins in the blood plasma. This dysfunction is particularly evident in coronary disease, diabetes and obesity.
The concept intended to explain the development of atherosclerosis has mainly been focused on the metabolism of cholesterol and on the metabolism of triglycerides.
However, since the research studies by Randle et al. (Lancet, 1963, 785-789), an original concept has been proposed: a glucose-fatty acid cycle or Randle cycle, which describes regulation of the equilibrium between the metabolism of lipids, in terms of triglycerides and cholesterol, and the oxidation of glucose. According to this concept, the inventors have developed an original programme, the aim of which is to find novel compounds which act simultaneously on the metabolism of lipids and glucose.
Fibrates are well-known therapeutic agents with a mechanism of action via the “Peroxisome Proliferator Activated Receptors”. These receptors are the main regulators of lipid metabolism in the liver (PPAR&agr; isoform). In the last ten years, thiazolidinediones have been described as powerful hypoglycaemiant agents in animals and man. It has been reported that thiazolidinediones are powerful selective activators of another form of PPARs: PPAR&ggr; (Lehmann et al., J. Biol. Chem., 1995, 270, 12953-12956).
The inventors have discovered a novel class of compounds which are powerful activators of the PPAR&agr; and PPAR&ggr; isoforms. On account of this activity, these compounds have a substantial hypolipidaemiant and hypoglycaemiant effect.
The compounds of the invention correspond to formula I below:
in which
X and Y represent, independently of each other, a methylene group; an oxygen or sulphur atom; or —NR
a
— in which R
a
represents a hydrogen atom, a (C
1
-C
7
)alkyl, (C
6
-C
10
)aryl group or a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, S and N; the said aryl group and the said heterocycle optionally being substituted with one or more radicals Z as defined below;
R represents a hydrogen atom; a (C
1
-C
7
)alkyl group; a phthalamido (C
1
-C
7
) alkyl group; (C
3
-C
12
) cycloalkyl; a group —(CH
2
)
p
—COOR
b
in which p is an integer from 0 to 6 and R
b
represents a hydrogen atom or a (C
1
-C
7
)alkyl group; a (C
6
-C
10
)aryl group; a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, S and N; a (C
6
-C
10
)aryl(C
1
-C
7
)alkyl group; it being understood that the aryl groups present in R and the said heterocycle are optionally substituted with one or more substituents chosen from a radical Z as defined below and a (C
1
-C
7
)alkylene chain;
R
1
represents a hydrogen atom; a (C
1
-C
7
)alkyl group; (C
1
-C
7
)hydroxyalkyl; a (C
6
-C
10
)aryl group optionally substituted with one or more radicals W as defined below; a group —P(O) (OR
8
) (OR
9
) in which R
8
and R
9
are, independently, a hydrogen atom or a (C
1
-C
7
)alkyl group; a group —(CH
2
)
t
—COOR
c
in which t is an integer from 0 to 6 and R
c
represents a hydrogen atom or a (C
1
-C
7
)alkyl group; a group —CONR
10
R
11
in which R
10
and R
11
independently represent a hydrogen atom, a (C
1
-C
7
)alkyl group, a group R
d
O—CO—(C
1
-C
7
)alkyl in which R
d
represents H or (C
1
-C
7
)alkyl, or alternatively R
10
and R
11
together form a —(CH
2
) chain in which r is an integer equal to 4, 5 or 6;
R
2
and R
3
independently represent a hydrogen atom; a (C
1
-C
7
)alkyl group; (C
3
-C
12
)cycloalkyl; (C
6
-C
10
)aryl; (C
6
-C
10
)aryl(C
1
-C
7
)alkyl; a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, N and S; or a fluorenyl group; the said aryl groups present in R
2
or R
3
, the said heterocycle and the said fluorenyl optionally being substituted with one or more radicals Z as defined below;
or alternatively R
2
and R
3
together form a chain —(CH
2
)
r1
in which r1 is an integer equal to 2, 3, 4 or 5;
or alternatively R
2
and R
3
together form the group (a):
 in which A
1
and A
2
independently represent (C
6
-C
10
)aryl or a 5- to 10-membered aromatic heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from N, O and S, the said aryl group and the said heterocycle optionally bearing, in addition to the substituents R
12
and R
13
, one or more other substituents chosen from the radicals Z as defined below; and in which R
12
and R
13
together form a chain
—(CH
2
)
m
—E—(CH
2
)
n
— or —CHR
14
═CHR
15
—
in which m and n are, independently, an integer from 0 to 6; E represents a bond, O, S, —NR
e
—, in which R
e
represents a hydrogen atom or (C
1
-C
7
)alkyl or alternatively E represents a (C
1
-C
7
)alkylene or (C
6
-C
10
)arylene chain or a 3- to 10-membered divalent heterocyclic radical comprising 1 to 4 endocyclic hetero atoms chosen from O, N and S; and
R
14
and R
15
are chosen, independently, from a hydrogen atom, (C
1
-C
7
)alkyl and (C
6
-C10)aryl;
R
4
, R
5
, R
6
and R
7
independently represent a hydrogen atom; (C
1
-C
7
)alkyl; (C
6
-C10)aryl optionally substituted with one or more radicals Z as defined below; or a 3- to 10-membered heterocycle comprising 1 to 4 endocyclic hetero atoms chosen from O, N and S, the said heterocycle optionally being substituted with one or more radicals Z as defined below;
Z is chosen from a halogen atom; a hydroxyl group; nitro; cyano; phenyl; phenyl (C
1
-C
7
) alkyl; trifluoromethoxy; (C
1
-C
7
) alkyl optionally substituted with one or more halogen atoms; (C
1
-C
7
)alkoxy; (C
1
-C
7
)alkylthio; (C
2
-C
7
)acylthio; (C
1
-C
7
)alkylsulphonyl; (C
1
-C
7
) alkylsulphinyl; carbamoyl; N—(C
1
-C
7
)alkylcarbamoyl; N,N-di(C
1
-C
7
)alkylcarbamoyl; (C
1
-C
7
) alkylamino; di( C
1
-C
7
) alkylamino; a group —A—COOR
f
in which R
f
represents a hydrogen atom or a (C
1
-C
7
)alkyl group and A represents (C
1
-C
7
)alkylene, (C
2
-C
7
) alkenylene, (C
1
-C
7
)oxyalkylene in which the alkylene chain is linked to the group COORf or alternatively A is nothing; or a group —B—P(O)(OR
x
)(OR
y
) in which B takes one of the meanings given for A above and R
x
and R
y
independently take one of the meanings given for R
f
above;
W represents —G—COORg in which G represents (C
1
-C
7
)alkylene, (C
2
-C
7
)alkenylene, (C
1
-C
7
)oxyalkylene in which the alkylene chain is linked to the group COOR
g
or alternatively G is nothing, and R
g
represents a hydrogen atom or a (C
1
-C
7
)alkyl group; or alternatively W represents
—D—P(O)(OR
z
)(OR
t
) in which D takes one of the meanings given above for G and R
z
and R
t
independently take one of the meanings given above for R
g
;
and the pharmaceutically acceptable salts thereof,
 it being understood that
(i) when R
2
, R
3
, R
5
and R
7
represent a hydrogen atom; X and Y represent an oxygen atom; R
4
represents methyl; and R
6
represents a hydrogen atom or a meth

Affiliated with

Also associated with

Rating

Cyclic compounds useful in the treatment of dyslipidaemia,... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Cyclic compounds useful in the treatment of dyslipidaemia,..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cyclic compounds useful in the treatment of dyslipidaemia,... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3041638