Benzopyrans and benzoxepines, pharmaceutical compositions...

Details Benzopyrans and benzoxepines, pharmaceutical compositions... Benzopyrans and benzoxepines, pharmaceutical compositions...

2001-06-29

2003-07-22

Trinh, Ba K. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S432000, C514S456000, C549S023000, C549S355000, C549S405000, C549S408000

Reexamination Certificate

active

06596758

ABSTRACT:

The present invention relates to benzopyrans and benzoxepines which can be used in the treatment of dyslipidaemias, atherosclerosis and diabetes, to pharmaceutical compositions comprising them and to processes allowing the preparation of these compounds. compounds in the preparation of medicaments intended for the treatment of dyslipidaemias, atherosclerosis and diabetes.
Cardiovascular disease remains, in most countries, one of the main diseases and the main cause of mortality. Approximately a third of men develop a major cardiovascular disease before the age of 60, women exhibiting a lower risk (ratio of 1 to 10). This disease becomes more prevalent with age (after the age of 65, women become just as vulnerable to cardiovascular diseases as men). Vascular diseases, such as coronary disease, strokes, restenosis and peripheral vascular disease, remain the main cause of mortality and handicap across the world.
While diet and lifestyle can accelerate the development of cardiovascular diseases, a genetic predisposition leading to dyslipidaemias is a significant factor in strokes and deaths.
The development of atherosclerosis seems to be related 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 was mainly focused on the metabolism of cholesterol and on the metabolism of triglycerides.
However, since the studies by Randle et al. (lancet, 1963, 785-789), a novel concept has been proposed: a glucose-fatty acid cycle or Randle cycle, which describes the 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 a novel programme having the aim of finding new compounds which act simultaneously on the metabolism of lipids and the metabolism of 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 the metabolism of lipids in the liver (PPAR&agr; isoform). In the last ten years, thiazolidinediones have been described as powerful hypoglycaemic agents in animals and man. It has been reported that thiazolidinediones are powerful selective activators of another isoform of PPARs: the various PPAR&ggr; (Lehmann et al., J. Biol. Chem. 1995, 270, 12953-12956).
The Inventors have discovered a new class of compounds which are powerful activators of the PPAR&agr; and PPAR&ggr; isoforms. Due to this activity, these compounds exhibit a significant hypolipidaemic and hypoglycaemic effect.
The compounds of the invention correspond to the formula (I) below:
in which:
X represents O or S;
A represents either the divalent radical —(CH
2
)
s
—CO—(CH
2
)
t
— or the divalent radical —(CH
2
)
s
—CR
3
R
4
—(CH
2
)
t
—
in which radicals s=t=0 or else one of s and t has the value 0 and the other has the value 1;
R
4
represents a hydrogen atom or a (C
1
-C
15
)alkyl group;
R
1
and R
2
independently represent the Z chain defined below; a hydrogen atom; a (C
1
-C
18
)alkyl group; a (C
2
-C
18
)alkenyl group; a (C
2
-C
18
)alkynyl group; a (C
6
-C
10
)aryl group optionally substituted by a halogen atom, by an optionally halogenated (C
1
-C
5
)alkyl group or by an optionally halogenated (C
1
-C
5
)alkoxy group; or a mono- or bicyclic (C
4
-C
12
)heteroaryl group comprising one or more heteroatoms chosen from O, N and S which is optionally substituted by a halogen atom, by an optionally, halogenated (C
1
-C
5
)alkyl group or by an optionally halogenated (C
1
-C
5
)alkoxy group;
R
3
takes any one of meanings given above for R
1
and R
2
, with the exception of the Z chain; or else
R
3
and R
4
together form a (C
2
-C
6
)alkylene chain optionally substituted by a halogen atom or by optionally halogenated (C
1
-C
5
)alkoxy;
R is chosen from a halogen atom; a cyano group; a nitro group; a carboxy group; an optionally halogenated (C
1
-C
18
)alkoxycarbonyl group; an R
a
—CO—NH— or R
a
R
b
N—CO— group [in which R
a
and R
b
independently represent optionally halogenated (C
1
-C
18
)alkyl; a hydrogen atom; (C
6
-C
10
)aryl or (C
6
-C
10
)aryl(C
1
-C
5
)alkyl (where the aryl parts are optionally substituted by a halogen atom, by an optionally halogenated (C
1
-C
5
)alkyl group or by an optionally halogenated (C
1
-C
5
)alkoxy group); (C
3
-C
12
)cycloalkyl optionally substituted by a halogen atom, by an optionally halogenated (C
1
-C
5
)alkyl group or by an optionally halogenated (C
1
-C
5
)alkoxy group]; an optionally halogenated (C
1
-C
18
)alkyl group; optionally halogenated (C
1
-C
18
)alkoxy; and (C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
1
-C
5
)alkyl, (C
6
-C
10
)aryloxy, (C
3
-C
12
)cycloalkyl, (C
3
-C
12
)cycloalkenyl, (C
3
-C
12
)cycloalkyloxy, (C
3
-C
12
)cycloalkenyloxy or (C
6
-C
10
)aryloxycarbonyl in which the aryl, cycloalkyl and cycloalkenyl parts are optionally substituted by a halogen atom, by optionally halogenated (C
1
-C
5
)alkyl or by optionally halogenated (C
1
-C
5
)alkoxy;
p represents 0, 1, 2, 3 or 4;
Z represents the radical:
where
n is 1 or 2;
the R′ groups independently represent a hydrogen atom; a (C
1
-C
5
)alkyl group; a (C
6
-C
10
)aryl group optionally substituted by a halogen atom, by an optionally halogenated (C
1
-C
5
)alkyl group or by optionally halogenated (C
1
-C
5
)alkoxy; or a mono- or bicyclic (C
4
-C
12
)heteroaryl group comprising one or more heteroatoms chosen from O, N and S which is optionally substituted by a halogen atom, by an optionally halogenated (C
1
-C
5
)alkyl group or by an optionally halogenated (C
1
-C
5
)alkoxy group;
Y represents —OH; (C
1
-C
5
)alkoxy; or the —NR
c
R
d
group (in which R
c
and R
d
independently represent a hydrogen atom; (C
1
-C
5
)alkyl; (C
3
-C
8
)cycloalkyl optionally substituted by a halogen atom, by optionally halogenated (C
1
-C
5
)alkyl or by optionally halogenated (C
1
-C
5
)alkoxy; (C
6
-C
10
)aryl optionally substituted by a halogen atom, by optionally halogenated (C
1
-C
5
)alkyl or by optionally halogenated (C
1
-C
5
)alkoxy; it being understood that one and one alone from R
1
and R
2
represents the Z chain.
The invention is also targeted, depending on the functional groups present in the molecule, at the salts of these compounds with pharmaceutically acceptable acids or bases.
When the compound of formula (I) comprises an acidic functional group, for example a carboxyl functional group, the latter can form a salt with an inorganic or organic base.
Mention may be made, as example [sic] of salts with organic or inorganic bases, of the salts formed with metals and in particular alkali, alkaline earth and transition metals (such as sodium, potassium calcium, magnesium or aluminium) or with bases, such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine), or with basic amino acids or with osamines (such as meglumine) or with aminoalcohols (such as 3-aminobutanol and 2-aminoethanol).
When the compound of formula (I) comprises a basic functional group, for example a nitrogen atom, the latter can form a salt with an organic or inorganic acid.
The salts with organic or inorganic acids are, for example, the hydrochloride, hydrobromide, sulphate, hydrogensulphase, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulphonate and para-toluene-sulphonate salts.
The invention also covers the salts which make possible a suitable separation or a suitable crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulphonic acid.
The formula (I) encompasses all the types of geometric isomers and stereoisomers of the compounds of formula (I).
According to the invention, the term “alkyl” denotes a linear or branched hydrocarbon-comprising radical, such as methyl, ethyl, propyl

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