Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1994-12-19
2001-09-11
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06288095
ABSTRACT:
This invention relates to certain substituted thiazolidinedione derivatives, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
European Patent Applications, Publication Numbers 0008203, 0139421, 0155845, 0177353, 0193256, 0207581 and 0208420 relate to thiazolidinedione derivatives which are disclosed as having hypoglycaemic and hypolipidaemic activity. Chem. Pharm. Bull 30 (10) 3580-3600 also relates to certain thiazolidinedione derivatives having hypoglycaemic and hypolipidaemic activities.
It has now surprisingly been discovered that certain novel substituted-thiazolidinedione derivatives show improved blood-glucose lowering activity and are therefore of potential use in the treatment and/or prophylaxis of hyperglycaemia and are of particular use in the treatment of Type II diabetes. These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia and hypertension.
They are also indicated to be of use in the treatment and/or prophylaxis of cardiovascular disease, especially atherosclerosis. In addition these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.
Accordingly, the present invention provides a compound of formula (I):
or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvate thereof, wherein:
A
1
represents a substituted or unsubstituted aromatic heterocyclyl group;
R
1
represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group;
R
2
and R
3
each represent hydrogen, or R
2
and R
3
together represent a bond;
A
2
represents a benzene ring having in total up to five substituents; and
n represents an integer in the range of from 2 to 6.
Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
Favoured aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 4 to 7 ring atoms, preferably 5 or 6 ring atoms.
In particular, the aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
Suitable values for A
1
when it represents a 5-membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.
Suitable values for A
1
when it represents a 6-membered aromatic heterocyclyl group include pyridyl or pyrimidinyl.
Suitably R
2
and R
3
each represent hydrogen.
Preferably, A
1
represents a moiety of formula (a), (b) or (c):
wherein:
R
4
and R
5
each independently represents a hydrogen atom, an alkyl group or a substituted or unsubstituted aryl group or when R
4
and R
5
are each attached to adjacent carbon atoms, then R
4
and R
5
together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R
4
and R
5
together may be substituted or unsubstituted; and in the moiety of formula (a)
X represents oxygen or sulphur.
Aptly, A
1
represents a moiety of the abovedefined formula (a).
Aptly, A
1
represents a moiety of the abovedefined formula (b).
Aptly, A
1
represents a moiety of the abovedefined formula (c).
In one favoured aspect R
4
and R
5
together represent a moiety of formula (d):
wherein R
6
and R
7
each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
Suitably, R
6
and R
7
each independently represent hydrogen, halogen, alkyl or alkoxy.
Favourably, R
6
represents hydrogen. Favourably, R
7
represents hydrogen.
Preferably, R
6
and R
7
both represent hydrogen.
In a further favoured aspect R
4
and R
5
each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R
4
and R
5
each independently represent hydrogen, alkyl or phenyl.
Preferably, for the moiety of formula (a), R
4
and R
5
together represent the moiety of formula (d).
Preferably, for the moieties of formula (b) or (c), R
4
and R
5
both represent hydrogen.
It will be appreciated that the five substituents of A
2
include three optional substituents. Suitable optional substituents for the moiety A
2
include halogen, substituted or unsubstituted alkyl or alkoxy.
Favourably, A
2
represents a moiety of formula (e):
wherein R
8
and R
9
each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
Suitably, R
8
and R
9
each independently represent hydrogen, halogen, alkyl or alkoxy. Preferably, R
8
and R
9
each represent hydrogen.
Favourably, X represents oxygen. Favourably, X represents sulphur.
In one preferred aspect the present invention provides a class of compounds, which fall wholly within the scope of formula (I), of formula (II):
or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, wherein A
1
, R
1
, R
2
, R
3
, and n are as defined in relation to formula (I) and R
8
and R
9
are as defined in relation to formula (e).
Suitably, n represents an integer 2, 3 or 4, notably 2 or 3 and especially 2.
Suitably, R
1
represents hydrogen, alkyl, acyl, especially acetyl, or benzyl.
When R
1
represents an alkyl group, examples of such alkyl groups include methyl and isopropyl. Preferably, R
1
represents a methyl group.
As indicated above a compound of formula (I) may exist in one of several tautomeric forms, all of which are encompassed by the present invention. It will be appreciated that the present invention encompasses all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, including any stereoisomeric forms thereof, whether as individual isomers or as mixtures of isomers.
Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a benzene ring, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
When used herein the term ‘aryl’ includes phenyl and naphthyl optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
When used herein the term ‘halogen’ refers to fluorine, chlorine, bromine and iodine; preferably chlorine.
When used herein the terms ‘alkyl’ and ‘alkoxy’ relate to groups having straight or branched carbon chains, containing up to 12 carbon atoms.
When used herein the term ‘acyl’ includes alkylcarbonyl groups.
Suitable alkyl groups are C
1-12
alkyl groups, especially C
1-6
alkyl groups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl groups.
Suitable substituents for any alkyl group include those indicated above in relation to the term “aryl”.
Suitable pharmaceutically acceptable salts include salts of the thiazolidinedione moiety, and, where appropriate, salts of carboxy groups.
Suitable pharmaceutically acceptable salts of the thiazolidinedione moiety include metal salts especially alkali metal salts such as the lithium, sodium and potassium salts.
Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as sodium or potassium, alkaline ea
Cawthorne Michael Antony
Hindley Richard Mark
Beecham Group p.l.c.
Gerstl Robert
Kinzig Charles M.
Stercho Yuriy P.
Venetianer Stephen
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