Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-06-25
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...
C514S364000, C514S376000, C548S132000, C548S183000, C548S226000
Reexamination Certificate
active
06288096
ABSTRACT:
FIELD OF INVENTION
The present invention relates to certain novel thiazolidinedione, oxazolidinedione and oxadiazolidinedione derivatives, to a process for preparing such derivatives, having the utility in clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceutical compositions containing them.
BACKHROUND 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 and 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. Ciglitazone is the prototype in this class. In IRS these compounds seem to correct insulin resistance and the associated hypertrigiyceridaemia 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
EP 08 203 discloses thiazolidinedione derivatives of the general formula:
wherein Ris alkyl, cycloalkyl, phenylalkyl, phenyl, a five- or six membered heterocyclic group including one or two hetero-atoms selected from nitrogen, oxygen and sulphur or a group of the formula
(where R
3
and R
4
are the same or different and each is lower alkyl or R
3
and R
4
are combined with each other either directly or interrupted by a heteroatom selected from nitrogen, oxygen and sulphur to form a five- or six-membered ring); R
2
means a bond or a lower alkylene group; L
1
and L
2
are the same or different and each is lower alkyl or L
1
and L
2
are combined to form an alkylene group, provided that, when R
1
is other than alky, L
1
and L
2
may be further hydrogen, as remedies for diabetes and hyperlipemia.
One compound comprised by the formula above is
This compound has been reported [Chem. Pharm. Bull. 30(10)3580-3600 (1982)] to have undesirable effects, such as a considerable increase in liver lipids.
EP 139 421 discloses a compound of the formula
wherein
R
1
and R
2
are the same or different and each represents a hydrogen atom or a C
1
-C
5
alkyl group;
R
3
represents a hydrogen atom, a C
1
-C
6
aliphatic acyl group, a (C
5
-C
7
cycloalkane) carbonyl group, an aromatic acyl group which is a benzoyl or naphthoyl group optionally with one or more nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy substituents, a heterocyclic acyl group having one or more oxygen, sulphur or nitrogen hetero atoms and with 4 to 7 ring atoms, an optionally halosubstituted phenylacetyl or phenylpropionyl group, a cinnamoyl group, a (C
1
-C
6
alkoxy) carbonyl group or a benzoyloxycarbonyl group;
R
4
and R
5
are the same or different and each represents a hydrogen atom, a C
1
-C
5
alkyl group or a C
1
-C
5
alkoxy group, or R
4
and R
5
together represent a C
1
-C
4
alkylenedioxy group;
n is 1, 2 or 3;
W represents the —CH—, >CO or >CH—OR
6
group (in which R
6
represents any one of the atoms or groups defined for R
3
and may be the same as or different from R
3
); and Y and Z are the same or different and each represents an oxygen atom or an imino (═NH) group, having the ability to lower blood lipid and blood sugar levels.
Among the compounds comprised by the general formula above is troglitazone having the chemical formula
This substance has a very low potency in animal models of IRS.
DESCRIPTION OF THE INVENTION
It has now been found that compounds of the general formula (I)
and stereo and optical isomers and racemates thereof as well as pharmaceutically acceptable salts, solvates and hydrates thereof, in which formula
is a single or double bond,
R is H or alkyl,
A is S, O or NH,
B is C, CH or N,
D is situated in the ortho, meta or para position and is representing CN or —X—Y—Z,
D′ is situated in the ortho, meta or para position and is representing H, —O-alkyl, alkyl, halogen or —X—Y—Z, wherein
X is O, NR
1
, SO
2
or S and R
1
is H or alkyl,
Y is SO
2
, CO, or a chemical bond,
Z is alkyl, alkyl substituted by one or more fluoro or chloro atoms, aryl, substituted aryl, alkylaryl, OR
2
or NHR
3
, wherein
R
2
is alkyl aryl, alkylaryl, substituted aryl or substituted alkyl
R
3
is H, alkyl, aryl, alkylaryl, substituted aryl or substituted alkyl
provided that
when X is O or NR
1
, then Y is either SO
2
or CO and Z is, when Y is a) SO
2
, selected from the group consisting of alkyl, alkyl substituted by one or more fluoro or chloro atoms, aryl, substituted aryl and alkylaryl, when Y is b) CO, selected from the group consisting of OR
2
and NHR
3
wherein R
2
and R
3
are as defined above,
when X is SO
2
, then Y is a chemical bond and Z is selected from the group consisting of alkyl, alkyl substituted by one or more fluoro or chloro atoms, aryl, substituted aryl, alkylaryl and OR
2
, wherein R
2
is as defined above,
when X is S, then Y is a chemical bond and Z is selected from the group consisting of alkyl, alkyl substituted by one or more fluor or chloro atoms, aryl, substituted aryl and alkylaryl,
and further provided that when B is N, A is O,
are effective in conditions associated with insulin resistance.
Preferred compounds of the invention are those of the formula I wherein
is a single or double bond,
R is a H or alkyl,
A is S or O,
B is C, CH or N,
D is situated in the ortho, meta or para position and is representing —X—Y—Z,
D′ is situated in the ortho, meta or para position and is representing H, —O-alkyl or —X—Y—Z,
X is O, NR
1
, SO
2
or S wherein R
1
is H or alkyl,
Y is SO
2
, CO or a chemical bond,
Z is alkyl, aryl, alkylaryl, substituted aryl, CF
Andersson Kjell
Boije Maria
Lindstedt Eva-Lotte
Ljung Bengt
Nordén Bo
Astrazeneca AB
Gerstl Robert
White & Case LLP
LandOfFree
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