Heterocyclic analogs of diphenylethylene compounds

Details Heterocyclic analogs of diphenylethylene compounds Heterocyclic analogs of diphenylethylene compounds

1999-04-06

2001-12-18

Barts, Samuel (Department: 1614)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S227000, C548S226000, C548S318500, C514S369000, C514S376000, C514S389000, C514S390000

Reexamination Certificate

active

06331633

ABSTRACT:

BACKGROUND OF THE INVENTION
The present application is directed to novel anti-diabetic compounds formed by chemically coupling diphenylethylene compounds with thiazolidine or oxazolidine intermediates. These compounds are effective in lowering blood glucose, serum insulin and triglyceride levels in animal models of type II diabetes. However, surprisingly, these compounds increase the leptin level and have no liver toxicity.
The causes of type I and type II diabetes are yet unknown, although both genetics and environment seem to be the factors. Insulin dependent type I and non-insulin type II are the types which are known. Type I is an autonomic immune disease in which the responsible auto antigen is still unknown. Patients of type I need to take insulin intravenously to survive. However, type II diabetes, the more common form, is a metabolic disorder resulting from the body's inability to make a sufficient amount of insulin or to properly use the insulin that is produced. Insulin secretion and insulin resistance are considered the major defects, however, the precise genetic factors involved in the mechanism remain unknown.
Patients with diabetes usually have one or more of the following defects:
Less production of insulin by the pancreas;
Over secretion of glucose by the liver;
Independent of the glucose uptake by the skeletal muscles;
Defects in glucose transporters, desensitization of insulin receptors; and
Defects in the metabolic breakdown of polysaccharides.
Other than the intravenous application of insulin, there are about 4 classes of oral hypoglycemic agents used.
Approved
Mechanisms of
Class
Drugs
Action
Limitations
sulfonylurea
4 (1st
acts on
dev. of
generation)
pancreas to
resistance
and
release more
2 (2nd
insulin
generation)
biguanides
metformin
reduces
liver
glucose
problems,
secretion by
lactic
liver;
acidosis
improves
insulin
sensitivity
alpha-
acarbose
interferes
only useful
glucosidase
with
at post-
inhibitor
digestive
pradiandio
process;
level
reduces
glucose
absorption
thiazolidin
troglitazone
reduces
“add-on”
e-dione
insulin
with
resistancy
insulin; not
useful for
people with
heart and
liver
disease
As is apparent from the above table, each of the current agents available for use in treatment of diabetes has certain disadvantages. Accordingly, there is a continuing interest in the identification and development of new agents, particularly, water soluble agents which can be orally administered, for the use of treatment of diabetes.
SUMMARY OF THE INVENTION
Anti-diabetic compounds of the following formula I are provided:
n, m, q and r are independently integers from zero to 4; p and s are independently integers from zero to 5; a, b and c are double bonds which may be present or absent;
R, R′ and R″ are independently H, C
1
-C
20
linear or branched alkyl, C
2
-C
20
linear or branched alkenyl, —CO
2
H, —CO
2
R′″, —NH
2
, —NHR′″, —NR
2
′″, —OH, —OR′″, halo, substituted C
1
-C
20
linear or branched alkyl or substituted C
2
-C
20
linear or branched alkenyl, wherein R′″ is C
1
-C
20
linear or branched alkyl or linear or branched alkenyl;
A, A′ and A″ are independently H, C
1
-C
20
acylamino;
C
1
-C
20
acyloxy; C
1
-C
20
alkanoyl;
C
1
-C
20
alkoxycarbonyl; C
1
-C
20
alkoxy;
C
1
-C
20
alkylamino; C
1
-C
20
alkylcarboxylamino; carboxyl; cyano; halo; hydroxy;
B, B′ and B″ are independently H;
C
1
-C
20
acylamino; C
1
C
20
acyloxy; C
1
-C
20
alkanoyl;
C
1
-C
20
alkenoyl; C
1
-C
20
alkoxycarbonyl;
C
1
-C
20
alkoxy; C
1
-C
20
alkylamino;
C
1
-C
20
alkylcarboxylamino; aroyl, aralkanoyl; carboxyl; cyano; halo; hydroxy;
X, X′ are independently —NH, —NR′″, O or S.
Pharmaceutical compositions containing compounds of the formula I are provided for treatment of diabetes and comprise a therapeutically effective amount of the compound in a physiologically acceptable carrier.
A method of treating diabetes is also provided comprising the step of orally administering to a subject suffering from a diabetic condition a therapeutically effective amount of a compound of formula I.


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