Compounds to treat diabetes and associated conditions

Details Compounds to treat diabetes and associated conditions Compounds to treat diabetes and associated conditions

1999-11-08

2003-02-25

Killos, Paul J. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C560S055000, C560S011000, C560S016000, C560S044000, C560S045000, C560S076000, C560S081000, C562S426000, C562S429000, C562S433000, C562S450000, C562S465000, C562S471000, C562S489000

Reexamination Certificate

active

06525093

ABSTRACT:

BACKGROUND OF THE INVENTION
The present application is directed to novel antidiabetic compounds.
The causes of Type I and Type II diabetes are still unknown, although both genetic and environmental factors seem to be involved. Type I diabetes (or insulin-dependent diabetes) is an autonomic immune disease in which the responsible autoantigen is still unknown. Patients with Type I diabetes need to take insulin intravenously to survive. Type II diabetes (formerly referred to as non-insulin dependent diabetes) is a metabolic disorder resulting from the body's inability either 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 metabolic defects, but the precise genetic factors involved remain unknown.
Patients with diabetes usually have one or more of the following defects:
Under-production of insulin by the pancreas
Over-secretion of glucose by the liver
Defects in glucose transporters
Desensitization of insulin receptors
Defects in metabolic breakdown of polysaccharides
In addition to the IV administration of insulin, currently available medications used for diabetes include 4 classes of oral hypoglycemic agents listed in the following table.
Marketed
Mechanism of
Class
Drugs
Action
Limitations
Sulfonylureas
First generation:
Signals beta cells
Development of
2
to release more
resistance
Second generation:
insulin
Hypoglycemia
3
Biguanides
Metformin
Reduces hepatic
Adverse hepatic effects
glucose production
Lactic acidosis
Improves
Unwanted
sensitivity to
gastrointestinal effects
insulin
Glucosidase
Acarbose
Reduces glucose
Works only after meals
inhibitors
absorption from
GI side effects
gut
Thiazolidinediones
Troglitazone
Reduce insulin
Not effective in 25% of
Rosiglitazone
resistance
patients
Piaglitazone
Require frequent liver
function tests
Have very long onset of
action
Cause weight gain
As is apparent from the above table, there are disadvantages to each of the currently available agents for use in the treatment of diabetes. Accordingly, there is a continuing interest in the identification and development of new agents, particularly orally administered, water-soluble agents that can be used for the treatment of diabetes.
SUMMARY OF THE INVENTION
Compounds having the general formula (I)-(III) have glucose-lowering activity.
Stereocenters (designated by *) could be R— or S—.
Each bond represented by dotted lines could be a double or a single bond, and the geometry across the bond could be E or Z.
R and R′ are independently H or C
1
-C
20
linear or branched alkyl or alkenyl groups that may be substituted, or functional groups like COOR
3
, where R
3
=H, a cation C
1
-C
20
linear or branched alkyl or C
5
-C
10
aryl; CONR
1
R
2
, where R
1
and R
2
may be independently or together H, linear or branched C
1
-C
20
alkyl or C
5
-C
20
aryl, NH
2
, OH, C
1
-C
20
linear or branched alkoxy, halo, cyano, or R+R′=O.
A, A′, A″, and C are independently H, C
1
-C
20
acylamino, C
1
-C
20
acyloxy, linear or branched C
1
-C
20
alkanoyl, C
1
-C
20
alkoxycarbonyl, C
1
-C
20
linear or branched alkoxy; C
1
-C
20
linear or branched alkylamino, C
1
-C
20
alkylcarboxylamino, C
1
-C
20
carbalkoxy; carboxyl, cyano, halo, hydroxy; and n, m, and p and v are independently integers from 0 to 3;
B, B′, and B″ are independently H, C
1
-C
20
acylamino, C
1
-C
20
acyloxy; C
1
-C
20
linear or branched alkanoyl, C
1
-C
20
linear or branched alkenyl, C
1
-C
20
alkoxycarbonyl, C
1
-C
20
linear or branched alkoxy; C
1
-C
20
linear or branched alkyl amino, C
1
-C
20
alkyl carboxyl amino, C
1
-C
20
carbalkoxy; aroyl, araalkanoyl, carboxyl, cyano, halo, hydroxy; and q, r and s are independently integers from 0 to 3;
R″, R′″ and R″″ are independently H, C
1
-C
20
linear or branched alkyl or alkenyl groups which may contain substituents, COOH, C
1
-C
20
alkoxycarbonyl, NH
2
, CONH
2
, C
1
-C
20
acylamino, OH, C
1
-C
20
alkoxy, halo, or cyano.
X═NH, O, S, S═O, or SO
2
.
Stereocenters (designated by *) could be R— or S—.
Each bond represented by the dotted line could be a double or a single bond, and the geometry across it may be E or Z.
A, A′, and C are independently H, C
1
-C
20
acylamino, C
1
-C
20
acyloxy, C
1
-C
20
alkoxycarbonyl, C
1
-C
20
alkoxy, C
1
-C
20
linear or branched alkyl amino, C
1
-C
20
alkylcarboxylamino, C
1
-C
20
carbalkoxy; carboxyl, cyano, halo, hydroxy; and t, u, and w are independently integers from 0 to 3;
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
alkenyl, C
1
-C
20
alkoxycarbonyl, C
1
-C
20
linear or branched alkoxy, C
1
-C
20
linear or branched alkyl amino, C
1
-C
20
alkylcarboxylamino, C
1
-C
20
carbalkoxy, C
6
-C
20
aroyl, C
6
-C
20
araalkanoyl, carboxyl, cyan, halo, hydroxy; and x and y are independently integers from 0 to 3;
R′, R″, and R′″ are independently H or C
1
-C
20
linear or branched alkyl or alkenyl groups which may contain substituents, COOH, C
1
-C
20
alkoxycarbonyl, NH
2
, CONH
2
, C
1
-C
20
acylamino, C
1
-C
20
alkoxycarbonyl, OH, C
1
-C
20
alkoxy, halo or cyano.
X═NH, O, S, S═O, or SO
2
Stereocenters (designated by *) could be R— or S—.
The bond represented by the dotted line could be a double or a single bond, and the geometry across it may be E or Z.
A and C are independently H, C
1
-C
20
acylamino, C
1
-C
20
acyloxy, C
1
-C
20
linear or branched alkanoyl, C
1
-C
20
alkoxycarbonyl, C
1
-C
20
linear or branched alkoxy, C
1
-C
20
linear or branched alkyl amino, C
1
-C
20
alkylcarboxylamino, C
1
-C
20
carbalkoxy; carboxyl, cyano, halo, hydroxy; thiol, SOR or SOR
2
; and f and g are independently integers from 0 to 3;
B is independently H, C
1
-C
20
acylamino, C
1
-C
20
acyloxy; C
1
-C
20
linear or branched alkanoyl, C
1
-C
20
linear or branched alkenoyl, C
1
-C
20
linear or branched alkenyl, C
1
-C
20
alkoxycarbonyl, C
1
-C
20
linear or branched alkoxy, C
1
-C
20
linear or branched alkyl amino, C
1
-C
20
alkylcarboxylamino, C
1
-C
20
carbalkoxy, C
5
-C
20
aroyl, C
6
-C
20
araalkanoyl, carboxyl, cyan, halo, hydroxy; and e is an integer from 1 to 3;
R′, R″, and R′″ are independently H or C
1
-C
20
linear and branched alkyl or alkenyl groups which may contain substituents, COOH, C
1
-C
20
alkoxycarbonyl, NH
2
, CONH
2
, C
1
-C
20
acylamino, C
1
-C
20
alkoxycarbonyl, OH, C
1
-C
20
alkoxy, halo, cyano.


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