Methods using PTPase inhibitors and insulin

Details Methods using PTPase inhibitors and insulin Methods using PTPase inhibitors and insulin

2002-06-06

2004-09-28

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S232800, C514S410000, C514S443000, C514S468000, C514S866000

Reexamination Certificate

active

06797693

ABSTRACT:

This invention relates to methods and pharmaceutical compositions utilizing a PTPase inhibiting compounds and one or more insulins in methods for use in control and maintenance of type II diabetes in a mammal.
BACKGROUND OF THE INVENTION
The prevalence of insulin resistance in glucose intolerant subjects has long been recognized. Reaven et al (
American Journal of Medicine
1976, 60, 80) used a continuous infusion of glucose and insulin (insulin/glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance existed in a diverse group of nonobese, nonketotic subjects. These subjects ranged from borderline glucose tolerant to overt, fasting hyperglycemia. The diabetic groups in these studies included both insulin dependent (IDDM) and noninsulin dependent (NIDDM) subjects.
Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas.
The association of hyperinsulinemia with obesity and with ischemic diseases of the large blood vessels (e.g. atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout,
Metabolism
1985, 34, 7, and in more detail by Pyorala et al,
Diabetes/Metabolism Reviews
1987, 3, 463). Statistically significant plasma insulin elevations at 1 and 2 hours after oral glucose load correlates with an increased risk of coronary heart disease.
Since most of these studies actually excluded diabetic subjects, data relating the risk of atherosclerotic diseases to the diabetic condition are not as numerous, but point in the same direction as for nondiabetic subjects (Pyorala et al). However, the incidence of atherosclerotic diseases in morbidity and mortality statistics in the diabetic population exceeds that of the nondiabetic population (Pyorala et al; Jarrett
Diabetes/Metabolism Reviews
1989, 5, 547; Harris et al, Mortality from diabetes, in
Diabetes in America
1985).
The independent risk factors obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin/glucose clamps, tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (principally muscle) and correlates directly with the severity of hypertension (DeFronzo and Ferrannini,
Diabetes Care
1991, 14, 173). In hypertension of the obese, insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit further weight gain via thermogenesis, but insulin also increases renal sodium reabsorption and stimulates the sympathetic nervous system in kidneys, heart, and vasculature, creating hypertension.
It is now appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor. Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose), strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (reviewed by Haring,
Diabetalogia
1991, 34, 848).
Protein-tyrosine phosphatases (PTPases) play an important role in the regulation of phosphorylation of proteins. The interaction of insulin with its receptor leads to phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase. PTPases dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity. PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase. The enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity, include PTP1B, LAR, PTP&agr; and SH-PTP2 (B. J. Goldstein,
J. Cellular Biochemistry
1992, 48, 33; B. J. Goldstein,
Receptor
1993, 3, 1-1,; F. Ahmad and B. J. Goldstein
Biochim. Biophys Acta
1995, 1248, 57-69).
McGuire et al. (
Diabetes
1991, 40, 939), demonstrated that nondiabetic glucose intolerant subjects possessed significantly elevated levels of PTPase activity in muscle tissue vs. normal subjects, and that insulin infusion failed to suppress PTPase activity as it did in insulin sensitive subjects.
Meyerovitch et al (
J. Clinical Invest
. 1989, 84, 976) observed significantly increased PTPase activity in the livers of two rodent models of IDDM, the genetically diabetic BB rat, and the STZ-induced diabetic rat. Sredy et al (
Metabolism
, 44, 1074, 1995) observed similar increased PTPase activity in the livers of obese, diabetic ob/ob mice, a genetic rodent model of NIDDM.
The compounds of us in the methods of this invention have been shown to inhibit PTPases derived from rat liver microsomes and human-derived recombinant PTPase-1B (hPTP-1B) in vitro. Their synthesis and use in treatments of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels is taught in published PCT Application WO 99/61435 (Wrobel et al.).
DESCRIPTION OF THE INVENTION
This invention provides methods of using PTPase inhibitors and insulin(s) for the management of type 2 diabetes and for improving the cardiovascular and cerebrovascular risk profiles in mammals experiencing or subject to type II diabetes (non-insulin-dependent diabetes mellitus), preferably in human type II diabetics. These methods may also be characterized as the inhibition or reduction of risk factors for heart disease, stroke or heart attack in a type II diabetic.
These methods include the reduction of hyperlipidemia in type II diabetics, including methods in type II diabetics for lowering low density lipoprotein (LDL) blood levels. The methods herein may further be characterized as inhibiting, preventing or reducing atherosclerosis in a type II diabetic, or the risk factors thereof.
These methods also include the lowering free fatty acid blood levels and triglyceride levels in type II diabetics.
Each of the methods of this invention comprises administering to a mammal in need thereof a pharmaceutically effective amount of an insulin and a pharmaceutically effective amount of a compound of formula I:
A is hydrogen, halogen, or OH;
B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR
1
R
1a
, —NR
1
COR
1a
, —NR
1
CO
2
R
1a
, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —COR
1b
or OR;
R is hydrogen, alkyl of 1-6 carbon atoms, —COR
1
, —(CH
2
)
n
CO
2
R
1
, —CH(R
1a
)CO
2
R
1
, —SO
2
R
1
, —(CH
2
)
m
CH(OH)CO
2
R
1
, (CH
2
)
m
COCO
2
R
1
, —(CH
2
)
m
CH═CHCO
2
R
1
, or —(CH
2
)
m
O(CH
2
)
o
CO
2
R
1
;
R
1
is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH
2
CO
2
R
1′
;
R
1′
is hydrogen or alkyl of 1-6 carbon atoms
E is S, SO, SO
2
, O, or NR
1c
;
X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino, NR
2
R
2a
, NR
2
COR
2a
, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon

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