Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-05-10
2001-08-28
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S369000, C514S370000, C514S371000
Reexamination Certificate
active
06281234
ABSTRACT:
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, 1-15,; 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 filled 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.
2-Aminothiazoleacetic acid derivatives have been used extensively in chemical and patent literature as intermediates for penam and cepham classes of antibiotics, but the long (C
16
, C
18
) unsaturated carboxamide chains at C
2
of the thiazoleacetic acid moiety makes these compounds novel. WO 9616650 and JP 07149745 generically claim “lower alkyl” amides of 2-aminothiazoleacetic acid are antibacterial and antiinflammatory (elastase inhibitors) agents, respectively. U.S. Pat. No. 5,688,821 (1997, to AHP) teaches that some of the same compounds that are in this invention are inhibitors of the enzymes phospholipase A
2
derived from human sources (anti-inflammatory agents), but others are not and vice-versa. Certain long acylhydrocarbon chain derivatives of 2-aminothiazoleacetic acid have been prepared (Toth,
Liebigs Ann. Chem. EN
, 7, 685, 1994).
DESCRIPTION OF THE INVENTION
The compounds of this invention have been shown to inhibit rat-derived and human derived recombinant PTPase-1B (rPTP-1B) in vitro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
This invention provides a method of using a compound of formula I having the structure
wherein
R
1
, R
2
are both hydrogen or form a bond, or are each, independently, alkyl of 1-6 carbon atoms or aryl of 6-12 carbon atoms;
m=0-10;
n=1-3; and
p=0-10;
with the proviso that m+p is less than or equal to 15;
or a pharmaceutically acceptable salt thereof in the treatment of metabolic disorders related to insulin resistance or hyperglycemia, primary hypertension, or atherosclerosis.
Pharmaceutically acceptable salts can be formed from organic and inorganic bases, such as alkali metals (sodium, potassium, or lithium), alkaline earth metals (calcium or magnesium), ammonium, primary, secondary alkyl amines, or tertiary alkyl amines. The use of tromethamine salts of the compounds of this invention showed improved water solubility and bioavailability.
It is understood that the compounds of this invention can exhibit E (trans) or Z (cis) stereoisomerism about the double bond, and that this invention covers both the E and Z isomers, at each double bond, and in particular when R
1
and R
2
are both hydrogen, alkyl, or aryl. When R
1
and R
2
are not a bond, it is preferred that they both are hydrogen.
Preferred compounds of this invention are those in which:
m=1 and n=3 and p=6;
m=4 and n=3 and p=3;
m=5 and n=1 and p=6 or 8;
m=7 and n=1 and p=6; and
m=10 and n=1 and p=3.
Aryl is defined as an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen (i.e., phenyl from benzene). It is preferred that the aryl moiety is a phenyl or naphthyl group; with phenyl being most preferred. The aryl moiety may be optionally mono-, di-, or tri- substituted with a substituent sele
American Home Products Corporation
Criares Theodore J.
Kim Jennifer
Milowsky Arnold S.
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