Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-28
2003-11-25
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S311000, C514S315000, C514S319000, C514S332000, C514S357000, C514S365000, C514S374000, C514S385000, C514S415000, C514S428000, C514S438000, C514S447000, C514S451000, C514S459000, C514S461000, C514S471000, C514S521000, C514S503000, C514S568000, C514S576000, C514S613000, C514S615000, C514S619000, C514S620000, C544S238000, C544S239000, C544S240000, C544S241000, C544S242000, C544S333000, C544S334000, C544S335000, C544S336000, C546S139000, C546S146000, C546S149000, C546S152000, C546S157000, C546S
Reexamination Certificate
active
06653321
ABSTRACT:
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The present invention relates to methods, pharmaceutical compositions, and compounds for enhancing insulin-dependent glucose uptake. The compounds of the invention activate the insulin receptor kinase, leading to an increased sensitivity to insulin and an increase in glucose uptake. The invention relates in particular to the use of the compounds in methods for the treatment of humans with hyperglycemia, and especially for the treatment of Type II diabetes.
(b) Description of Related Art
Among the many functions performed by peptide and protein hormones in metabolism is the ability to interact with receptors with high specificity. The insulin receptor is present on virtually all cells and at high concentrations on the cells for the liver, skeletal muscles, and adipose tissue. Stimulation of the insulin receptor with insulin is an essential element in carbohydrate metabolism and storage.
Diabetics either lack sufficient endogenous secretion of the insulin hormone (Type I) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (Type II, or non-insulin-dependent diabetes mellitus (NIDDM)). Type II diabetes is the most common form of diabetes, affecting about 5% of individuals in the industrialized nations. In Type II diabetics, major insulin-responsive tissues such as liver, skeletal muscle and fat exhibit the insulin resistance (Haring and Mehnert,
Diabetologia
36:176-182 (1993); Haring et al.,
Diabetologia
, 37 Suppl 2:S149-54 (1994)). The resistance to insulin in Type II diabetes is complex and likely multifactorial but appears to be caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. Impairment of the insulin receptor kinase has been implicated in the pathogenesis of this signaling defect. Insulin resistance is also found in many non-diabetic individuals, and may be an underlying etiologic factor in the development of the disease (Reaven,
Diabetes
, 37:1595-1607 (1988)).
Considerable information is known concerning the insulin receptor itself. The receptor consists of four separate subunits consisting of two identical &bgr; and two identical &bgr; chains. The &bgr; subunits contain a tyrosine kinase activity and the ATP binding sites. The insulin receptor is activated by autophosphorylation of key tyrosine residues in its cytoplasmic tyrosine kinase domain. This autophosphorylation is required for subsequent activity of the insulin receptor. The autophosphorylation stabilizes the activated receptor kinase resulting in a phosphorylation cascade involving intracellular signaling proteins.
At present there are limited pharmacologic approaches to treatment of Type II diabetes. Insulin is currently used as a treatment, but is disadvantageous because it must be injected and because its extreme potency requires careful titration of dose. Although several peptide analogs of insulin have been described, none with a molecular weight below about 5000 Daltons retains activity. Some peptides which interact with sites on the &bgr;-subunit of the insulin receptor have shown enhancement of the activity of insulin on its receptor (Kole et al.,
J. Biol Chem
., 271:31619-31626 (1996); Kasuya et al.,
Biochem. Biophys. Res. Commun
., 200:777-83 (1994)). Kohanski and others have reported on a variety of polycationic species that generate a basal effect, but do little to enhance insulin action (Kohanski,
J. Biol. Chem
., 264:20984-91 (1989); Xu et al.,
Biochemistry
30:11811-19 (1991). These peptides apparently act on the cytoplasmic kinase domain of the insulin receptor.
In addition, certain non-peptide components have been found to enhance the agonist properties of peptide hormones, but none appear to act directly on the insulin receptor kinase. For instance, the ability of thiazolidinediones, such as pioglitazone, to enhance adipocyte differentiation has been described (Kletzien, et al.,
Mol. Pharmacol
., 41:393 (1992)). These thiazolidinediones represent a class of potential anti-diabetic compounds that enhance the response of target tissues to insulin (Kobayashi,
Diabetes
, 41:476 (1992)). The thiazolidinediones act at an unknown site downstream from the insulin receptor itself and do not have a direct effect on the insulin receptor kinase. Other anti-diabetic agents currently in use include both insulin secretagogues (such as the sulfonylureas) and biguanides (such as metformin) that inhibit hepatic glucose output. To date, non-peptide substances which can mimic the activating effect of insulin on the insulin receptor have eluded discovery.
A variety of polyanionic sulfonic acid derivatives including suramin, azo dyes and related compounds are known in the art and have been established as potential therapeutics for a variety of disease indications. Suramin, described in 1917, is a polysulfonic acid that has been extensively researched (Dressel,
J. Chem. Ed
., 38:585 (1961); Dressel,
J. Chem. Ed
., 39:320 (1962)). It has therapeutic uses as an anthelmintic and antiprotozoal. More recently, it has been described as an inhibitor to reverse transcriptase in certain avian and murine retroviruses (De Clercq,
Cancer Letters
, 8:9 (1979); Mitsuya et al.,
Science
, 226:172 (1984)). Large numbers of compounds relating to suramin exist. Most of the suramin analogs which have been reported have multiple sulfonic acid functionality on each aryl ring. Recent studies indicate that polyanionic suramin analogs have anti-angiogenic, antiproliferative activity, and anti-viral activity (Gagliardi et al.,
Cancer Chemother. Pharmacol
., 41:117 (1988); Doukas et al.,
Cancer Res
., 55: 5161 (1995); Mohan et al.,
Antiviral Chem
., 2:215 (1991)). A number of other bisnaphthylsulfonic acids have been described in the patent literature as complement inhibitors (U.S. Pat. No. 4,132,730, U.S. Pat. No. 4,129,591, U.S. Pat. No. 4,120,891, U.S. Pat. No. 4,102,917, U.S. Pat. No. 4,051,176). Additionally, there are a number of azo dye patents (DE 19521589, U.S. Pat. No. 3,716,368, DE 2216592, FR 1578556) which disclose polysulfonated naphthalene azo compounds. However, none of the suramin analogs or azo dyes have been suggested to be useful in the treatment of hyperglycemia or diabetes.
SUMMARY OF THE INVENTION
This invention is directed to pharmaceutical compositions comprising naphthalene sulfonic acids and related compounds which enhance glucose uptake into cells, to the naphthalene sulfonic acids and related compounds, and to methods for enhancing glucose uptake in mammals using these pharmaceutical compositions and compounds.
In one aspect, this invention is directed to pharmaceutical compositions comprising (i) a pharmaceutically acceptable carrier and (ii) as an active ingredient, a compound of formula I:
where:
R
1
and R
2
are, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, —C(O)R
4
, —C(O)OR
4
, —C(O)NR
4
R
5
, —S(O)
2
R
4
, —S(O)
2
OR
4
, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, aryl(lower)alkyl, substituted aryl(lower)alkyl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, or lower alkenyl, or R
1
and R
2
together with the conjoining nitrogen are C
3
-C
9
heteroaryl, C
3
-C
5
heterocyclyl, or both R
1
and R
2
are oxygen and together with the conjoining nitrogen forming —NO
2
,
R
3
is a substituent on the B ring and is —SO
2
OR
6
, —C(O)OR
6
, —SO
2
NR
6
2
, —C(O)NR
6
2
or tetrazolyl;
each R
4
and R
5
is, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryl(lower)alkyl, substituted aryl(lower)alkyl, substituted heteroaryl, heteroaryl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, or lower alkenyl,
each R
6
and R
7
is, independently, hydrogen or lower alkyl,
each R
8
is, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl(lower)alkyl, substituted aryl(lower)alkyl, substituted heteroaryl, heteroaryl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)
Kozlowski Michael R.
Lum Robert T.
Manchem Prasad V. V. S. V.
Park Jeong Weon
Robinson Louise
Covington Raymond
Heller Ehrman White & McAuliffe LLP
Rotman Alan L.
Telik, Inc.
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