Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonic acids or salts thereof
Reexamination Certificate
2001-09-06
2003-07-29
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonic acids or salts thereof
C562S452000, C562S453000, C562S455000, C562S573000, C564S153000, C514S381000, C514S553000, C514S563000, C514S616000, C514S674000, C548S250000
Reexamination Certificate
active
06600069
ABSTRACT:
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The present invention relates to chemical compounds, pharmaceutical compositions comprising said compounds, uses of said compounds and compositions, and processes for their preparation. Specifically, this invention relates to means to enhance insulin-dependent glucose uptake. More specifically, the invention concerns compounds and pharmaceutical compositions that activate the insulin receptor kinase, which leads to an increased sensitivity to insulin and an increase in glucose uptake, as well as processes for preparation of the compounds. As such, the invention also concerns methods or uses of the compounds for the treatment of animals with hyperglycemia, especially for the treatment of type 2 diabetes.
(b) Description of Related Art
High specificity interaction with receptors is among the many functions performed by peptide and protein hormones in metabolism. The insulin receptor-is present on virtually all cells and at high concentrations on the cells of the liver, skeletal muscle, and adipose tissue. Specific binding by insulin and resulting stimulation of the insulin receptor is an essential element in carbohydrate metabolism and storage.
Diabetics either lack sufficient endogenous secretion of the insulin hormone (type 1) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (type 2, or non-insulin-dependent diabetes mellitus (NIDDM)). Type 2 diabetes is the most common form of diabetes, affecting about 5% of individuals in the industrialized nations. In type 2 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 2 diabetes is complex and likely multi-factorial but appears to be caused by an impaired signal from the insulin receptor to the glucose transport system and to glycogen synthase. Impairment of 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 &agr; and two identical &bgr;-subunits. 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 2 diabetes. Insulin is currently used as a treatment, but is disadvantageous because it must be injected. 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 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 switch on PPAR&ggr;, the nuclear transcription factor involved in adipocyte differentiation (Kliewer et al.,
J. Bio. Chem,.
170:12953 (1995)). 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.
Trimesic acid amides have been extensively studied. There are numerous citations regarding their use in polymers and polymer generation (e.g. U.S. Pat. No. 5,973,076, EP 940431A1), however, these compounds are generally highly lipophilic and do not have an acidic functionality appended onto them. Compounds with carboxylic acids as terminal groups are found to be useful as transition metal chelates for preparation of polymers (DE 4229182), rigid polyamide gels (
Polym. Mater. Sci. Eng
. (1992), 66, 154), and as coatings for aluminum and aluminum alloys (DE 3327191).
Some trimesic acid amide compounds have been found to have biological effects. Trimesic acid amides have been described as platelet aggregation inhibitors (JP 08333324A2) and anti-inflammatories (U.S. Pat. No. 5,750,573, U.S. Ser. No. 184,540), but these compounds have a highly basic guanidine, amidine, or a unique amidinohydrazone or guanylhydrazone as terminating functionalities. Compounds with highly acidic terminal functional groups include (EP 741128A2, WO 96/14324A1) sulfate esters of aminosugars as cell migration and proliferation inhibitors, and multianionic compounds as complement inhibitors (U.S. Pat. No. 4,123,455).
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 antihelminthic and antiprotozoal. More recently, it has been described as an inhibitor of reverse transcriptase in certain avian and murine retroviruses (De Clercq,
Cancer Letter,
8:9 (1979); Mitsuya et al.,
Science,
226:172 (1984)). 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 substituted-hydroxy-naphthalenedisulfonic acids and bisnaphthylsulfonic acids have been described in the patent literature as complement inhibitors (U.S. Pat. Nos. 4,046,805, 4,132,730, 4,129,591, 4,120,891, 4,102,917, 4,051,176). However, the literature on the trimesic acid amides does not suggest that these compounds will be useful in the treatment of hyperglycemia or diabetes.
The documents referred to in this application, including Prov. App. No. 60/230,738, are incorporated herein by reference.
SUMMARY OF THE INVENTION
In a first aspect, this invention is compounds of formula I:
where:
R
1
and R
2
are, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, 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 and R together with the conjoining nitrogen are C
3
-C
9
heteroaryl, or C
3
-C
5
heterocyclyl; and
Z is OH, Cl, Br, F, OR
1
or NR
1
R
2
wherein R
1
and R
2
are as
Cairns Nicolas
Manchem Prasad V. V. S. V.
Robinson Louise
Schow Steven R.
Heller Ehrman White & McAuliffe LLP
Kumar Shailendra
Telik, Inc.
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