Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-05-31
2002-11-12
Barts, Samuel (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S534000, C514S538000, C514S562000, C514S564000, C560S019000, C562S457000
Reexamination Certificate
active
06479548
ABSTRACT:
BACKGROUND OF THE INVENTION
(a) Field of The Invention
The present invention relates to chemical compounds that activate the insulin receptor kinase, and to methods for treating humans with hyperglycemia, especially for the treatment of Type II diabetes.
(b) Description of Related Art
Peptide and protein hormones, such as insulin, 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 diabetes) or have an insulin receptor-mediated signaling pathway that is resistant to endogenous or exogenous insulin (Type II diabetes, 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 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 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 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 &agr; and two identical &bgr; chains. The &bgr; subunits contain 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 pharmacological approaches to treatment of Type II diabetes. Insulin is currently used as a treatment but is disadvantageous, because insulin must be injected. Although several peptide analogs of insulin have been described, none with a molecular weight below 5000 Dalton 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
., 200:777-783 (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
. 264:20984-20991 (1989); Xu et al.,
Biochemistry
30:11811-11819 (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 effects of insulin, but none appear to act directly on the insulin receptor kinase. For example, thiazolidinediones, such as pioglitazone, enhance adipocyte differentiation [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 peroxisome proliferator-activated receptor &ggr; (PPAR&ggr;), the nuclear transcription factor involved in adipocyte differentiation [Kliewer et al.,
J. Biol. Chem
., 270:12953 (1995)], 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 methformin) that inhibit hepatic glucose output.
Stilbenes and derivatives are prevalent throughout the chemical literature, with a large number of functionalized stilbenes described. Tri- and tetra- aryl stilbenes are known but have relatively few examples. The substituted stilbenes have biological activity and are reported as treatments to inflammatory and proliferative skin diseases [Nusbaumer, PCT International Publication No. WO 96/28430], as a method for inhibiting apoptosis [Babior et al., PCT International Publication No. WO 9634604], and as anti-virals [Haugwitz et al., PCT International Publication No. WO 9625399]. Tetra-substituted stilbenes, such as tamoxifen, are used in treating breast cancer [Furr et al.,
Pharmacol. Ther
. 25:127-205 (1984)]. There is extensive literature describing the use of the stilbenes in the preparation of interesting polymers.
The disclosures of these and other documents referred to elsewhere in this application are incorporated herein by reference.
SUMMARY OF THE INVENTION
In a first aspect, the invention is compounds of formula I:
where
R
1
, R
3
, and R
4
are, independently, hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, optionally substituted lower alkyloxy, —NR
11
R
12
, or —C(O)NR
11
R
12
, where R
11
and R
12
are, independently, hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, aryl(lower)alkyl, substituted aryl(lower)alkyl, heteroaryl(lower)alkyl, substituted heteroaryl(lower)alkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, or substituted heteroaryl, or —C(O)OR
13
where R
13
is hydrogen or lower alkyl;
R
2
is hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, lower alkoxy, substituted lower alkyloxy, carboxyl, —NR
11
R
12
, —NR
11
C(O)R
12
, or —C(O)NR
11
R
12
, where R
11
and R
12
have the above meanings, or
R
2
and R
3
, together with the carbon atoms to which they are attached, form a heterocyclic ring;
R
5
is hydrogen, lower alkyl, substituted lower alkyl, or aryl;
R
6
and R
7
are, independently, hydrogen, lower alkyl or —C(O)OR
13
, where R
13
has the above meaning;
R
8
and R
9
are, independently, hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxyl, lower alkoxy, carboxyl, —NR
11
R
12
, or —C(O)N R
11
R
12
, where R
11
and R
12
have the above meanings,
R
10
is hydrogen, lower alkyl, substituted lower alkyl, halo, hydroxy, lower alkoxy, —C(O)OR
13
where R
13
is hydrogen or lower alkyl, —SO
3
H, or —C(O)NR
11
R
12
, where R
11
and R
12
have the above meanings;
and the pharmaceutically acceptable salts thereof; as single stereoisomers or mixtures of stereoisomers.
These compounds are useful for stimulating and/or enhancing the uptake of glucose into cells in a mammal or for treating a mammalian disease state selected from the group consisting of hyperglycemia, type I diabetes, and type II diabetes.
In a second embodiment, this invention is pharmaceutical compositions comprising (a) at least one pharmaceutically acceptable carrier and (b) a compound of the first aspect of the invention as the active ingredient.
These compositions are useful for stimulating and/or enhancing the uptake of glucose into cells in a mammal or for treating a mammalian disease state selected from the group consisting of hyperglycemia, type I diabetes, and type II diabetes.
In a third embodiment, this invention is methods of treatment of hyperglycemia, type I diabetes, or type 1I diabetes in a mammal, such as a human, by administering a therapeutically effective amount of a compound of the first aspect of the invention, or a composition of the second aspect of the invention.
In a fourth embodiment, this invention is a method of stimulating the kinase activity of the insulin receptor or activating the insulin receptor
Lum Robert T.
Park Sophia
Patterson John
Spevak Wayne R.
Barts Samuel
Heller Ehrman White & McAuliffe LLP
Telik, Inc.
Zucker Paul A.
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