Substituted heteroarylalkanoic acids

Abstract: Disclosed are substituted heteroarylalkanoic acids of the following formula D-A-C(O)R′, where D, A, and R′ are defined herein. These compounds are useful in the treatment of chronic complications arising from diabetes mellitus. Also disclosed are pharmaceutical compositions containing the compounds and methods of treatment employing the compounds, as well as methods for their synthesis. (end of abstract)

Substituted heteroarylalkanoic acids description/claims

Brief Patent Description

Full Patent Description

Patent Application Claims

BACKGROUND OF INVENTION

This application claims benefit of U.S. Provisional Application Ser. No. 60/336,055, filed Nov. 15, 2001, and U.S. Provisional Application Ser. No. 60/378,626, filed May 7, 2002.

FIELD OF THE INVENTION

The present invention relates to heteroarylalkanoic acids and derivatives thereof. More specifically, it relates to such compounds capable of inhibiting aldose reductase and lowering uric acid levels.

DESCRIPTION OF THE RELATED ART

The use of aldose reductase inhibitors (ARIs) for the treatment of diabetic complications is well known. The complications arise from elevated levels of glucose in tissues such as the nerve, kidney, retina and lens that enters the polyol pathway and is converted to sorbitol via aldose reductase. Because sorbitol does not easily cross cell membranes, it accumulates inside certain cells resulting in changes in osmotic pressure, alterations in the redox state of pyridine nucleotides (i.e. increased NADH/NAD⁺ ratio) and depleted intracellular levels of myoinositol. These biochemical changes, which have been linked to diabetic complications, can be controlled by inhibitors of aldose reductase.

Uric acid containing deposits (also known as trophi) resulting from unphysiologically elevated plasma uric acid levels tend to occur in various tissues throughout the body, leading to the disease condition known as gout and gouty arthritis. Uric acid containing deposits in such conditions may occur in cartilage, bone, bursae, tendons, connective tissue overlying bony prominences, as well as, subcutaneously and in the area of kidney. Elevated blood uric acid levels also occur in number of other disease conditions including myeloid leukemia, myeloid dysplasia, pernicious anemia, psoriasis, diabetes mellitus and renal disease.

Acute gout responds to colchicine. Nonsteroidal anti-inflammatory agents are also useful in acute attacks. Long-term therapy is directed to preventing hyperuricemia by giving uriosuric drugs. Patients with gout have a tendency to form uric acid kidney stones.

Treatment for gout consists of the administration of anti-inflammatory agents, dietary modifications, and the use of drugs that diminish uric acid formation, as well as drugs that enhance excretion of uric acid by the kidney. The latter drugs are the uricosuric agents, some of which act as competitive inhibitors of both uric acid transport and the transport of other organic anions.

One of the peculiar characteristics of the uric acid transport system is that, although the net activity of tubular function is reabsorption of uric acid, the molecule is both secreted and reabsorbed during its passage through the nephron. The secretory and reabsorptive mechanisms vary in importance along the proximal tubule, with reabsorption dominating in the S1 and S3 segments and secretion dominating in the S2 segment. As a consequence of this bidirectional transport, drugs that inhibit uric acid transport may decrease rather than increase the excretion of uric acid. Obviously, such an effect compromises their therapeutic usefulness.

SUMMARY OF THE INVENTION

This invention provides heterarylalkanoic acids that interact with and inhibit aldose reductase. Such compounds preferably have high affinity for aldose reductase. Such compounds also preferably have high selectivity for the enzyme. More preferably, they have both high affinity and high selectivity for the enzyme.

In a broad aspect, the invention provides compounds of Formula I

D-A-C(O)R′ I

or a pharmaceutically acceptable salt thereof wherein