Heterocyclic compounds as aldose reductase inhibitors

Details Heterocyclic compounds as aldose reductase inhibitors Heterocyclic compounds as aldose reductase inhibitors

1992-09-17

1994-03-15

Lee, Mary C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514379, 514682, 548240, 548242, 548410, 549404, 549406, 568328, C07D49310, A61K 3140

Patent

active

052946355

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The field of art to which this invention relates is heterocyclic compounds which are useful in the field of medicinal chemistry. More particularly the invention relates to spirocyclic heterocylic compounds which are aldose reductase inhibitors useful for the control of diabetic complications such as neuropathy, nephropathy, retinopathy and cataractogenesis.


BACKGROUND ART

In the past, various attempts have been made by numerous investigators in the field of organic medicinal chemistry to obtain new and better oral antidiabetic agents. Many of these efforts have involved the syntheses and testing of various new and unavailable organic compounds, particularly in the area of the sulfonylureas, in an endeavor to determine their ability to lower blood sugar (i.e., glucose) levels to a substantially high degree when given by the oral route of administration. The effect of other organic compounds in preventing or arresting certain chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy, etc. has also been studied. For example, K. Sestanj et al. in U.S. Pat. No. 3,821,383 discloses that certain aldose reductase inhibitors like 1,3-dioxo-1H-benz[d,e]isoquinoline-2(3H)-acetic acid and some closely related derivatives thereof are useful for these purposes, even though these particular compounds are not known to be hypoglycemic in nature.
In addition, for example, commonly assigned U.S. Pat. No. 4,130,714 entitled "Hydantoin Therapeutic Agents" the disclosure of which is hereby incorporated by reference discloses dextrorotatory spiro-hydantoin compounds such as d-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and d-6'-fluoro-spiroimidazolidine-4,4'-thiochroman-2,5-dione.
Non-hydantoin compounds previously reported to inhibit aldose reductase include 1H-benz[d,e]isoquinoline-1,3(2H)-dione-2-acetic acid derivatives, Sestanj et al., U.S. Pat. No. 3,821,383; halogen substituted chroman-4-carboxylic and chroman-4-acetic acids, Belletire, U.S. Pat. No. 4,210,663; spiro-]chroman-4,5'-oxazolidin]-2',3'-diones, Schnur, U.S. Pat. No. 4,200,642; and variously substituted phthalazin-1(2H)-on-4-acetic acids, Larson et al., published European Patent Application No. 222,576.
These aldose reductase inhibitors all function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses (like glucose and galactose) to the corresponding polyols (such as sorbitol and galactitol) in the human body. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects, and of sorbitol in the lens, peripheral nervous cord and kidney of various diabetic subjects, and thereby reduced or prevented. As a result, these compounds are of value as aldose reductase inhibitors for controlling chronic diabetic complications, including but not restricted to those of an ocular nature, since it is known that the presence of polyols in an eye lens invariably leads to cataract formation and a loss of lens clarity.
Although compounds such as the hydantoins have proven useful for the treatment of diabetic complications there is a continuing search in this field of art for different, more effective inhibitors for the treatment of diabetic complications.


SUMMARY OF THE INVENTION

This invention is directed to spirocyclic heterocyclic compounds that are useful as aldose reductase inhibitors. The compounds of this invention have the formula ##STR1## wherein
Y is ##STR2##
X is --O-- or ##STR3##
R.sub.1 and R.sub.2 are each independently H, alkyl C.sub.1 -C.sub.6, aryl or arylalkyl (C.sub.1 -C.sub.6);
W.sub.1 and W.sub.2 are each independently hydrogen, halogen or nitro; and
the pharmaceutically acceptable cationic salts thereof.
Particularly preferred are compounds of formula (I) where X is ##STR4## Preferred within this group are compounds where W.sub.1 is hydrogen, W.sub.2 is fluorine, Y is ##STR5## and R.sub.1 and R.sub.2 are each independently H or alkyl (C.sub.1 -C.sub.6). Preferred within this group is a compoun

REFERENCES:
patent: 3821383 (1974-06-01), Sestanj et al.
patent: 4130714 (1978-12-01), Sarges
patent: 4147795 (1979-04-01), Sarges
patent: 4200642 (1980-04-01), Schnur
patent: 4210663 (1980-07-01), Belletire
patent: 4307108 (1981-12-01), Belletire et al.
patent: 4680388 (1987-07-01), Sundeen et al.
Cox, M., et al., "Spirocyclic Beta-Oxo Sulphoxides and Sulphones as Potential Aldose Reductase Inhibitors", J. Chem. Soc., Perkin Trans. I, pp. 3217-3221 (1988).
Jaspan, J., et al, "Clinical Studies With an Aldose Reductae Inhibitor in the Autonomic and Somatic Neuropathies of Diabetes", Metabolism, vol.35, No. 4, Suppl. 1, pp. 83-92 (1986).
Mattingly, P., et al, "Titanium Trichloride Reduction of Substituted N-Hydroxy-2-azetidinones and Other Hydroxamic Acids", J. Org. Chem., 45: 410-415 (1980).
Schnur, R., et al, "Spiro Oxazolidinedione Aldose Reductase Inhibitors", J. Med. Chem., 25: 1451-1454 (1982).
Graf, R., "Reactions with N-Carbonylsulfamoyl Chloride", Angew. Chem. Internat. Edit., vol. 7 No. 3, pp. 172-182 (1968).
Miller, M., et al., "Synthesis of Beta-Lactams form Substituted Hydroxamic Acids", J. Am. Chem. Soc., 102: 7026-7032 (1980).
Sarges, et al., J. Med. Chem., vol. 28, No. 11, pp. 1717-1719 (1985).

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