Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1988-06-30
1990-07-10
Sutto, Anton S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544354, C07D24150, A61K 31495
Patent
active
049407082
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to new quinoxalinone derivatives of interest to those in the field of medicinal chemistry and chemotherapy. More particularly, it is concerned with a novel series of 4-substituted-3,4-dihydro-2(1H)-quinoxalinone-1-alkanoic acid compounds and their esters for the control of certain chronic complications arising from diabetes mellitus (e.g., diabetic cataracts, retinopathy and neuropathy).
BACKGROUND ART
Past attempts to obtain new and better oral antidiabetic agents have, for the most part, involved an endeavor to synthesize new compounds that lower blood sugar levels. More recently, several studies have been conducted concerning the effect of various organic compounds in preventing or arresting certain chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy, etc. For instance, 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 they are not known to be hypoglycemic. These compounds function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for catalyzing 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 or sorbitol in the lens, retina, peripheral nervous system and kidney of diabetic subjects are prevented or reduced. As a result, these compounds control certain chronic diabetic complications, including those of an ocular nature, since it is already known in the art that the presence of polyols in the lens of the eye leads to cataract formation and concomitant loss of lens clarity.
DISCLOSURE OF THE INVENTION
The present invention relates to novel 4-substituted-3,4-dihydro-2(1H)-quinoxalinone-1-alkanoic acid compounds useful as aldose reductase inhibitors for the control of certain chronic complications arising in a diabetic subject. It is also concerned with their corresponding esters which are useful for controlling the same diabetic complications, in addition to being useful as intermediates leading to the aforesaid aldose reductase inhibitor acids. More specifically, the novel compounds of this invention are selected from the group consisting of 4-arylsulfonyl-3,4-dihydro-2(1H)-quinoxalinone-1-alkanoic acids of the formula: ##STR1## and the C.sub.1 -C.sub.6 alkyl ester derivatives thereof, and the base salts of said acids with pharmacologically acceptable cations, wherein R is phenyl, hydroxyphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, C.sub.1 -C.sub.4 alkylphenyl or C.sub.1 -C.sub.4 alkoxyphenyl, and n is one or two. These novel compounds possess the ability to reduce or inhibit sorbitol formation in the lens and peripheral nerves of diabetic subjects.
One group of compounds of the present invention of particular interest is that wherein n is one and R is as previously defined, including their C.sub.1 -C.sub.6 alkyl esters. Preferred compounds within this group include those where R is phenyl, p-fluorophenyl, p-chlorophenyl, 2,5-dichlorophenyl, o-tolyl, p-tolyl and o-anisyl, including their ethyl esters.
Another group of compounds of the present invention of interest is that of the aforesaid structural formula wherein n is two and R is as previously defined, including their C.sub.1 -C.sub.6 alkyl esters. Preferred compounds within this group include the acid compound where R is phenyl and the ethyl ester derivative thereof.
Of special interest are such typical and preferred member compounds of the invention as ethyl 4-benzenesulfonyl-3,4-dihydro-2(1H)-quinoxalinone-1-acetate, ethyl 4-(p-fluorobenzenesulfonyl)-3,4-dihydro-2(1H)-quinoxalinone-1-acetate, ethyl 4-(p-chlorobenzenesulfonyl)-3,4-dihydro-2(1H)-quinoxalinone-1-acetate, ethyl 4-(2,5-dichlorobenzenesulfonyl)-3,4-dihydro-2(1H)-qui-noxalinone-1-acetat
REFERENCES:
patent: 3821383 (1974-06-01), Sestanj et al.
patent: 4209527 (1980-06-01), Sarges
Sarges et al., Chemical Abstracts, vol. 110, No. 212764 (1989).
Bernhardt E.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Sutto Anton S.
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