Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-05-05
1991-04-30
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544237, 546 99, 514296, A61K 31495, A61K 3144, C07D23730, C07D47106
Patent
active
050118404
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to new imidazolidinedione derivatives of interest to those in the field of medicinal chemistry and chemotherapy. More particularly, it is concerned with a novel series of 5-substituted imidazolidinedione compounds 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 of 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 5-substituted imidazolidinedione compounds useful as aldose redutase inhibitors for the control of certain chronic complications arising in a diabetic subject. More specifically, the novel compounds of this invention are selected from the group consisting of 5-substituted imidazolidinedione derivatives of the formula: ##STR1## or a base salt thereof with a pharmacologically acceptable cation, wherein Z is ##STR2## wherein X is hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; and R is naphthylmethyl, furfuryl, thenyl or phenylalkyl having from one to three carbon atoms in the alkyl moiety wherein said phenylalkyl is optionally substituted with one or two identical or non-identical substituents on the phenyl ring, said identical substituents being fluorine, chlorine, bromine, trifluoromethyl, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy and said non-identical substituents being fluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl. These novel compounds are aldose reductase inhibitors and therefore, 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 interest is that of the general formula I where Z is of the formula II wherein X is hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy. Preferred compounds within this group include those where X is hydrogen, chlorine, bromine, nitro, methyl or methoxy.
Another group of compounds of the present invention of interest is that of the general formula I wherein Z is of the formula III wherein R is naphthylmethyl, furfuryl, thenyl, or phenylalkyl having from one to three carbon atoms in the alkyl moiety wherein said phenylalkyl is optionally substituted with one or two identical or non-identical substituents on the phenyl ring, said identical substituents being fluorine, chlorine, bromine, trifluoromethyl, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy and said non-identical substituents being fluorine, chlorine, bromine, methyl, met
REFERENCES:
patent: 3821383 (1974-06-01), Sestanj et al.
patent: 4139532 (1979-02-01), Scheuermann et al.
patent: 4209527 (1980-06-01), Sarges
patent: 4251528 (1981-02-01), Brittain et al.
patent: 4782064 (1988-11-01), Wright, Jr. et al.
Ginsburg Paul H.
Lee Mary C.
Pfizer Inc.
Richardson Peter C.
Whittenbaugh Robert C.
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