Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-03-14
1987-07-14
Schwartz, Richard A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548309, 549 70, 549 72, 549 73, 549483, 549488, A61K 31415, C07D491107, C07D49510
Patent
active
046803068
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel spiro-imidazolones useful in the treatment of certain chronic complications arising from diabetes mellitus, such as diabetic cataracts, retinopathy and neuropathy, to pharmaceutical compositions containing such compounds and to a method of using these compounds
BACKGROUND ART
In the past various attempts have been made to obtain more effective oral anti-diabetic agents. Generally these efforts have involved synthesis of new organic compounds, particularly sulfonyl ureas, and determination of their ability to substantially lower blood sugar levels when administered orally. However, little is known about the effect of organic compounds in preventing or alleviating chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy. U.S. Pat. No. 3,821,383 discloses aldose reductase inhibitors like 1, 3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and derivatives thereof to be useful for the treatment of these conditions. U.S. Pat. No. 4,117,230 teaches the use of certain hydantoins for treating complications of diabetes as aldose reductase inhibitors. Such aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In this way unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, of peripheral nervous cord and kidneys of various diabetic subjects are prevented or reduced. Accordingly, such compounds are of therapeutic value as aldose reductase inhibitors for controlling certain chronic diabetic complications, including those of an ocular nature, since it is known in the art that the presence of polyols in the lens of the eye leads to cataract formation, with a concomitant loss of lens clarity.
Carr et al., U.S. Pat. No. 3,985,888, teach certain spiroalkanone-imides and their use as sedatives. European Patent Application Publication No. 0065392 discloses certain spiro-succinimide derivatives and their use as aldose reductase inhibitors.
Sarges et al. in U.S. Pat. No. 4,127,665 disclose that certain thiophene spiro-imidazolidindiones are useful as aldose reductase inhibitors.
DISCLOSURE OF INVENTION
The compounds of the present invention are spiroimidazolones of the formula ##STR1## or a pharmaceutically acceptable salt thereof, wherein X is oxygen or sulfur, Y is hydrogen, halo or alkyl having 1-4 carbon atoms, and R is hydrogen, methyl or ethyl.
Preferred compound are those wherein R is hydrogen or methyl, Y is hydrogen and X is sulfur.
Both mixtures of optically active isomers and partially or completely optically resolved isomers of the compounds claimed herein are within the scope of the present invention.
Also embraced by the present invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and a compound of formula I. The present invention further comprises a method of treating a diabetic host for diabetes-associated complications which comprises administering to the host an effective amount of a compound of formula I.
DETAILED DESCRIPTION
The numbering system of the spiro compounds of formula I is as shown. ##STR2## The compounds are spiro[benzo[b]-thiophene (X=S) or furan (X=O) -7(6H), 4'-imidazolidine]-2',5'-dione-2-Y-5-R-4-ones.
Compounds of formula I can be prepared according to the Synthetic Scheme described hereinafter.
The aldehyde of formula II is reacted with 1-methyl- or 1-ethyl-cyanoethylene if R is methyl or ethyl, respectively, in the presence of an alkali metal cyanide such as sodium or potassium cyanide, preferably sodium cyanide in an aprotic polar organic solvent such as dimethylformamide at a temperature range of about 0 to 60.degree. C., preferably about 35.degree. C., to obtain the condensation product of formula III. The compounds of formula III wherein Y is hydrogen and R is hydr
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patent: 3821383 (1974-06-01), Sestanj et al.
patent: 3985888 (1976-10-01), Carr et al.
patent: 4117230 (1978-09-01), Sarges
patent: 4127665 (1978-11-01), Sarges et al.
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patent: 4386100 (1983-05-01), Brittain et al.
patent: 4503066 (1985-03-01), Brittain et al.
patent: 4575507 (1986-03-01), Lipinski
Knuth Charles J.
Pfizer Inc.
Richardson Peter C.
Schwartz Richard A.
Sheyka Robert F.
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