Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1987-10-09
1989-08-01
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514437, 514453, 514455, 514456, 514866, 549 23, 549 25, 549 27, 549 28, 549345, 549383, 549384, 549389, 549395, A61K 3138, A61K 3135, C07D31196, C07D31104, C07D33506
Patent
active
048534102
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention is concerned with certain racemic and optically active (2R,4R) hydroxyacetic acid derivatives which are 4-c-hydroxy-2-r-(substituted)-chroman (and thiochroman)-4-acetic acids and pharmaceutically-acceptable salts thereof which, by their inhibition of the aldose reductace enzyme, are useful in the treatment of diabetic complications. It is also concerned with intermediates useful in the synthesis of these compounds.
Compounds, such as sorbinil (S-6-fluorospiro[chroman-4,4'-imidazoline]-2',5'-dione), which have aldose reductase inhibitory activity, are of value in controlling certain chronic complications arising from diabetes mellitus (e.g., diabetic cataracts and neuropathy). The racemic precursor of sorbinil (and analogs thereof) were originally reported by Sarges in U.S. Pat. No. 4,117,230. Sorbinil itself, which is chiral, was first reported by Sarges in U.S. Pat. No. 4,130,714. Its chloro analog (in which 6-chloro replaces 6-fluoro) has also been reported (Sarges, U.S. Pat. No. 4,286,098), as has the 2R-methyl analog of sorbinil (Ueda et al., U.S. Pat. No. 4,540,704).
Non-hydantoin compounds previously reported to inhibit aldose reductase include halogen substituted chroman-4-carboxylic and chroman-4-acetic acids (Belletire, U.S. Pat. No. 4,210,663), and spiro[chroman-4,5'-oxazolidin]-2',3'-diones (Schnur, U.S. Pat. No. 4,200,642).
The chemical nomenclature employed herein is that of the "IUPAC Nomenclature of Organic Chemistry, 1979 Edition," Pergammon Press. Thus, chromans are named as such as permitted under Rule B-2.12 at page 62; thiochromans (in which sulfur replaces the oxygen atom of chroman) are named according to Rule B-4 "replacement nomenclature" at page 68 as 3,4-dihydro-2H-1-thianaphthalenes; racemic cis-trans isomers are named according to Rule E-2.3.4 at page 478 in which c is used as an abbreviation for cis and r is used as an abbreviation for the reference group; and R and S are used to designate chiral carbon atoms according to Rule E-4.9 at 481 and the Sequence Rule at page 486 et seq.
SUMMARY OF THE INVENTION
The present invention is directed to a racemic compound having the relative stereochemical formula or a chiral compound having the absolute stereochemical formula ##STR1## wherein
Z is --O--, --S--, ##STR2##
R.sup.1 and R.sup.2 are taken separately; where n is 0, 1 or 2 and Ar is phenyl or phenyl mono- or disubstituted by methoxy, fluoro, chloro or bromo, where disubstituents are the same or different; and together and are (CH.sub.2).sub.4 or (CH.sub.2).sub.5 ;
R.sup.3 is hydrogen or methyl; with the provisos that when either Z is other than --O--, or R.sup.1 is other than methyl, ethyl or trifluoromethyl, both R.sup.2 and R.sup.3 are hydrogen;
X is hydrogen, a first substituent at the 6-position which is fluoro, chloro, bromo, methyl, nitro, cyano, methanesulfonyl or benzoyl, with the proviso that when Z is other than --O--, X is other than hydrogen and is a first substituent at the 6-position which is fluoro, chloro, cyano or nitro; and
X.sup.1 and X.sup.2 are taken separately; chloro, bromo, carboxy or methyl, or a second substituent at either the 5- or 7-position which is fluoro, chloro, bromo, (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy or benzyloxy; and which is fluoro, chloro, bromo or (C.sub.1 -C.sub.3)alkyl; or
X.sup.1 and X.sup.2 are taken together and are 7,8-benzo; or a pharmaceutically-acceptable cationic salt thereof.
For their generally greater activity, the chiral variants of the compound of the formula (I) are preferred, the preferred value of R.sup.1 is methyl with R.sup.2 and R.sup.3 as hydrogen, the preferred value of Z is oxygen (--O--), and the preferred value of X is 6-fluoro, 6-chloro, 6-cyano or 6-nitro with X.sup.1 as hydrogen, 7-fluoro, 7-chloro, 7-bromo, 7-methyl, 7-ethyl or 7-methoxy and X.sup.2 as hydrogen. Most preferred racemic compounds of the formula (I) are:
(1) those in which Z is --O--, R.sup.1 is methyl, R.sup.2, R.sup.3 and X.sup.2 are each hydrogen and X/X.sup.1 are 6-fluoro-7-c
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patent: 4117230 (1978-09-01), Sarges
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patent: 4210663 (1980-07-01), Belletire
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patent: 4305955 (1981-12-01), Belletire
patent: 4486428 (1984-12-01), Eggler
patent: 4503066 (1985-03-01), Brittain et al.
patent: 4540704 (1985-09-01), Ueda et al.
Ricci et al; C. R. Acad. Sci. Paris Serie C; 1975, pp. 1023-1025.
Blackwood Robert K.
Howard Mary Sue
Lee Mary C.
Lumb J. Trevor
Pfizer Inc.
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