Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-10-05
1996-04-23
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514456, 549281, 549300, 549400, C07D49308, C07D31124, A61K 3135, A61K 31365
Patent
active
055103731
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/U.S. Pat. No. 93/02102 filed Mar. 8, 1993.
This invention relates to certain hydroxy derivatives of 3,4-dihydro-2,5,7,8-tetraalkyl-2H-l-benzopyran-2carboxylic acids and the lactones thereof, to the processes and intermediates useful for their preparation and to their use as free radical scavengers useful in the treatment of tissue damage implicated with free oxygen radicals.
More particularly, this invention relates to compounds of the formulae ##STR1## their individual isomers and mixtures thereof, and the pharmaceutically acceptable salts thereof wherein
As used herein the term alkyl includes the straight and branched-chain radicals having the designated number of carbon atoms with methyl and ethyl being preferred. The --C(O)R.sub.3 moiety embraces formyl and the straight and branched-chain alkylcarbonyl moieties with formyl, methylcarbonyl and ethylcarbonyl being preferred. In the instance wherein R.sub.4 forms an amide it is preferred that both alkyl groups be the same and that the alkyl radicals are methyl or ethyl in both mono- or di-alkylated amido situations. When variables such as R are used more than once to define a structure, it is to mean that in each instance the variable may represent a different moiety.
The compounds of the present invention include stereoisomers; the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric isomers (cis/trans), and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
In general the compounds of Formulae 1A and 1B (collectively referred to as compounds of Formula 1) may be prepared, isolated and converted to the desired salts by chemical processes, work-up and crystallization techniques analogously known in the art. Conveniently, the starting materials are either known or may be prepared by standard procedures.
The preparation of the compounds of Formula I may be schematically depicted in the following reaction schemes A and B. ##STR2## wherein R and R.sub.1 are as previously defined an Ac is the preferred acyl moiety.
In this reaction sequence the acids (2) are sequentially esterified and acetylated to produce compounds (3) which are dehydrogenated, using a reagent such as DDQ (2,3-dichloro5,6-dicyano-1,4-benzoquinone) to the intermediate (4). Cis-dihydroxylation with a reagent such as osmium tetroxide gives the lactones (6) and the dihydroxyesters (5). Both can be hydrolyzed to the dihydroxy acids (9) (in which the hydroxy groups are cis- to each other) but only one can relactonize to (10). Starting with resolved (2), i.e., the R- or S-enantiomers of (2), two of the four possible enantiomers of (10), and four of the eight possible enantiomers of (9) can be obtained. Trans-dihydroxylation with a reagent such as dimethyldioxirane gives the lactones (7) and dihydroxyesters (8) which, analogously give the remaining enantiomers of (9) and (10).
Similarly, as shown in Reaction Scheme B, starting from the homologous acids (11) the foregoing process technique of Reaction Scheme A gives the .delta.-lactones (12) and the dihydroxy acids (13). Cis- and trans-dihydroxylation of the amides (14) gives the dihydroxy amides (15); the amides being derived by hydrolysis and amidation of compounds (4) or amidation of compounds (11). ##STR3##
The following examples illustrate the details and techniques for the preparation of the compounds of this invention.
EXAMPLE 1
METHYL (2-R,S)-ACETYLOXY-2,5,7,8-TETRAMETHYL-2-H-1-BENZOPYRAN-2-CARBOXYLATE
A solution of 100 g of (2-R,S)-3,4-dihydro-6-hydroxy2,5,7,8-tetramethyl-2-H-1-benzopyran-2-carbox ylic acid and 1 g of p-toluene sulfonic acid in 700 ml of dry methanol is stirred at reflux temperature for 20 hours. About 400 ml of methanol is evaporated and residue is allowed to cool for crystallization. The ester is collected, washed with a little methanol, and dried.
The ester is dissolved in 500 m
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Bolkenius Frank
Grisar J. Martin
Petty Margaret A.
Dentz Bernard
Merrell Pharmaceuticals Inc.
Moon Carolyn D.
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