Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-10-06
1996-08-13
Chan, Nicky
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549407, A61K 31355, C07D31172
Patent
active
055456600
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/US93/02311 filed Mar. 12, 1993.
This invention relates to novel hydrazide acyl hydrazinium derivatives of certain 3,4-dihydro-2H-1-benzopyrans, to the intermediates, processes and techniques for their preparation, to their ability to manifest the property of being free radical scavengers, and to their end-use application in the treatment of disease conditions capable of being ameliorated by free radical scavengers.
More specifically this invention relates to compounds of the formula ##STR3## the stereoisomers and mixtures thereof, their inner salts, and the pharmaceutically acceptable salts thereof wherein ##STR4## with R.sub.8 being H or halogeno, n is zero, 1, 2, or 3 and formed
As used herein the term alkyl includes the straight or branched saturated aliphatic hydrocarbyl moieties having the designated number of carbon atoms, preferably methyl or ethyl, but including propyl, isopropyl, n-butyl, t-butyl, hexyl and the like. The term --C(O)R includes those acyl moieties wherein R includes H and C.sub.1-6 alkyl, embracing formyl and methylcarbonyl as preferred species but including ethylcarbonyl and the like. In the acyl hydrazinium moiety (i.e., --C(O)NHN.sup..sym. (R.sub.3)(R.sub.4)(R.sub.5).X.sup..crclbar.) the R.sub.3, R.sub.4 and R.sub.5 preferably are the same alkyl with methyl and ethyl being preferred and when R.sub.5 is not alkyl the preferred radicals are benzyl or R.sub.8 -substituted benzyl moieties with R.sub.8 preferably being chloro or bromo. The X.sup..crclbar. moiety includes a halogen, preferably chloro or bromo, or a --S(O).sub.3 R.sub.6 moiety wherein R.sub.6 is H, C.sub.1-6 alkyl, phenyl, or, preferably, 4-methylphenyl.
The inner salts include those compounds wherein the acyl hydrazinium moiety would have the structure configuration ##STR5## as its terminal 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 this invention may be prepared by standard chemical processes and techniques analogously known in the art from materials which are either known per se or which may be prepared in an analogous manner. Preferably the starting materials are in the desired enantiomeric form. The overall process for the preparation of the compounds of this invention may be depicted by the following reaction scheme with the chemical process and techniques being taught by the specific examples herein described. ##STR6## wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, n and X are as previously defined.
In essence, the reaction scheme entails the conversion of the acids (2) to a mixed anhydride (3) by reaction with ethylchloroformate at low temperatures (below 0.degree. C.) under anhydrous conditions. The resulting mixed anhydrides are treated with an unsymmetrical dialkylhydrazine, preferably, at about room temperature to produce the hydrazides of formula (4). Upon reaction with the appropriate alkylhalide or alkylsulfonates (e.g. R.sub.5 X wherein X is a halide or SO.sub.3 R.sub.5) the hydrazide is converted to its corresponding acyl hydrazinium salt (5) and, by treatment with base, preferably sodium hydroxide, to the inner salt (6). Of course acylation of a hydroxy function at the 6-position of the 3,4-dihydro-benzopyran may be effected by reaction with an acid anhydride or acid halide to produce the desired formyl or alkylcarbonyloxy moieties. Conversion back to the 6-OH moiety may be effected by hydrolysis, said acylation and hydrolysis reaction being well known in the art.
The following examples illustrate the processes by which the compounds of this invention may be prepared.
EXAMPLE 1
2-[(3,4-Dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl
]-1,1,1-trimethylhydrazi
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Bolkenius Frank
Grisar J. Martin
Petty Margaret A.
Chan Nicky
Merrell Pharmaceuticals Inc.
Moon Carolyn D.
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