Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-12-22
1998-02-24
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514253, 514278, 514320, 514409, 514422, 514462, 514469, 544 70, 544153, 544230, 544295, 544376, 546 15, 546196, 548407, 548525, 549467, A61K 31535, A61K 31495, C07D40506, C07D41306
Patent
active
057212333
DESCRIPTION:
BRIEF SUMMARY
This invention relates to certain derivatives of 2,3-dihydro-benzofuranol; to the intermediates and processes useful 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 such as, for example, stroke, nervous system trauma or reperfusion damage.
More specifically this invention relates to compounds of the formula ##STR1## the stereoisomers and mixtures thereof, and their pharmaceutically acceptable salts thereof, wherein with the carbon atom to which they are attached, form a C.sub.5-6 cyclic hydrocarbyl moiety; --Q.sup..crclbar., pyrrolidino, piperidino morpholino, or ##STR2## R.sub.8 is H, C.sub.1-6 alkyl, or --(CH.sub.2).sub.m --A, with m being 2,3 or 4; ##STR3##
n is 1, 2, 3 or 4, p is 1,2 or 3; cyclohexylmethyl, hydroxyalkyl (C.sub.2-6), dihydroxyalkyl (C.sub.3-6), C.sub.2-9 acyloxyalkyl (C.sub.2-6), C.sub.1-4 alkoxyalkyl (C.sub.1-6), ##STR4## with t being 0, 1, or 2, or pyrimidinyl; R.sub.11 is H, C.sub.1-4 alkoxy, C.sub.1-4 alkyl or halogeno; R.sub.1 being H, C.sub.1-6 alkyl, aryl or aralkyl.
As used herein the term "alkyl" includes the straight and branched chain saturated aliphatic hydrocarbyl moieties having the indicated number of carbon atoms, preferably methyl or ethyl, but including others such as propyl, isopropyl, n-butyl and the like. The term --C(O)R includes moieties wherein R is B or a C.sub.1-9 alkyl moiety, embracing, for example, formyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl and the like. The --NR.sub.7 R.sub.9 moieties include the amino and mono and di-substituted amines with R.sub.7 and R.sub.9 being as defined. The ##STR5## moiety includes benzyl, phenylethyl, phenylpropyl or phenylbutyl moieties; the phenyl moieties of which may bear 1,2 or 3 substituents represented by R.sub.11 selected from the group consisting of C.sub.1-4 alkoxy (preferably methoxy) C.sub.1-4 alkyl (preferably methyl) or halogen (preferably chloro but including bromo and iodo). Similarly, mono and di-hydroxy substituted alkyl moieties are those moieties wherein the alkyl moiety can bear one or two OH groups (other than two hydroxy groups on one carbon atom), preferably moieties bearing a hydroxy group on a terminal carbon atom. C.sub.2-9 acyloxy alkylene (C.sub.2-6) are those compounds wherein the acyloxy moiety has 2 to 9 carbon atoms and the alkylene moiety has 2 to 6 carbon atoms such as exemplified by --CH.sub.2 CH.sub.2 --OC(O)CH.sub.3. The --C.sub.2-6 alkylene O--(CH.sub.2).sub.2-4 OH moieties have respectively a divalent 1-6 carbon atom moiety attached to an oxygen (O). The oxygen is also attached to a 1-4 carbon moiety terminating in a hydroxy moiety. One example is --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.2 CH.sub.2 OH. Piperidino is illustrated by ##STR6## and pyrrolidino ##STR7## It is preferred that both R.sub.2 alkyl moieties be the same (e.g. 2,2-dimethyl or 2,2-diethyl) but both need not be the same for any one compound. Similarly in those instances wherein A represents a tertiary amine both of R.sub.7 and R.sub.9 are preferably the same, preferably both being methyl or ethyl, and when R.sub.9 is other than H or alkyl, benzyl is preferred. The moiety --N.sup..sym. R.sub.6 R.sub.6 R.sub.6. Q.sup..crclbar. represents a quaternary ammonium moiety wherein Q includes all halides with chloro and bromo being preferred, and aryl includes phenyl or its alkylated derivatives with toluene as the preferred species and aralkyl includes benzyl or phenethyl and their alkylated derivatives.
The pharmaceutically acceptable salts include those acid addition salts derived by reaction with such acids as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acids and such organic carboxylic acids as acetic, propionic, glycolic, maleic, tartaric, citric, salicylic, 2-acetyloxybenzoic acids or organic sulfonic acids such as methanesulfonic 4-toluenesulfonic as naphthalensulfonic acids. Of course other acids well known to the pharmaceutical
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Bolkenius Frank
Grisar J. Martin
Petty Margaret A.
Bernhardt Emily
Merrell Pharmaceuticals Inc.
Moon Carolyn D.
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