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US 5,476,944 AGranted
Derivatives of cyclic phenolic thioethers
AssigneeG. D. Searle & Co.
InventorsRichard A. Partis, Richard A. Mueller, Francis J. Koszyk, Richard M. Weier
Life of this patent
Estimating the term…
Abstract
The present invention relates to derivatives of cyclic phenolic thioethers of the formula: ##STR1## and the pharmaceutically acceptable salts thereof, which are inhibitors or stimulators of superoxide generation, and which may also inhibit cyclooxygenase and/or 5-lipoxygenase, to pharmaceutical compositions containing one or more of these compounds in combination with a pharmaceutically-acceptable carrier, and to medical methods of treatment employing these compounds.
Claims23
A compound of the formula:
- ##STR140## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2 and R.sup.10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, nitro or alkylthio, or hydrogen, with the proviso that when each of R.sup.1 and R.sup.2 is either tert-alkyl or phenyl, R.sup.10 is not 4-hydroxy;
- q is 0 or 1;
- R.sup.3 is hydrogen, alkyl, alkoxy, or hydroxy;
- X is O, S or (CH.sub.2).sub.m wherein m is an integer from 0 to 4;
- A is O or S(O)n wherein n is 0, 1, or 2, with the two As being the same or different;
- Alk.sup.1 is straight or branched chain alkyl having 1 to 6 carbon atoms;
- p is an integer of from 0 to 2, but cannot be O when R is OH;
- and R is:
- (a) alkyl, with the proviso that, when A is oxygen, p is 0, q is 0, and R.sup.1, R.sup.2 and R.sup.10 are all hydrogen, or are 2,4,6-trimethyl, or R.sup.1 and R.sup.2 are 2,4-dinitro and R.sup.10 is hydrogen, or R.sup.1 and R.sup.2 are H and R.sup.10 is 4-chloro or 4-nitro or 4-methyl, then R is not methyl;
- (b) OH;
- (c) OR.sup.4 wherein R.sup.4 is alkyl of 1 to 6 carbon atoms;
- (d) NR.sup.5 R.sup.6 wherein R.sup.5 is hydrogen or alkyl, and R.sup.6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR.sup.8 R.sup.9 wherein Alk is alkyl of 1 to 10 carbon atoms and R.sup.8 and R.sup.9 each independently are hydrogen or alkyl;
- or NR.sup.5 R.sup.6 together form a heterocyclic ring which may optionally be substituted;
- or
- (e) (CH.sub.2).sub.t COOR.sup.7 wherein t is an integer from 1 to 4 and R.sup.7 is hydrogen or alkyl of 1 to 4 carbon atoms.
12 more elements
A compound of the formula:
- ##STR141## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2 and R.sup.10 are the same or different and independently represent alkyl, alkoxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen;
- q is 0 or 1;
- R.sup.3 is hydrogen, alkyl, alkoxy, or hydroxy;
- X is O, S or (CH.sub.2).sub.m wherein m is an integer from 0 to 4;
- A is 0 or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- p is an integer of from 0 to 2, but cannot be O when R is OH;
- and R is:
- (a) alkyl, with the proviso that, when A is oxygen, p is 0, q is 0, and R.sup.1, R.sup.2 and R.sup.10 are all hydrogen, or are 2,4,6-trimethyl, or R.sup.1 and R.sup.2 are 2,4-dinitro and R.sup.10 is hydrogen, or R.sup.1 and R.sup.2 are H and R.sup.10 is 4-chloro or 4-nitro or 4-methyl, then R is not methyl;
- (b) OH;
- (c) OR.sup.4 wherein R.sup.4 is alkyl of 1 to 6 carbon atoms;
- (d) NR.sup.5 R.sup.6 wherein R.sup.5 is hydrogen or alkyl, and R.sup.6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR.sup.8 R.sup.9 wherein Alk is alkyl of 1 to 10 carbon atoms and R.sup.8 and R.sup.9 each independently are hydrogen or alkyl;
- or NR.sup.5 R.sup.6 together form a heterocyclic ring which may optionally be substituted;
- or
- (e) (CH.sub.2).sub.t COOR.sup.7 wherein t is an integer from 1 to 4 and R.sup.7 is hydrogen or alkyl of 1 to 4 carbon atoms.
11 more elements
A compound of the formula:
- ##STR142## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2 and R.sup.10 are the same or different and independently represent tert-alkyl of 4 to 10 carbon atoms, phenyl, halogen, or hydrogen;
- R.sup.3 is hydrogen or alkyl of 1 to 4 carbon atoms;
- X is O, S or (CH.sub.2).sub.m wherein m is 1 or 2;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- p is an integer of from 0 to 4, but cannot be O when R is OH;
- and R is:
- (a) alkyl of 1 to 4 carbon atoms, with the proviso that when A is oxygen, p is 0, and R.sup.1, R.sup.2 and R.sup.10 are all hydrogen, then R is not methyl;
- (b) OH;
- (c) OR.sup.4 wherein R.sup.4 is alkyl of 1 to 4 carbon atoms;
- (d) NR.sup.5 R.sup.6 wherein R.sup.5 is hydrogen or alkyl, and R.sup.6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR.sup.8 R.sup.9 wherein Alk is straight or branched chain alkyl of 1 to 6 carbon atoms and R.sup.8 and R.sup.9 each independently are hydrogen or alkyl of 1 to 4 carbon atoms;
- or NR.sup.5 R.sup.6 together form a heterocyclic ring which may optionally be substituted;
- or
- (e) (CH.sub.2).sub.t COOR.sup.7 wherein t is an integer from 1 to 4 and R.sup.7 is hydrogen or alkyl of 1 to 4 carbon atoms.
10 more elements
A compound having the structure:
- ##STR145##
A pharmaceutical composition for use in inhibiting superoxide generation in an animal which comprises an amount of a compound of the formula:
- ##STR146## or a pharmaceutically acceptable salt thereof wherein R.sup.1, R.sup.2 and R.sup.10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when each of R.sup.1 and R.sup.2 is either tert-alkyl or phenyl, R.sup.10 is not 4-hydroxy;
- q is 0 or 1;
- R.sup.3 is hydrogen, alkyl, alkoxy, or hydroxy;
- X is O, S or (CH.sub.2).sub.m wherein m is an integer from 0 to 4;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- and Alk.sup.1 is straight or branched chain alkyl having 1 to 6 carbon atoms, which is effective to inhibit superoxide generation;
- and a pharmaceutically acceptable carrier.
4 more elements
A pharmaceutical composition for use in inhibiting superoxide generation in a mammal which comprises an amount of a compound of the formula:
- ##STR147## wherein R.sup.1 and R.sup.2 are the same or different and independently represent tert-alkyl, phenyl, halogen or hydrogen;
- R.sup.3 is hydrogen or alkyl of 1 to 4 carbon atoms;
- X is O, S or (CH.sub.2).sub.m wherein m is 1 or 2;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- and p is an integer of from 1 to 4;
- or a pharmaceutically acceptable salt thereof, which is effective to inhibit superoxide generation;
- and a pharmaceutically acceptable carrier.
4 more elements
A pharmaceutical composition for use in stimulating superoxide generation in an animal which comprises a compound of the formula:
- ##STR148## or a pharmaceutically acceptable salt thereof wherein R.sup.1, R.sup.2 and R.sup.10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when each of R.sup.1 and R.sup.2 is either tert-alkyl or phenyl, R.sup.10 is not 4-hydroxy;
- q is 0 or 1;
- R.sup.3 is hydrogen, alkyl, alkoxy, or hydroxy;
- X is O, S or (CH.sub.2).sub.m wherein m is an integer from 0 to 4;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- Alk.sup.1 is straight or branched chain alkyl having 1 to 6 carbon atoms;
- p is 0 or 1;
- and R is OR.sup.4 wherein R.sup.4 is alkyl of 1 to 6 carbon atoms;
- or NR.sup.5 R.sup.6 wherein R.sup.5 is hydrogen or alkyl, and R.sup.6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, or substituted phenylalkyl, or Alk-NR.sup.8 R.sup.9 wherein Alk is alkyl of 1 to 10 carbon atoms and R.sup.8 and R.sup.9 each independently are hydrogen or alkyl;
- or NR.sup.5 R.sup.6 together form a heterocyclic ring which may optionally be substituted which is effective to stimulate superoxide generation and a pharmaceutically acceptable carrier.
7 more elements
A pharmaceutical composition for use in stimulating superoxide generation in an animal which comprises an amount of a compound of the formula:
- ##STR149## wherein R.sup.1 and R.sup.2 are the same or different and independently represent tert-alkyl, phenyl, or hydrogen;
- R.sup.3 is hydrogen or alkyl of 1 to 4 carbon atoms;
- X is O, S or (CH.sub.2).sub.m wherein m is 1 or 2;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- p is an integer from 1 to 4;
- and R is OR.sup.4 wherein R.sup.4 is alkyl of 1 to 4 carbon atoms;
- or NR.sup.5 R.sup.6 wherein R.sup.5 is hydrogen or alkyl, and R.sup.6 is hydrogen, alkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl or Alk-NR.sup.8 R.sup.9 wherein Alk is alkyl of 1 to 6 carbon atoms and R.sup.8 and R.sup.9 each independently are hydrogen or alkyl of 1 to 4 carbon atoms;
- or NR.sup. 5 R.sup.6 together form a heterocyclic ring which may optionally be substituted;
- or a pharmaceutically acceptable salt thereof, which is effective to stimulate superoxide generation and a pharmaceutically acceptable carrier.
6 more elements
A method of inhibiting superoxide generation in an animal which comprises administering to an animal in need of such treatment an amount of a compound of the formula:
- ##STR150## or a pharmaceutically acceptable salt thereof wherein R.sup.1, R.sup.2 and R.sup.10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when each of R.sup.1 and R.sup.2 is either tert-alkyl or phenyl, R.sup.10 is not 4-hydroxy;
- t is 0 or 1;
- R.sup.3 is hydrogen, alkyl, alkoxy, or hydroxy;
- X is O, S or (CH.sub.2).sub.m wherein m is an integer from 0 to 4;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- and Alk.sup.1 is straight or branched chain alkyl having 1 to 6 carbon atoms, which is effective to inhibit superoxide generation.
3 more elements
A method of inhibiting superoxide generation in an animal which comprises administering to an animal in need of such treatment an amount of a compound of the formula:
- ##STR151## wherein R.sup.1 and R.sup.2 are the same or different and independently represent tert-alkyl, phenyl, or hydrogen;
- R.sup.3 is hydrogen or alkyl of 1 to 4 carbon atoms;
- X is O, S or (CH.sub.2).sub.m wherein m is 1 or 2;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- and p is an integer from 1 to 4;
- or a pharmaceutically acceptable salt thereof, which is effective to inhibit superoxide generation.
3 more elements
A method of stimulating superoxide generation in an animal which comprises administering to an animal in need of such treatment an amount of a compound of the formula:
- ##STR152## or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2 and R.sup.10 are the same or different and independently represent alkyl, alkoxy, hydroxy, phenyl, halogen, trifluoromethyl, cyano, or hydrogen, with the proviso that when each of R.sup.1 and R.sup.2 is either tert-alkyl or phenyl, R.sup.10 is not 4-hydroxy;
- t is 0 or 1;
- R.sup.3 is hydrogen, alkyl, alkoxy, or hydroxy;
- X is O, S or (CH.sub.2).sub.m wherein m is an integer from 0 to 4;
- A is O or S(O).sub.n, wherein n is 0, 1, or 2, with the two As being the same or different;
- Alk.sup.1 is straight or branched chain alkyl having 1 to 6 carbon atoms;
- p is 0 or 1;
- and R is OR.sup.4 wherein R.sup.4 is alkyl of 1 to 6 carbon atoms or NR.sup.5 R.sup.6 wherein R.sup.5 is hydrogen or alkyl, and R.sup.6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, or substituted phenylalkyl, or Alk-NR.sup.8 R.sup.9 wherein Alk is alkyl of 1 to 10 carbon atoms and R.sup.8 and R.sup.9 each independently are hydrogen or alkyl;
- or NR.sup.5 R.sup.6 together form a heterocyclic ring which may optionally be substituted, which is effective to stimulate superoxide generation.
6 more elements
A method of stimulating superoxide generation in an animal which comprises administering to an animal in need of such treatment an amount of a compound of the formula:
- ##STR153## wherein R.sup.1 and R.sup.2 are the same or different and independently represent tert-alkyl, phenyl, or hydrogen;
- R.sup.3 is hydrogen or alkyl of 1 to 4 carbon atoms;
- X is O, S or (CH.sub.2).sub.m wherein m is 1 or 2;
- A is O or S(O).sub.n wherein n is 0, 1, or 2, with the two As being the same or different;
- p is an integer from 0 to 4;
- and R is OR.sup.4 wherein R.sup.4 is alkyl of 1 to 4 carbon atoms;
- NR.sup.5 R.sup.6 wherein R.sup.5 is hydrogen or alkyl, and R.sup.6 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, heterocyclealkyl, substituted heterocyclealkyl, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, or Alk-NR.sup.8 R.sup.9 wherein Alk is alkyl of 1 to 6 carbon atoms and R.sup.8 and R.sup.9 each independently are hydrogen or alkyl of 1 to 4 carbon atoms;
- or NR.sup.5 R.sup.6 together form a heterocyclic ring which may optionally be substituted;
- or a pharmaceutically acceptable salt thereof, which is effective to stimulate superoxide generation.
6 more elements
Dependencies are inferred from the claim text.