4-Amino-4-phenylcyclohexanone ketal compositions and process of use
AssigneeThe Upjohn Company
InventorDaniel Lednicer
Life of this patent
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Abstract
A class of new 4-amino-4-arylcyclohexanones, their ketals, and acid addition salts have been synthesized and found to be useful for relieving pain in animals. Their analgesic activity appears to be of high order, and in addition some exhibit narcotic antagonist activity that is useful in modifying the cardiovascular, respiratory, and behavioral depression caused by other analgesics. Several show mixed analgesic and narcotic antagonist activity. Preferred compounds of the class are 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone ethylene ketal, and 4-(m-hydroxyphenyl)-4-(n-butylmethylamino)cyclohexanone ethylene ketal as free bases and as their hydrochloride salts. Processes for synthesis and intermediates are described. Unit dosage forms and therapeutic treatments are disclosed.
Claims72
A compound of the formula:
- ##STR23## wherein X is ##STR24## wherein n is zero or one and R.sub.4 is hydrogen or methyl;
- R.sub.5 is hydrogen, phenyl, --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive, or methyl;
- aryl is ##STR25## wherein m is zero, one or two, and Y is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, hydroxy, cycloalkyloxy of 3 to 6 carbon atoms, inclusive, alkanoyloxy of 2 to 4 carbon atoms, inclusive, alkylthio of 1 to 4 carbon atoms, inclusive, or ##STR26## where Y' is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive;
- R.sub.1 is hydrogen, or alkyl of 1 to 8 carbon atoms, inclusive, R.sub.2 is hydrogen, alkyl of 1 to 8 carbon atoms, inclusive, --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 8 carbon atoms, inclusive, acetyl, cycloalkylalkyl wherein cycloalkyl is of 3 to 6 carbon atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, inclusive, .beta.-hydroxyethyl, carbethoxymethyl, cycloalkyl of 3 to 6 carbon atoms, inclusive, ##STR27## and R.sub.3 is hydrogen, alkyl of 1 to 5 carbon atoms, inclusive, and the acid addition salts thereof.
An intermediate compound of the formula:
- ##STR35## wherein X is ##STR36## wherein n is zero or one and R.sub.4 is hydrogen or methyl;
- R.sub.5 is hydrogen, methyl, phenyl, or --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive;
- aryl is ##STR37## wherein m is zero, one or two, and Y is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, cycloalkyloxy of 3 to 6 carbon atoms, inclusive, alkylthio of 1 to 4 carbon atoms, inclusive, ##STR38## where Y' is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive, or the acid addition salts thereof.
An intermediate compound of the formula:
- ##STR39## wherein X is ##STR40## wherein n is zero or one and R.sub.4 is hydrogen or methyl;
- R.sub.5 is hydrogen, methyl, phenyl, --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive;
- aryl is ##STR41## wherein m is zero, one or two, and Y is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, cycloalkyloxy of 3 to 6 carbon atoms, inclusive, alkylthio of 1 to 4 carbon atoms, inclusive, ##STR42## wherein Y' is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive, or the acid addition salts thereof.
A pharmaceutical composition in unit dosage form for relieving pain in animals comprising as an active ingredient an analgetic effective amount of a compound of the formula:
- ##STR43## wherein X is ##STR44## wherein n is zero or one and R.sub.4 is hydrogen or methyl;
- R.sub.5 is hydrogen, phenyl, --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive, or methyl;
- aryl is ##STR45## wherein m is zero, one or two, and Y is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, hydroxy, cycloalkyloxy of 3 to 6 carbon atoms, inclusive, alkanoyloxy of 2 to 4 carbon atoms, inclusive, alkylthio of 1 to 4 carbon atoms, inclusive, or ##STR46## where Y' is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive;
- R.sub.1 is hydrogen, or alkyl of 1 to 8 carbon atoms, inclusive, R.sub.2 is hydrogen, or alkyl of 1 to 8 carbon atoms, inclusive, --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 8 carbon atoms, inclusive, acetyl, cycloalkylalkyl wherein cycloalkyl of 3 to 6 carbon atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, inclusive, .beta.-hydroxyethyl, carbethoxymethyl, cycloalkyl of 3 to 6 carbon atoms, inclusive, ##STR47## or ##STR48## and R.sub.3 is hydrogen, alkyl of 1 to 5 carbon atoms, inclusive, and the acid addition salts thereof, in association with a pharmaceutical carrier.
A process for inducing analgesia in humans and animals comprising the administration of an analgetic amount of a compound of the formula:
- ##STR56## wherein X is ##STR57## wherein n is zero or one and R.sub.4 is hydrogen or methyl;
- R.sub.5 is hydrogen, phenyl, --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 4 carbon atoms, inclusive, or methyl;
- aryl is ##STR58## wherein m is zero, one or two, and Y is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, alkoxy of 1 to 4 carbon atoms, inclusive, hydroxy, cycloalkyloxy of 3 to 6 carbon atoms, inclusive, alkanoyloxy of 2 to 4 carbon atoms, inclusive, alkylthio of 1 to 4 carbon atoms, inclusive, or ##STR59## where Y' is halogen, CF.sub.3, alkyl of 1 to 4 carbon atoms, inclusive, or alkoxy of 1 to 4 carbon atoms, inclusive;
- R.sub.1 is hydrogen, or alkyl of 1 to 8 carbon atoms, inclusive, R.sub.2 is hydrogen, alkyl of 1 to 8 carbon atoms, inclusive, --CH.sub.2 -alkenyl wherein alkenyl is of 2 to 8 carbon atoms, inclusive, acetyl, cycloalkylalkyl wherein cycloalkyl is of 3 to 6 carbon atoms, inclusive, and alkyl is of 1 to 3 carbon atoms, inclusive, .beta.-hyhydroyethyl, carbethoxymethyl, cycloalkyl of 3 to 6 carbon atoms, inclusive, ##STR60## or ##STR61## and R.sub.3 is hydrogen, alkyl of 1 to 5 carbon atoms, inclusive, and the acid addition salts thereof, to a human or animal subject.
Dependencies are inferred from the claim text.