Alkyl, azido, alkoxy and fluoro-substituted and fused quinoxalinediones and the use thereof as glycine receptor antagonist

A method of treating chronic pain, treating or preventing anxiety, treating or preventing convulsions, inducing anesthesia, treating or preventing NMDA receptor-ion channel psychosis, inducing a hypnotic effect, or treating or preventing opiate tolerance, comprising:

• administering to an animal in need of such treatment an effective amount of a compound having the Formula:
• ##STR47## or a tautomer or a pharmaceutically acceptable salt thereof;
• wherein R.sup.1 is nitro, cyano, CF.sub.3, carboxy, or alkanoyl;
• R.sup.2 is alkoxy, aralkoxy, thioalkyl, hydroxy, mercaptoalkyl, or azido;
• R.sup.3 is halo, haloalkyl, nitro, alkyl, alkoxy, azido, or cyano;
• and
• R.sup.4 is hydrogen.

A pharmaceutical composition, comprising:

• (a) a pharmaceutically acceptable carrier;
• and
• (b) a compound having the Formula:
• ##STR48## or a tautomer or a pharmaceutically acceptable salt thereof;
• wherein R.sup.1 is alkyl, azido, alkoxy, hydroxy, haloalkyl, halo, nitro, cyano or alkanoylamino;
• R.sup.2 is alkyl, azido, alkoxy, aralkoxy, cyano, haloalkyl, halo, hydroxy or nitro;
• R.sup.3 is alkyl, azido, alkoxy, cyano, halo, haloalkyl or hydroxy;
• R.sup.4 is hydrogen or fluoro;
• provided that (a) at least one of R.sup.1, R.sup.2 or R.sup.3 is hydroxy or azido, or (b) at least one of R.sup.2 or R.sup.3 is alkyl or alkoxy, or (c) R.sup.1 is cyano.

A pharmaceutical composition, comprising:

• (a) a pharmaceutically acceptable carrier;
• and
• (b) a compound having the Formula:
• ##STR49## or a tautomer or a pharmaceutically acceptable salt thereof;
• wherein R.sup.1 is nitro, cyano, CF.sub.3, carboxy, or alkanoyl;
• R.sup.2 is alkoxy, aralkoxy, thioalkyl, hydroxy, mercaptoalkyl, or azido;
• R.sup.3 is halo, haloalkyl, nitro, alkyl, alkoxy, azido, or cyano;
• and
• R.sup.4 is hydrogen.

A method of antagonizing excitatory amino acids at the NMDA receptor complex, comprising administering to an animal in need thereof an effective amount of a compound of the Formula ##STR50## or a tautomer or a pharmaceutically acceptable salt thereof;

• wherein
• R is hydrogen;
• R.sup.1 is alkyl, azido, alkoxy, hydroxy, haloalkyl, halo, nitro, cyano or alkanoylamino;
• R.sup.2 is alkyl, azido, alkoxy, aralkoxy, cyano, haloalkyl, halo, hydroxy or nitro;
• R.sup.3 is alkyl, azido, alkoxy, cyano, halo, haloalkyl or hydroxy;
• R.sup.4 is hydrogen or fluoro;
• provided that (a) at least one of R.sup.1, R.sup.2 or R.sup.3 is hydroxy or azido, or (b) at least one of R.sup.2 or R.sup.3 is alkyl or alkoxy, or (c) R.sup.1 is cyano.

A method of antagonizing excitatory amino acids at the NMDA receptor complex, comprising administering to an animal in need thereof an effective amount of a compound having the Formula ##STR51## or a tautomer or a pharmaceutically acceptable salt thereof;

• wherein R.sup.1 is nitro, cyano, CF.sub.3, carboxy, or alkanoyl;
• R.sup.2 is alkoxy, aralkoxy, thioalkyl, hydroxy, mercaptoalkyl, or azido;
• R.sup.3 is halo, haloalkyl, nitro, alkyl, alkoxy, azido, or cyano;
• and
• R.sup.4 is hydrogen.