Short-acting benzodiazepines
It has now been found that compounds of the present invention as described in Benzodiazepine derivatives of Formula (I) containing a carboxylic ester moiety and thereby capable of being inactivated by nonspecific tissue esterases in an organ-independent elimination mechanism and thereby providing a more predictable and reproducible pharmacodynamic profile. The compounds of the present invention are suitable for therapeutic purposes, including sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant purposes and are useful to be administered intravenously in the following clinical settings: preoperative sedation, anxiolysis, and amnestic use for perioperative events; conscious sedation during short diagnostic, operative or endoscopic procedures; as a component for the induction and maintenance of general anesthesia, prior and/or concomitant to the administration of other anesthetic agents; ICU sedation.
1. A compound of formula (I):
wherein
W is H, a C 1 -C 4 branched alkyl, or straight chained alkyl;
X is CH 2 , NH or NCH 3 ; n is 1 or 2;
Y is O or CH 2 ; m is 0 or 1, provided that if X is CH 2 , n is 1 and m is 0, then R 1 is not CH 2 CH 3 ;
R 1 is H, a C 1 -C 7 straight chain alkyl, a C 3 -C 7 branched chain alkyl, a C 1-4 haloalkyl, a C 3 -C 7 cycloalkyl, an aryl, a heteroaryl, an aralkyl, or a heteroaralkyl;
R 2 is phenyl, 2-halophenyl or 2-pyridyl,
R 3 is H, Cl, Br, F, I, CF 3 or NO 2 ;
R 8 is hydrogen, C 1-4 alkyl or C 1-3 hydroxyalkyl;
U is CR 9 where R 9 is H, C 1-3 hydroxyalkyl, C 1-4 alkoxy, or C 1-4 alkyl;
and V is CH;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound of claim 1 wherein
W is H;
X is CH 2 , n is 1;
Y is CH 2 , m is 1;
R 1 is CH 3 or CH 2 CH(CH 3 ) 2 ;
R 2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl;
R 3 is Cl or Br; and
R 8 is H, CH 3 or CH 2 OH.
3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 .
4. A pharmaceutical formulation composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 2 .
5. A method of producing sedation or hypnosis, inducing anxiolysis, inducing muscle relaxation in a mammal, or treating convulsions in a mammal, comprising:
administering to the mammal an effective amount of a compound of claim 1 .
6. The method of claim 5 wherein the mammal is in need of sedation.
7. The method of claim 5 wherein the mammal is in need of hypnosis.
8. The method of claim 5 wherein the mammal is in need of muscle relaxation.
9. The method of claim 5 wherein the mammal suffers from convulsions.
10. A method of providing sedation or hypnosis, inducing anxiolysis, inducing muscle relaxation in a mammal, or treating convulsions in a mammal, comprising:
administering to the mammal an effective amount of a compound of claim 2 .