Short-acting benzodiazepines
The present invention provides a compound of formula (I): wherein all variables are as defined herein, pharmaceutical formulations containing the same, processes for preparing the same and their use therapy.
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 , 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 N or CR 9 where R 9 is H, C 1-3 hydroxyalkyl, C 1-4 alkoxy or C 1-4 alkyl;
and
V is N or CH, with one but not both of U and V being N;
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-chiorophenyl or 2-pyridyl;
R 3 is Cl or Br; and
R 8 is H, CH 3 or CH 2 OH.
3. A compound of claim 1 wherein U is N and V is CH.
4. A compound of claim 1 wherein U is CR 9 where R 9 is H, C 1-4 alkyl, C 1-3 hydroxyalkyl, C 1-4 alkoxy or C 1-4 alkyl, and V is N.
5. 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 ; R 2 is 2-pyridyl; R 3 is Cl; R 8 is CH 3 ; U is CH; and V is N.
6. 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 ; R 2 is 2-fluorophenyl; R 3 is Cl; R 8 is CH 3 ; U is N; and V is CH.
7. 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 ; R 2 is 2-pyridyl; R 3 is Br; R 8 is H; U is C—CH 3 ; and V is N.
8. A compound of claim 1 wherein W is H, X is CH 2 , n is 1, Y is CH 2 , m is 1, and R 1 , R 2 , R 3 , R 8 , U and V are as follows:
R 1
R 2
R 3
R 8
U
V
CH 3
2-fluorophenyl
Cl
H
CH
N
CH 3
2-fluorophenyl
Cl
CH 3
CH
N
CH 3
2-fluorophenyl
Cl
H
C—CH 3
N
CH 3
2-fluorophenyl
Cl
H
C—CH 2 OH
N
CH 3
2-fluorophenyl
Cl
CH 2 OH
CH
N
CH 3
2-pyridyl
Cl
H
CH
N
CH 3
2-pyridyl
Cl
CH 3
CH
N
CH 3
2-pyridyl
Br
CH 3
CH
N
CH 3
2-pyridyl
Br
H
C—CH 3
N
CH 3
2-pyridyl
Cl
H
C—CH 3
N
CH 3
2-pyridyl
Cl
H
C—CH 2 OH
N
CH 3
2-pyridyl
Cl
CH 2 OH
CH
N
CH 3
2-pyridyl
Cl
CH 3
C—CH 3
N
CH 3
2-fluorophenyl
Cl
H
N
CH
CH 3
2-fluorophenyl
Cl
CH 3
N
CH
CH 3
2-pyridyl
Cl
CH 3
C—CH 2 OH
N.
9. A compound of claim 1 wherein X is CH 2 .
10. A compound of the following formula:
wherein W is H; X is CH 2 ; n is 1; Y is CH 2 m is 1; R 1 is CH 3 ; R 2 is 2-fluorophenyl; R 3 is Cl; R 8 is H; U is C—CH 2 O-t-butyl and V is N;
or a pharmaceutically acceptable salt or solvate thereof.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 1 .
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 2 .
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 3 .
14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim 4 .
15. 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 1 .
16. The method of claim 15 wherein the mammal is in need of sedation.
17. The method of claim 15 wherein the mammal is in need of hypnosis.
18. The method of claim 15 wherein the mammal is in need of muscle relaxation.
19. The method of claim 15 wherein the mammal suffers from convulsions.
20. A process for preparing a compound of the following formula:
wherein
R 1 is H, C 1-7 straight chain alkyl, C 3-7 branched chain alkyt, C 1-4 haloalkyl, C 3-7 cycloalkyl, aryl, heteroaryl, aralkyl or 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 H or C 1-4 alkyl;
W is H; U is N; V is CH; X and Y are CH 2 ; n and m are 1;
the process comprising
reacting a compound of formula (M)
with a strong base to produce an anion; and
reacting the anion with a suitable Michael receptor.