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 , 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 ; and wherein
R 4 and R 5 together is a double bond in the diazepine ring and R 6 represents the group NHR 7 wherein R 7 is H, C 1-4 alkyl, benzyl, benzyl mono or disubstituted independently with halogen substituents, C 1-4 alkylpyridyl or C 1-4 alkylimidazolyl;
or a pharmaceutically acceptable salt or solvate thereof.
2. A compound of formula (I):
wherein
W is H;
X is CH 2 or NH; n is 1;
Y is CH 2 ; m is 0 or 1, provided that if X is CH 2 and m is 0, then R 1 is not CH 2 CH 3 ;
R 1 is CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , benzyl or 4-pyridylmethyl; provided that when R 1 is CH 3 or benzyl then m=1;
R 2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl,
R 3 is Cl, Br or NO 2 ;
R 4 is H, CH 3 or CH 2 CH 2 N(CH 2 CH 3 ) 2 ;
R 5 and R 6 together are O or S;
or a pharmaceutically acceptable salt or solvate thereof.
3. A compound of formula (I):
wherein
W is H;
X is CH 2 or NH; n is 1;
Y is CH 2 ; m is 0 or 1, provided that if X is CH 2 and m is 0, then R 1 is not CH 2 CH 3 ;
R 1 is CH 3 , CH 2 CH 3 , (CH 2 ) 3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , benzyl or 4-pyridylmethyl; provided that when R 1 is 4-pyridylmethyl, then X is CH 2 , n is 1, Y is CH 2 , m is 1, R 2 is 2-fluorophenyl, R 3 is Cl, R 4 is H and R 5 and R 6 together are O; and further provided that when R 1 is CH 3 or benzyl then m=1;
R 2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl,
R 3 is Cl, Br or NO 2 ;
R 4 is H, CH 3 or CH 2 CH 2 N(CH 2 CH 3 ) 2 ; provided that when R 4 is CH 2 CH 2 N(CH 2 CH 3 ) 2 , X is CH 2 , n is 1, Y is CH 2 , m is 1, R 1 is CH 3 or benzyl, R 2 is 2-fluorophenyl, R 3 is Cl and R 5 and R 6 together are O; R 5 and R 6 together are O or S;
or a pharmaceutically acceptable salt or solvate thereof.
4. A compound of formula (I):
wherein W is H, and X, n, Y, m, R 1-6 are as follows:
R 5 and
X
n
Y
m
R 1
R 2
R 3
R 4
R 6
CH 2
1
CH 2
1
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
CH 3
2-fluorophenyl
Br
H
O
CH 2
1
CH 2
1
CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
CH 3
2-fluorophenyl
Cl
CH 3
O.
5. A compound of formula (I):
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 4 is H and R 5 and R 6 together are O.
6. A compound according to claim 1 wherein R 4 and R 5 together form a double bond in the diazepine ring, R 6 is the group NHR 7 and R 1 is CH 3 .
7. A compound according to claim 6 , 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, 2-chlorophenyl or 2-pyridyl, R 3 is Cl or Br and R 7 is CH 3 , CH 2 CH 3 , benzyl, 4-pyridylmethyl-, 4-pyridylethyl, CH(CH 3 ) 2 , or 4-imidazolylethyl.
8. A compound according to claim 6 , wherein W is H, X is CH 2 , n is 1, Y is CH 2 , m is 1, R 1 is CH 3 , and R 2 , R 3 and R 7 are as follows:
R 2
R 3
R 7
2-fluorophenyl
Cl
CH 3
2-pyridyl
Cl
CH 3
2-fluorophenyl
Cl
CH 2 CH 3
2-fluorophenyl
Cl
benzyl
2-fluorophenyl
Cl
4-pyridylmethyl
2-fluorophenyl
Cl
4-pyridylethyl
2-fluorophenyl
Cl
CH 2 CH(CH 3 ) 2
2-fluorophenyl
Cl
2-(4-imidazolyl)ethyl
2-fluorophenyl
Br
CH 3
2-chlorophenyl
Cl
CH 3 .
9. A compound according to claim 6 , 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 chlorine or bromine and R 7 is methyl.
10. A compound according to claim 6 , 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 and R 7 is CH 3 .
11. Methyl-3-[(3S)-7-chloro-5-(2-fluorophenyl)-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-3-yl]propanoate and pharmaceutically acceptable salts or solvates thereof.
12. Methyl-3-[(3S)-7-chloro-5-(2-fluorophenyl)-2-(methylamino)-3H-1,4-benzodiazepin-3-yl]propanoate and pharmaceutically acceptable salts or solvates thereof.
13. A compound of formula (I)
wherein W is H and X, n, Y, m, Z, p and R 1-6 are as follows:
R 5 and
X
N
Y
m
Z
p
R 1
R 2
R 3
R 4
R 6
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
—
0
—
0
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Br
H
O
CH 2
1
CH 2
1
—
0
benzyl
2-fluorophenyl
Cl
H
O
CH 2
1
—
0
—
0
benzyl
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-chlorophenyl
Cl
H
O
CH 2
1
CH 2
2
—
0
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
benzyl
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-pyridyl
Br
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
2
—
0
C(CH 3 ) 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
NO 2
H
O
CH 2
1
CH 2
1
—
0
(CH 2 ) 2 CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
—
0
4-pyridyl-
2-fluorophenyl
Cl
H
O
methyl
CH 2
1
CH 2
1
—
0
(CH 2 ) 3 CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
(CH 2 ) 3 CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 2 CH(CH 3 ) 2
2-pyridyl
Cl
H
O
CH 2
1
—
0
—
0
CH 2 CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH(CH 3 ) 2
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
CH 2 CH 2 N(CH 2 CH 3 ) 2
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
CH 3
O
CH 2
1
—
0
—
0
benzyl
2-fluorophenyl
Cl
CH 3
O
CH 2
1
CH 2
1
—
0
benzyl
2-fluorophenyl
Cl
CH 2 CH 2 N(CH 2 CH 3 ) 2
O
NH
1
CH 2
1
—
0
CH 3
2-chlorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
H
S
CH 2
1
CH 2
1
—
0
CH 3
2-chlorophenyl
Cl
H
S
CH 2
1
CH 2
1
—
0
CH 3
2-pyridyl
Cl
H
S
CH 2
1
CH 2
1
O
1
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
benzyl
phenyl
NO 2
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
H
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-pyridyl
NO 2
H
O
CH 2
1
CH 2
1
—
0
benzyl
2-pyridyl
NO 2
H
O
CH 2
1
CH 2
1
—
0
benzyl
2-fluorophenyl
H
H
O
CH 2
1
CH 2
1
—
0
CH 3
phenyl
NO 2
H
O
CH 2
1
—
0
—
0
3-pyridyl-
2-fluorophenyl
Cl
H
O
methyl
CH 2
1
—
0
—
0
4-pyridyl-
2-fluorophenyl
Cl
H
O
methyl.
14. A compound of formula (I)
wherein W is H and X, n, Y, m, Z, p and R 1-6 are as follows:
R 5 and
X
n
Y
m
Z
p
R 1
R 2
R 3
R 4
R 6
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
—
0
—
0
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Br
H
O
CH 2
1
CH 2
1
—
0
benzyl
2-fluorophenyl
Cl
H
O
CH 2
1
—
0
—
0
benzyl
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-chlorophenyl
Cl
H
O
CH 2
1
CH 2
2
—
0
CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
benzyl
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-pyridyl
Br
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
2
—
0
C(CH 3 ) 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
NO 2
H
O
CH 2
1
CH 2
1
—
0
(CH 2 ) 2 CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 2 CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
—
0
4-pyridyl-
2-fluorophenyl
Cl
H
O
methyl
CH 2
1
CH 2
1
—
0
(CH 2 ) 3 CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
(CH 2 ) 3 CH 3
2-pyridyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 2 CH(CH 3 ) 2
2-pyridyl
Cl
H
O
CH 2
1
—
0
—
0
CH 2 CH 3
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH(CH 3 ) 2
2-fluorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
CH 2 CH 2 N(CH 2 CH 3 ) 2
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
CH 3
O
CH 2
1
—
0
—
0
benzyl
2-fluorophenyl
Cl
CH 3
O
CH 2
1
CH 2
1
—
0
benzyl
2-fluorophenyl
Cl
CH 2 CH 2 N(CH 2 CH 3 ) 2
O
NH
1
CH 2
1
—
0
CH 3
2-chlorophenyl
Cl
H
O
CH 2
1
CH 2
1
—
0
CH 3
2-fluorophenyl
Cl
H
S
CH 2
1
CH 2
1
—
0
CH 3
2-chlorophenyl
Cl
H
S
CH 2
1
CH 2
1
—
0
CH 3
2-pyridyl
Cl
H
S
CH 2
1
CH 2
1
O
1
CH 3
2-fluorophenyl
Cl
H
O.
15. A compound of formula (I):
wherein
W is H;
X is CH 2 or NH; n is 1;
Y is CH 2 ; m is 0 or 1, provided that if X is CH 2 and m is 0, then R 1 is not CH 2 CH 3 ;
R 1 is CH 2 CH 3 , (CH 2 ) 2 CH 3 , (CH 2 ) 3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , or 4-pyridylmethyl;
R 2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl,
R 3 is Cl, Br or NO 2 ;
R 4 is H, CH 3 or CH 2 CH 2 N(CH 2 CH 3 ) 2 ;
R 5 and R 6 together are O or S;
or a pharmaceutically acceptable salt or solvate thereof.
16. A compound of formula (I):
wherein
W is H;
X is CH 2 or NH; n is 1;
Y is CH 2 ; m is 0 or 1, provided that if X is CH 2 and m is 0, then R 1 is not CH 2 CH 3 ;
R 1 is CH 2 CH 3 , (CH 2 ) 3 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , or 4-pyridylmethyl; provided that when R 1 is 4-pyridylmethyl, then X is CH 2 , n is 1, Y is CH 2 , m is 1, R 2 is 2-fluorophenyl, R 3 is Cl, R 4 is H and R 5 and R 6 together are O;
R 2 is 2-fluorophenyl, 2-chlorophenyl or 2-pyridyl,
R 3 is Cl, Br or NO 2 ;
R 4 is H, CH 3 or CH 2 CH 2 N(CH 2 CH 3 ) 2 ; provided that when R 4 is CH 2 CH 2 N(CH 2 CH 3 ) 2 , X is CH 2 , n is 1, Y is CH 2 , m is 1, R 1 is CH 3 or benzyl, R 2 is 2-fluorophenyl, R 3 is Cl and R 5 and R 6 together are O;
R 5 and R 6 together are O or S;
or a pharmaceutically acceptable salt or solvate thereof.
17. A pharmaceutical composition comprising a compound of claim 1 .
18. A pharmaceutical composition comprising a compound of claim 11 .
19. A pharmaceutical composition comprising a compound of claim 12 .
20. A method of producing sedation or hypnosis, inducing anxiolysis, inducing muscle relaxation or treating convulsions in a mammal in need thereof which comprises administering to the mammal an effective amount of a compound of claim 1 .
21. A method of producing sedation or hypnosis, inducing anxiolysis, inducing muscle relaxation or treating convulsions in a mammal in need thereof which comprises administering to the mammal an effective amount of a compound of claim 6 .