1-aryl-or 1-alkylsulfonylbenzazole derivatives as 5-hydroxytryptamine-6 ligands
View Patent ↗The present invention provides a compound of formula I and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor
1. A compound of formula I
wherein
W is SO 2 , CO, CONH, CSNH or CH 2 ;
X is CR 7 ;
Y is CR 8 ;
Z is O, SO p or NR 9 ;
R 1 and R 2 are each independently H or C 1 -C 6 alkyl;
n is an integer of 2, 3 or 4;
R 3 and R 4 are each independently H or a cycloheteroalkyl group optionally substituted with the proviso that only one of R 3 or R 3 and R 4 may be H, or R 3 and R 4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring optionally containing an additional heteroatom selected from O, N or S;
R 5 is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R 16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, or phenyl group each optionally substituted;
m is an integer of 1, 2 or 3;
p and q are each independently 0 or an integer of 1 or 2;
R 6 is an optionally substituted C 1 -C 6 alkyl, aryl group;
R 7 and R 8 are each independently H, halogen or a C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkoxy group each optionally substituted;
R 9 is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, or aryl group each optionally substituted;
R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently H or C 1 -C 4 alkyl;
R 13 is H, COR 23 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or aryl group each optionally substituted;
R 14 is H or a C 1 -C 6 alkyl, or aryl group each optionally substituted;
R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, or aryl group each optionally substituted; and
R 22 and R 23 are each independently an optionally substituted C 1 -C 6 alkyl, or aryl group; or
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein W is SO 2 .
3. The compound according to claim 1 wherein Z is O.
4. The compound according to claim 1 wherein n is 2.
5. The compound according to claim 1 wherein R 6 is an or aryl group each optionally substituted.
6. The compound according to claim 1 wherein X is CR 7 and R 5 and R 7 are H.
7. The compound according to claim 2 wherein R 1 and R 2 are H; Z is O; and n is 2.
8. The compound according to claim 6 wherein W is SO 2 ; Z is O; and R 3 and R 4 are taken together with the atom to which they are attached to form a 5- or 6-membered ring containing one oxygen atom.
9. The compound according to claim 6 selected from the group consisting of:
4-(2-morpholin-4-ylethoxy)-1-(phenylsulfonyl)-1H-indole;
N-(2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethyl)tetrahydro-2H-pyran-4-amine; and
a pharmaceutically acceptable salt thereof.
10. A method for the treatment of a disorder of the central nervous system related to or affected by the 5-HT6 receptor wherein said disorder is schizophrenia, depression, Alzheimer's disease in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I:
wherein
W is SO 2 , CO, CONH, CSNH or CH 2 ;
X is CR 7 or N;
Y is CR 8 ;
Z is O, SO p or NR 9 ;
R 1 and R 2 are each independently H or C 1 -C 6 alkyl;
n is an integer of 2, 3 or 4;
R 3 and R 4 are each independently H or a cycloheteroalkyl, or heteroaryl group each optionally substituted with the proviso that only one of R 3 or R 4 may be H, or R 3 and R 4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring containing an additional heteroatom selected from O, N or S;
R 5 is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R 16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
m is an integer of 1, 2 or 3;
p and q are each independently O or an integer of 1 or 2;
R 6 is an optionally substituted C 1 -C 6 alkyl or aryl group;
R 7 and R 8 are each independently H, halogen or a C 1 -C 6 alkyl, aryl, heteroaryl or C 1 -C 6 alkoxy group each optionally substituted;
R 9 is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently H or C 1 -C 4 alkyl;
R 13 is H, COR 23 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl group each optionally substituted;
R 14 is H or a C 1 -C 6 alkyl, aryl heteroaryl group each optionally substituted;
R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and
R 22 and R 23 are each independently an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group; or
a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I:
wherein
W is SO 2 , CO, CONH, CSNH or CH 2 ;
X is CR 7 or N;
Y is CR 8 ;
Z is O, SO p or NR 9 ;
R 1 and R 2 are each independently H or C 1 -C 6 alkyl;
n is an integer of 2, 3 or 4;
R 3 and R 4 are each independently H or a cycloheteroalkyl, group optionally substituted with the proviso that only one of R 3 or R 4 may be H, or R 3 and R 4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring containing an additional heteroatom selected from O, N or S;
R 5 is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R 16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, or phenyl group each optionally substituted;
m is an integer of 1, 2 or 3;
p and q are each independently 0 or an integer of 1 or 2;
R 6 is an optionally substituted C 1 -C 6 alkyl or aryl group;
R 7 and R 8 are each independently H, halogen or a C 1 -C 6 alkyl, aryl, or C 1 -C 6 alkoxy group each optionally substituted;
R 9 is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, or aryl group each optionally substituted;
R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently H or C 1 -C 4 alkyl;
R 13 is H, COR 23 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or aryl group each optionally substituted;
R 14 is H or a C 1 -C 6 alkyl, or aryl group each optionally substituted;
R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, or aryl group each optionally substituted; and
R 22 and R 23 are each independently an optionally substituted C 1 -C 6 alkyl, or aryl group; or
a pharmaceutically acceptable salt thereof.
12. The composition according to claim 11 wherein W is SO 2 ; Z is O; and n is 2.
13. The composition according to claim 12 wherein R 6 is an or aryl group each optionally substituted.
14. The composition according to claim 13 wherein X is CR 7 and R 1 , R 2 , R 5 , and R 7 are H.
15. The composition according to claim 14 having a formula I compound selected from the group consisting of:
4-(2-morpholin-4-ylethoxy)-1-(phenylsulfonyl)-1H-indole;
N-(2-{[1-(phenylsulfonyl)-1H-indol-4-yl]oxy}ethyl)-tetrahydro-2H-pyran-4-amine;
a pharmaceutically acceptable salt thereof.
16. A method for the preparation of a compound of formula Ia
wherein
X is CR 7 or N;
Y is CR 8 ;
Z is O, SO p or NR 9 ;
R 1 and R 2 are each independently H or C 1 -C 6 alkyl;
n is an integer of 2, 3 or 4;
R 3 and R 4 are each independently H or a cycloheteroalkyl, or heteroaryl group each optionally substituted with the proviso that only one of R 3 or R 4 may be H, or R 3 and R 4 may be taken together with the atom to which they are attached to form an optionally substituted 3- to 6-membered ring containing an additional heteroatom selected from O, N or S;
R 5 is H, halogen, CN, OR 13 , CO 2 R 14 , CONR 15 R 16 , CNR 17 NR 18 R 19 , SO 2 NR 20 R 21 , SO q R 22 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
m is an integer of 1, 2 or 3;
p and q are each independently 0 or an integer of 1 or 2;
R 6 is an optionally substituted C 1 -C 6 alkyl, or aryl group;
R 7 and R 8 are each independently H, halogen or a C 1 -C 6 alkyl, aryl, heteroaryl or C 1 -C 6 alkoxy group each optionally substituted;
R 9 is H or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently H or C 1 -C 4 alkyl;
R 13 is H, COR 23 or a C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl group each optionally substituted;
R 14 is H or a C 1 -C 6 alkyl, or aryl group each optionally substituted;
R 20 and R 21 are each independently H or a C 1 -C 6 alkyl, aryl or heteroaryl group each optionally substituted; and
R 22 and R 23 are each independently an optionally substituted C 1 -C 6 alkyl, aryl or heteroaryl group
which method comprises reacting a compound of formula V′
wherein Hal is Cl, Br or I and X, Y, Z, n, m, R 1 , R 2 , R 5 and R 6 are as defined hereinabove with an amine, HNR 3 R 4 , wherein R 3 and R 4 are defined hereinabove optionally in the presence of a solvent to give the desired compound of formula Ia.