Benzenesulfonyl or sulfonamide compounds suitable for treating disorders that respond to the modulation of the serotonin 5-HT
View Patent ↗The present invention relates to benzenesulfonyl or sulfonamide compounds of formulae IA and IB wherein the variables have the meanings given in the claims and the description, pharmaceutical compositions containing them, and their use in therapy. The compounds possess valuable therapeutic properties and are particularly suitable for treating diseases that respond to modulation of the serotonin 5-HT 6 receptor.
1. A compound of formula (IA)
or a stereoisomer, tautomer, or a physiologically tolerated acid addition salt thereof,
wherein
X 1 is NR 4 ;
R 1 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl and fluorinated C 1 -C 4 -alkyl;
R 2 is selected from the group consisting of hydrogen and C 1 -C 4 -alkyl;
R 3 is selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, fluorinated C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and fluorinated C 1 -C 4 -alkoxy;
R 4 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl and fluorinated C 1 -C 4 -alkyl;
R 5 is selected from the group consisting of C 1 -C 6 -hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, fluorinated C 1 -C 6 -alkoxy, fluorinated C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, and a group -A-[O—B] p —O—R 7 ;
where
A and B are independently of each other C 1 -C 4 -alkylene or fluorinated C 1 -C 4 -alkylene;
R 7 is C 1 -C 4 -alkyl or fluorinated C 1 -C 4 -alkyl;
p is 0, 1, 2, 3, 4, 5 or 6;
R 6 is selected from the group consisting of halogen, C 1 -C 2 -alkyl, fluorinated C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy and fluorinated C 1 -C 2 -alkoxy;
G 1 is CH 2 or CH 2 CH 2 ;
G 2 is CH 2 or CH 2 CH 2 ;
o is 0, 1 or 2.
2. The compound of claim 1 , where A is C 1 -C 2 -alkylene.
3. The compound of claim 2 , where A is methylene (CH 2 ) or 1,1-ethylene [CH(CH 3 )].
4. The compound of claim 1 , where B is C 2 -C 3 -alkylene.
5. The compound of claim 1 , where p is 0.
6. The compound of claim 1 , where R 7 is C 1 -C 2 -alkyl or fluorinated C 1 -C 2 -alkyl.
7. The compound of claim 1 , where R 5 is selected from the group consisting of fluorinated C 1 -C 2 -alkoxy, C 1 -C 2 -alkoxy-methyl, 1-(C 1 -C 2 -alkoxy)-ethyl, (fluorinated C 1 -C 2 -alkoxy)-methyl and 1-(fluorinated C 1 -C 2 -alkoxy)-ethyl.
8. The compound of claim 7 , where R 5 is selected from the group consisting of fluoromethoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl, 2,2,2-trifluoroethoxymethyl and 1-methoxyethyl.
9. The compound of claim 8 , where R 5 is selected from the group consisting of difluoromethoxy, methoxymethyl, ethoxymethyl, 2,2,2-trifluoroethoxymethyl and 1-methoxyethyl.
10. The compound of claim 1 , where R 5 is bound in the 2- or 3-position, relative to the 1-position of the sulfonyl(amino) group SO 2 —X 1 .
11. The compound of claim 1 , where R 1 is hydrogen or C 1 -C 4 alkyl.
12. The compound of claim 1 , where R 2 is hydrogen.
13. The compound of claim 1 , where R 3 is selected from the group consisting of methoxy, ethoxy, methyl and ethyl.
14. The compound of claim 1 , where R 4 is hydrogen or methyl.
15. The compound of claim 1 , where R 6 is selected from the group consisting of F, Cl, methyl, difluoro-methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy.
16. The compound of claim 1 , where o is 0 or 1.
17. The compound of claim 1 , where G 1 is CH 2 and G 2 is CH 2 ; or G 1 is CH 2 and G 2 is CH 2 CH 2 ; or G 1 is CH 2 CH 2 and G 2 is CH 2 .
18. The compound of claim 1 , where
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is methyl;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-methoxymethyl, relative to the 1-position of the sulfonylamino group SO 2 —NH;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 0;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is methyl;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 CH 2 ;
G 1 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R is methyl;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-methoxymethyl, relative to the 1-position of the sulfonylamino group SO 2 —NH;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 0;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 CH 2 ;
G 1 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is methyl;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 ;
G 2 is CH 2 CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is ethoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 4-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ; G 1 is CH 2 CH 2 ;
G 1 is CH 2 ; and
o is 1;
or
X 1 is NH;
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-methoxymethyl, relative to the 1-position of the sulfonylamino group SO 2 —NH;
G 1 is CH 2 CH 2 ;
G 2 is CH 2 ; and
o is 0;
or
X 1 is NH;
R 1 is methyl;
R 2 is hydrogen;
R 3 is methoxy;
R 5 is 2-difluoromethoxy, relative to the 1-position of the sulfonylamino group SO 2 —NH;
R 6 is 5-methyl, relative to the 1-position of the sulfonylamino group SO 2 —NH and to the 2-position of 2-difluoromethoxy as radical R 5 ;
G 1 is CH 2 CH 2 ;
G 2 is CH 2 ; and
o is 1.
19. The compound of claim 1 , wherein at least one hydrogen atom has been replaced by a deuterium atom.
20. A pharmaceutical composition comprising at least one compound of claim 1 , a stereoisomer, tautomer and/or physiologically tolerated acid addition salt thereof, and at least one physiologically acceptable carrier and/or auxiliary substance.
21. The compound of claim 1 , or astereoisomer, tautomer, or physiologically tolerated acid addition salt thereof, selected from the group consisting of:
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-pyrrolidin-3-yl-benzenesulfonamide;
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(1-methyl-pyrrolidin-3-yl)-benzenesulfonamide;
4-Methoxy-N-(2-methoxymethyl-phenyl)-3-pyrrolidin-3-yl-benzenesulfonamide;
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-pipendin-4-yl-benzenesulfonamide;
N-(2-Difluoromethoxy-4-methyl-phenyl)-4-methoxy-3-pipendin-4-yl-benzenesulfonamide;
4-Methoxy-N-(2-methoxymethyl-phenyl)-3-piperidin-4-yl-benzenesulfonamide; and
N-(2-Difluoromethoxy-5-methyl-phenyl)-4-methoxy-3-(1-methyl-pipendin-4-yl)-benzenesulfonamide.