Quinoline derivatives and their use as 5-HT
Disclosed are quinoline compounds having affinity for the 5-HT 6 receptor and having the formula: where R 1 , R 2 , R 3 , R 4 , R 5 , n, m, p and A are defined herein, and salts thereof, compositions containing these compounds and salts and processes for making and using the same.
1. A compound of formula (I):
wherein:
R 1 represents hydrogen, methyl, ethyl, isopropyl, isobutyl or 2,2-dimethylpropyl;
R 2 represents hydrogen, methyl, or is linked to R 1 to form a (CH 2 ) 3 group;
R 3 represents hydrogen, methyl or halogen;
R 4 and R 5 independently represent hydrogen or methyl;
n represents 1;
p represents 1 or 2;
m represents 1 or 2, or m is 2 and both R 2 groups are linked to form a CH 2 group linking C-2 and C-5 of the piperizine ring;
A represents a group —Ar 1 , wherein Ar 1 represents unsubstituted phenyl or phenyl substituted by halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or trifluoromethoxy;
or a pharmaceutically acceptable salt thereof.
2. The compound or salt according to claim 1 , wherein R 1 represents hydrogen.
3. The compound or salt according to claim 1 , wherein R 2 represents hydrogen.
4. The compound or salt according to claim 1 , wherein R 3 represents hydrogen.
5. The compound or salt according to claim 1 , wherein m and p both represent 1.
6. The compound or salt according to claim 1 , wherein Ar 1 represents unsubstituted phenyl or phenyl substituted by halogen, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl or trifluoromethoxy.
7. The compound or salt according to claim 1 , wherein Ar 1 represents unsubstituted phenyl.
8. The compound or salt according to claim 1 , wherein
R 1 represents hydrogen or methyl;
R 2 represents hydrogen or methyl;
n represents 1;
m represents 1;
p represents 1;
A represents a group —Ar 1 , where Ar 1 represents phenyl optionally substituted with halogen, cyano, trifluoromethyl or trifluoromethoxy.
9. The compound or salt according to claim 1 , wherein
R 1 represents hydrogen or methyl;
R 2 represents hydrogen;
R 3 represents hydrogen or halogen;
n represents 1;
m represents 1;
p represents 1;
A represents a group —Ar 1 , where Ar 1 represents phenyl optionally substituted with halogen, cyano, trifluoromethyl or trifluoromethoxy.
10. The compound or salt according to claim 1 , wherein
R 1 represents hydrogen or methyl;
R 2 represents hydrogen or methyl;
n represents 1;
m represents 1;
p represents 1;
A represents a group —Ar 1 , where Ar 1 represents unsubstituted phenyl or phenyl substituted by halogen, trifluoromethyl or trifluoromethoxy.
11. A compound which is
8-(4-Methyl-piperazin-1-yl)-3-phenylsulfonylquinoline;
3-(2-Chloro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(3-Chloro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(2-Fluoro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(4-Chloro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(3-Fluoro)phenylsulfonyl-8-piperazin-1-yl-quinoline;
3-(4-Bromo-2-trifluoromethoxy)phenylsulfonyl-8-piperazin-1-yl-quinoline;
8-Piperazin-1-yl-3-(3-trifluoromethyl)phenylsulfonylquinoline;
7-Chloro-3-phenylsulfonyl-8-piperazin-1-yl-quinoline;
6-Methyl-3-phenylsulfonyl-8-piperazin-1-yl-quinoline;
(R)-8-(3-Methyl)piperazin-1-yl-3-phenylsulfonylquinoline;
(S)-8-(3-Methyl)piperazin-1-yl-3-phenylsulfonylquinoline;
8-Homopiperazin-1-yl-3-phenylsulfonylquinoline;
8-((S)-2-Methyl-piperazin-1-yl)-3-phenylsulfonyl-quinoline;
8-(4-Ethyl-piperazin-1-yl)-3-phenylsulfonylquinoline;
8-Piperazin-1-yl-3-(toluene-2-sulfonyl)-quinoline;
3-(2-Methoxy-benzenesulfonyl)-8-piperazin-1-yl-quinoline;
8-Piperazin-1-yl-3-(toluene-4-sulfonyl)-quinoline;
3-(4-Fluoro-benzenesulfonyl)-8-piperazin-1-yl-quinoline;
8-(4-Methyl-piperazin-1-yl)-3-(toluene-2-sulfonyl)-quinoline;
3-(2-Methoxy-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
8-(4-Methyl-piperazin-1-yl)-3-(toluene-4-sulfonyl)-quinoline;
3-(4-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(3-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(2-Fluoro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
3-(4-Chloro-benzenesulfonyl)-8-(4-methyl-piperazin-1-yl)-quinoline;
8-((S)-3-Methyl-piperazin-1-yl)-3-(toluene-2-sulfonyl)-quinoline;
3-(2-Methoxy-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
8-((S)-3-Methyl-piperazin-1-yl)-3-(toluene-4-sulfonyl)-quinoline;
3-(4-Fluoro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-(3-Fluoro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-(3-Chloro-benzenesulfonyl)-8-((S)-3-methyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-((R)-2-methyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-((2R,5S)-2,5-dimethyl-piperazin-1-yl)-quinoline racemate;
3-Benzenesulfonyl-8-(hexahydro-pyrrolo[1,2-α]pyrazin-2-yl)-quinoline racemate;
3-Benzenesulfonyl-8-(4-isopropyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-(4-isobutyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-[4-(2,2-dimethyl-propyl)-piperazin-1-yl]-quinoline;
3-Benzenesulfonyl-8-((R)-3,4-dimethyl-piperazin-1-yl)-quinoline;
3-Benzenesulfonyl-8-((S)-3,4-dimethyl-piperazin-1-yl)-quinoline;
3-Phenylsulfonyl 8-({1S,4S} 2,5-diazabicycloheptan-2-yl)quinoline;
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition which comprises the compound or salt according to claim 1 and a pharmaceutically acceptable carrier or excipient.
13. A method of treating a cognitive memory disorder which comprises administering a therapeutically effective amount of the compound or salt according to claim 1 to a patient in need thereof, wherein the cognitive memory disorder is selected from age related cognitive decline, mild cognitive impairment, and cognitive deficits in schizophrenia.
14. A method of treating Alzheimers disease which comprises administering a therapeutically effective amount of the compound or salt according to claim 1 to a human in need thereof.
15. A method of treating obesity which method comprises administering a therapeutically effective amount of the compound or salt according to claim 1 to a human in need thereof.