Quinoline compounds suitable for treating disorders that respond to modulation of the serotonin 5-HT6 receptor
View Patent ↗The present invention relates to novel quinoline compounds. The compounds possess valuable therapeutic properties and are particularly suitable, for treating diseases that respond to modulation of the serotonin 5-HT 6 receptor. wherein R is a moiety of the formula wherein A, R 1 to R 4 are as defined in the claims and the specification, n is 0, 1 or 2; m is 0, 1, 2 or 3; R a , R b are independently selected from the group consisting of halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C(O)R aa , C(O)NR cc R bb and NR cc R bb ; X is CH 2 , C(O), S, S(O) or S(O) 2 ; which is located in the 3- or 4-position of the quinoline ring; Ar is a radical Ar 1 , Ar 2 —Ar 3 or Ar 2 —O—Ar 3 , wherein Ar 1 , Ar 2 and Ar 3 are each independently selected from the group consisting of aryl or hetaryl wherein aryl or hetaryl moieties may be unsubstituted or may carry 1, 2, 3 substituents R x , wherein and physiologically tolerated acid addition salts and the N-oxides thereof.
1. Quinoline compounds of formula (I)
wherein
R is a moiety of the formulae
wherein
* indicates the binding site to the quinolinyl radical;
A is a chemical bond, CHR 5 or CH 2 CHR 5 ;
A′ is a single bond, CH 2 , CH 2 CH 2 , CHR 7 or CH 2 CHR 7 ;
R 3 is hydrogen or C 1 -C 4 -alkyl;
R 4 is hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 6 -haloalkoxy-C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, aryl-C 1 -C 4 -alkyl, hetaryl-C 1 -C 4 -alkyl, C 3 -C 6 -alkenyl, C 3 -C 6 -haloalkenyl, formyl, C 1 -C 4 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl;
R 5 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy;
R 6 is C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy; or
R 5 and R 6 together may also be linear C 1 -C 4 -alkylene, which may carry 1 or 2 radicals R 9 ;
R 7 and R 9 are independently selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;
n is 0, 1 or 2;
m is 0, 1, 2 or 3;
p is 0, 1, 2 or 3;
q is 0 or 1;
R a , R b are independently selected from the group consisting of halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C(O)R aa , C(O)NR cc R bb and NR cc R bb ; wherein R aa is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy, and R cc , R bb are independently selected from the group consisting of hydrogen and C 1 -C 4 -alkyl;
X is CH 2 , C(O), S, S(O) or S(O) 2 ; which is located in the 3- or 4-position of the quinoline ring;
Ar is a radical Ar 1 , Ar 2 —Ar 3 or Ar 2 —O—Ar 3 , wherein Ar 1 , Ar 2 and Ar 3 are each independently selected from the group consisting of aryl or hetaryl wherein aryl or hetaryl moieties may be unsubstituted or may carry 1, 2, 3 substituents R x , wherein
R x is halogen, CN, NO 2 , C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -haloalkylcarbonylamino, carboxy, NH—C(O)—NR x1 R x2 , NR x 1R x2 , NR x1 R x2 —C 1 -C 6 -alkylene, O—NR x1 R x2 , wherein R x1 and R x2 in the last 4 mentioned radicals are independently of each other hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkoxy or R x1 and R x2 in the last 4 mentioned radicals together with the nitrogen atom form an N-bound 5-, 6- or 7-membered, saturated heterocycle which is unsubstituted or which carries 1, 2, 3 or 4 radicals selected from C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -hydroxyalkyl and C 1 -C 4 -alkoxy and wherein 2 radicals R x , which are bound to adjacent carbon atoms of Ar may form a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring, which itself may carry a radical Rx;
and physiologically tolerated acid addition salts and the N-oxides thereof.
2. The compounds as claimed in claim 1 , wherein the moiety R is a radical of the formulae:
wherein R 3 , R 4 and R 6 are as defined in claim 1 , * indicates the binding site to the quinolinyl radical and wherein q is 0 or 1.
3. The compounds as claimed in claim 1 , wherein the moiety R is a radical of the formulae:
wherein R 4 and R 6 are as defined in claim 1 , * indicates the binding site to the quinolinyl radical and wherein q is 0 or 1.
4. The compounds as claimed in claim 1 , wherein R 4 is hydrogen.
5. The compounds as claimed in claim 1 , wherein X is SO 2 .
6. The compounds as claimed in claim 1 , wherein X is CH 2 .
7. The compounds as claimed in claim 1 , wherein X is C(O).
8. The compounds as claimed in claim 1 , wherein X is located in the 3-position of the quinolinyl moiety.
9. The compounds as claimed in claim 1 , wherein X is located in the 4-position of the quinolinyl moiety.
10. The compounds as claimed in claim 1 , wherein Ar is phenyl, naphthyl, thienyl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, benzofuranyl, benzothienyl, benzoxazinyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzomorpholinyl or indanyl, wherein the cyclic radical Ar is unsubstituted or may carry 1, 2 or 3 substituents R x as defined in claim 1 .
11. The compounds as claimed in claim 10 , wherein Ar is phenyl, which is unsubstituted or may carry 1, 2 or 3 substituents R x as defined in claim 1 .
12. The compounds as claimed in claim 1 , wherein Rx is selected from halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 6 -cycloalkyl and a group NR x1 R x2 .
13. The compounds as claimed in claim 1 , wherein m is 0.
14. The compounds as claimed in claim 1 , wherein n is 0.
15. A pharmaceutical composition comprising at least one compound as claimed in claim 1 , optionally together with at least one physiologically acceptable carrier or auxiliary substance.
16. A method for treating a medical disorder selected from diseases of the central nervous system, addiction diseases or obesity, said method comprising administering an effective amount of at least one compound as claimed in claim 1 to a subject in need thereof.
17. The method as claimed in claim 16 , wherein the medical disorder is a disease of the central nervous system.
18. The method as claimed in claim 16 , for treating cognitive dysfunctions.
19. The method as claimed in claim 16 , for treating cognitive dysfunctions associated with Alzheimer's disease.
20. The method as claimed in claim 16 , for treating cognitive dysfunctions associated with schizophrenia.
21. The method as claimed in claim 16 , wherein the medical disorder is an addiction disease.
22. The method as claimed in claim 16 , wherein the medical disorder is obesity.
23. A method for treating a medical disorder selected from diseases of the central nervous system, addiction diseases or obesity, the method comprising administering to a patient in need of treatment thereof a pharmaceutical composition as claimed in claim 15 .