4-benzylaminoquinolines, pharmaceutical compositions containing them, and their use in therapy

1. A 4-Benzylaminoquinoline of formula (I)

wherein

R 1 is hydrogen, C 1 -C 6 -alkyl or C 6 -C 12 -aryl;

R 2 , R 3 are independently hydrogen, C 1 -C 6 -alkyl, substituted C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 6 -C 12 -aryl, aminocarbonyl, amino or optionally substituted C 3 -C 12 -heterocyclyl;

R 4 is C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, di-(C 1 -C 6 -alkyl)amino, C 6 -C 12 -arylamino or sulfonylamino;

R 5 is hydrogen, halogen, C 1 -C 6 -alkyl, hydroxy, C 1 -C 6 -alkoxy, substituted C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 6 -C 12 -heteroaryloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, di-C 1 -C 6 -alkylaminosulfonyl, (optionally substituted C 6 -C 12 -aryl)aminosulfonyl, amino, substituted amino or optionally substituted C 3 -C 12 -heterocyclyl;

R 6a , R 6b , R 6c , R 6d , R 6e

are independently hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, C 1 -C 6 -alkoxycarbonyl, (halogenated C 1 -C 4 -alkoxy)carbonyl, cyano, C 1 -C 6 -alkoxy, halogenated C 1 -C 4 -alkoxy, optionally substituted C 6 -C 12 -aryl, C 1 -C 4 -alkylthio, (halogenated C 1 -C 4 -alkyl)thio, nitro, amino, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 4 -alkyl)carbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 4 -alkyl)sulfonylamino or C 6 -C 12 -arylsulfonylamino; or

R 6a , R 2 together are optionally substituted C 1 -C 4 -alkylene; or

R 6a and R 6b or R 6b and R 6c

together with the carbon atoms to which they are attached form an anellated aryl ring; or

together are C 1 -C 2 -alkylenedioxo; and

R 7 , R 8 , R 9 , R 10

are independently hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy,

or a physiologically tolerated salt thereof,

provided that the following compounds and the physiologically tolerated salts thereof are excluded:

a) 4′-[[(2-methyl-4-quinolinyl)amino]methyl]-[1,1′-biphenyl]-2-carboxylic acid, 1,1-dimethylethyl ester

b) 2-methyl-N-[[2′-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1′-biphenyl]-4-yl]methyl]-4-quinolinamine,

c) 2-methyl-N-[[3′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-4-quinolinamine,

d) 4′-[[(2-methyl-4-quinolinyl)amino]methyl]-[1,1′-biphenyl]-2-carboxylic acid,

e) 4′-[[(2-methyl-4-quinolinyl)amino]methyl]-[1,1′-biphenyl]-3-carboxylic acid, 1,1-dimethylethyl ester

f) 2-methyl-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-4-quinolinamine,

g) 4′-[[(8-methoxy-2-methyl-4-quinolinyl)amino]methyl]-[1,1′-biphenyl]-2-carboxylic acid,

h) 8-methoxy-2-methyl-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-4-quinolinamine,

i) 4′-[[(2-methyl-4-quinolinyl)amino]methyl]-N-(methylsulfonyl)-[1,1′-biphenyl]-2-carboxamide,

j) 4′-[[(2-methyl-4-quinolinyl)amino]methyl]-[1,1′-biphenyl]-2-carboxylic acid,

k) 4′-[[(2-methyl-4-quinolinyl)amino]methyl]-[1,1′-biphenyl]-2-carboxylic acid, methyl ester

l) N-[(2-methylphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

m) N-[(2-methoxyphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

n) N-[(2-ethylphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

o) N-[(2-bromophenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

p) N-[(2,6-dichlorophenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

q) N-[(2,6-dimethoxyphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

r) N-[(2,6-dimethylphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

s) N-[(2,3-dimethylphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

t) N-[(2,4-dimethylphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

u) N-[(2,5-dimethylphenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

v) N-[(2-chlorophenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

w) N-[(2-fluorophenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

x) N-[(2-chloro-6-fluorophenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

y) N-[(2,6-difluorophenyl)methyl]-8-methoxy-2-methyl-4-quinolinamine,

z) N-[[2-(trifluoromethyl)phenyl]methyl]-8-methoxy-2-methyl-4-quinolinamine,

aa) 4-[[(8-methoxy-2-methyl-4-quinolinyl)amino]methyl]-3-methyl-phenol,

ab) 4-[(p-chlorobenzyl)amino]-quinaldine,

ac) N-[(1S)-1-phenylethyl]-2-methyl-4-quinolinamine,

ad) N-(phenylmethyl)-2-methyl-4-quinolinamine,

ae) 4-[[1-(3,4-dimethoxyphenyl)hexyl]amino]-2-methyl-8-quinolinol,

af) 4-[[1-(2-hexyl-4,5-dimethoxyphenyl)ethyl]amino]-2-methyl-8-quinolinol,

ag) 4-[[1-(3,4-dimethoxyphenyl)hexyl]amino]-2-methyl-8-quinolinol,

ah) 4-[[1-(2-hexyl-4,5-dimethoxyphenyl)ethyl]amino]-2-methyl-4-quinolinol,

ai) N-[1-(3,4-dimethoxyphenyl)hexyl]-8-methoxy-2-methyl-4-quinolinamine, or

aj) N-[1-(2-hexyl-4,5-dimethoxyphenyl)ethyl]-8-methoxy-2-methyl-4-quinolinamine.

2. The compound of claim 1 , wherein R 1 is hydrogen.

3. The compound of claim 1 , wherein R 2 is hydrogen or C 1 -C 3 -alkyl.

4. The compound of claim 1 , wherein R 3 is C 1 -C 1 -alkyl substituted with amino, C 1 -C 4 alkylamino, di-C 1 -C 4 -alkylamino, (C 6 -C 12 -aryl-C 1 -C 2 -alkyl)amino or C 3 -C 12 -heterocyclyl.

5. The compound of claim 1 , wherein R 4 is methyl or dimethylamino.

6. The compound of claim 1 , wherein R 5 is hydrogen or halogen.

7. The compound of claim 1 , wherein R 5 is hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 6 -C 1 -aryloxy or C 6 -C 12 -heteroaryloxy.

8. The compound of claim 1 , wherein R 5 is a group of the formula (II):

-A 1 -A 2 -A 3 -R 5a   (II)

wherein

A 1 is O, NR 5b ;

A 2 is optionally substituted C 1 -C 4 -alkylene;

A 3 is O, NR 5b ;

R 5 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, C 1 -C 6 -alkylsulfonyl, (halogenated C 1 -C 6 -alkyl) sulfonyl, C 6 -C 12 -arylsulfonyl, (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)sulfonyl, C 3 -C 12 -heterocyclylsulfonyl or C 6 -C 12 -aryl; and

R 5b is hydrogen or C 1 -C 4 -alkyl; or

R 5a and R 5b

together with the nitrogen atom to which they are attached are C 3 -C 12 -heterocyclyl.

9. The compound of claim 1 , wherein R 5 is C 1 -C 4 -alkoxy substituted with C 1 -C 6 -alkoxy, amino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkoxycarbonylamino, C 1 -C 12 -heterocyclyl, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 4 alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino, (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)sulfonylamino, C 3 -C 1 -heterocyclylsulfonylamino or C 6 -C 12 -aryl.

10. The compound of claim 1 , wherein R 5 is C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, di-C 1 -C 6 -alkylaminosulfonyl or (optionally substituted C 6 -C 12 -aryl)aminosulfonyl.

11. The compound of claim 1 , wherein R 5 is amino.

12. The compound of claim 1 , wherein R 5 is C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, C 6 -C 12 arylsulfonylamino, di-(C 1 -C 6 -alkylsulfonyl)amino or optionally substituted C 3 -C 12 -heterocyclyl.

13. The compound of claim 1 , wherein at least one of R 6a , R 6b , R 6c , R 6d , or R 6e is different from hydrogen.

14. The compound of claim 13 , wherein at least one of R 6a , R 6b , R 6c , R 6d , or R 6e is halogen, C 1 -C 4 -hydroxyalkyl, cyano or nitro.

15. The compound of claim 1 , wherein R 7 , R 8 , R 9 , and R 10 are all hydrogen.

16. A 4-Benzylaminoquinoline of formula (I)

wherein

R 1 is hydrogen;

R 2 is hydrogen, C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)amino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 6 -C 12 -aryl, aminocarbonyl or C 3 -C 12 -heterocyclyl;

R 3 is hydrogen;

R 4 is methyl or dimethylamino;

R 5 is hydrogen, halogen, C 1 -C 6 -alkyl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 4 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 -aryl-C 1 -C 4 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 1 -C 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 6 -C 12 -heteroaryloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, di-C 1 -C 6 -alkylaminosulfonyl, (optionally substituted C 6 -C 12 -aryl)aminosulfonyl, amino, C 1 -C 6 -alkylamino, di-C 1 -C 6 -alkylamino, C 1 -C 6 -alkylcarbonylamino, C 6 -C 1 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, C 6 -C 12 -arylsulfonylamino, di-(C 1 -C 6 -alkylsulfonyl)amino or optionally substituted C 3 -C 12 -heterocyclyl;

R 6a , R 6e

are hydrogen;

R 6b , R 6c , R 6d

are independently hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkoxy, halogenated C 1 -C 4 -alkoxy, halogenated C 1 -C 4 -alkylthio, nitro, at least one of R 6b , R 6c , R 6d being different from hydrogen; and

R 7 , R 8 , R 9 , R 10

are all hydrogen,

or a physiologically tolerated acid addition salt thereof,

provided that 4-[(p-chlorobenzyl)amino]-quinaldine is excluded.

17. A pharmaceutical composition comprising a carrier and the compound of claim 1 .

18. A method for treating a neurologic disorder selected from the group consisting of dementia, cognitive impairment, and attention deficit disorder, or a psychiatric disorder selected from the group consisting of an anxiety disorder, a mood disorder, a bipolar disorder, schizophrenia, and a psychotic disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a 4-benzylaminoquinoline of formula (I)

wherein

R 1 is hydrogen, C 1 -C 6 -alkyl or C 6 -C 12 -aryl;

R 2 , R 3

are independently hydrogen, C 1 -C 6 -alkyl, substituted C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 6 -C 12 -aryl, aminocarbonyl, amino or optionally substituted C 3 -C 12 -heterocyclyl;

R 4 is C 1 -C 6 -alkyl, halogenated C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, di-(C 1 -C 6 -alkyl)amino, C 6 -C 12 -arylamino or sulfonylamino;

R 5 is hydrogen, halogen, C 1 -C 6 -alkyl, hydroxy, C 1 -C 6 -alkoxy, substituted C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 6 -C 12 -heteroaryloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, C 1 -C 6 -alkylaminosulfonyl, di-C 1 -C 6 -alkylaminosulfonyl, (optionally substituted C 6 -C 12 -aryl)aminosulfonyl, amino, substituted amino or optionally substituted C 3 -C 12 -heterocyclyl;

R 6a , R 6b , R 6c , R 6d , R 6e

are independently hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 6 -alkoxycarbonyl, (halogenated C 1 -C 4 -alkoxy)carbonyl, cyano, C 1 -C 6 -alkoxy, halogenated C 1 -C 4 -alkoxy, optionally substituted C 6 -C 12 -aryl, C 1 -C 4 -alkylthio, (halogenated C 1 -C 4 -alkyl)thio, nitro, amino, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 4 -alkyl)carbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 4 -alkyl)sulfonylamino or C 6 -C 12 -arylsulfonylamino; or

R 6a , R 2

together are optionally substituted C 1 -C 4 -alkylene; or

R 6a and R 6b or R 6b and R 6c

together with the carbon atoms to which they are attached form an anellated aryl ring; or together are C 1 -C 2 -alkylenedioxo; and

R 7 , R 8 , R 9 , R 10

are independently hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy,

or a physiologically tolerated salt thereof.