Aza-bicyclic N-biarylamides with affinity for the α7 nicotinic acetylcholine receptor

1. A compound of the formula (I)

in which

R 1 is a 1-azabicyclo[m.n.p]alkyl radical having 7 to 11 ring atoms,

in which m and n are independently of one another 2 or 3,

in which p is 1, 2 or 3,

and where the bicycloalkyl radical is optionally substituted by (C 1 –C 6 )-alkyl,

A is a bond, methylene, ethylene or propylene,

E is divalent, 5- to 6-membered heteroaryl or benzenediyl, where heteroaryl and benzenediyl are optionally substituted by radicals selected from the group of halogen, cyano, trifluoromethyl, trifluoromethoxy and (C 1 –C 6 )-alkyl,

R 2 is 5- to 6-membered heteroaryl or phenyl, where heteroaryl and phenyl are optionally substituted by radicals selected from the group of halogen, 5- to 6-membered heterocyclyl, —CO—NR 4 R 5 , —CO—OR 6 , —NR 7 R 8 , —NR 9 —CO—R 10 , —COR 13 , cyano, trifluoromethyl, trifluoromethoxy, nitro, optionally hydroxyl-, amino-, —NH—CO—R 11 —, —O—CO—NHR 14 —, halogen- or cyano-substituted (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkoxy and (C 1 –C 6 )-alkylthio,

in which R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 and R 14 are independently of one another hydrogen, (C 1 –C 6 )-alkyl, phenyl or benzyl, and

R 3 is hydrogen or (C 1 –C 6 )-alkyl,

and the salts, solvates and solvates of the salts thereof.

2. A compound as claimed in claim 1 , in which

R 1 is a 1-azabicyclo[m.n.p]alkyl radical having 7 to 11 ring atoms,

in which m and n are independently of one another 2 or 3,

in which p is 1, 2 or 3,

and where the bicycloalkyl radical is optionally substituted by (C 1 –C 6 )-alkyl,

A is a bond, methylene, ethylene or propylene,

E is divalent, 5- to 6-membered heteroaryl or benzenediyl, where heteroaryl and benzenediyl are optionally substituted by radicals selected from the group of halogen, cyano, trifluoromethyl, trifluoromethoxy and (C 1 –C 6 )-alkyl,

R 2 is 5- to 6-membered heteroaryl or phenyl, where heteroaryl and phenyl are optionally substituted by radicals selected from the group of halogen, formyl, —CO—NR 4 R 5 , —CO—OR 6 , —NR 7 R 8 , —NR 9 —CO—R 10 , cyano, trifluoromethyl, trifluoromethoxy, nitro, optionally hydroxyl-, amino-, —NH—CO—R 11 — or cyano-substituted (C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkoxy and (C 1 –C 6 )-alkylthio,

in which R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are independently of one another hydrogen, (C 1 –C 6 )-alkyl, phenyl or benzyl, and

R 3 is hydrogen or (C 1 –C 6 )-alkyl,

and the salts, solvates and solvates of the salts thereof.

3. A compound as claimed in claim 1 , where

R 1 is 1-azabicyclo[2.2.2]oct-3-yl,

and A, E, R 2 and R 3 have the meanings indicated in claim 1 .

4. A compound as claimed in claims 1 , where

R 1 is l-azabicyclo[2.2.2]oct-3-yl,

A is a bond or methylene,

E is benzenediyl which is optionally substituted by a radical selected from the group of fluorine, chlorine, cyano, methyl and trifluoromethyl,

R 2 is thienyl or phenyl, where the rings are optionally substituted by up to 2 radicals selected from the group of halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, morpholinyl, (C 1 –C 4 )-alkyl, (C 1 –C 4 )-alkoxy, (C 1 –C 4 )-alkylthio, —CO—NR 4 R 5 , —CO—OR 6 , —NR 9 —CO—R 10 and —CO—R 13 ,

where (C 1 –C 4 )-alkyl is optionally substituted by hydroxy, halogen and —O—CO—NHR 14 ,

where R 4 , R 5 , R 6 , R 9 , R 10 , R 13 and R 14 are independently of one another hydrogen or (C 1 –C 4 )-alkyl, and

R 3 is hydrogen,

and the salts, solvates and solvates of the salts thereof.

5. A compound as claimed in claim 1 , where

R 1 is 1-azabicyclo[2.2.2]oct-3-yl,

A is a bond,

E is benzenediyl which is optionally substituted by 1 to 3 radicals selected from the group of fluorine, chlorine, cyano, methyl and trifluoromethyl,

R 2 is thienyl or phenyl, where the rings are optionally substituted by 1 to 3 radicals selected from the group of halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, (C 1 –C 4 )-alkyl, hydroxymethyl, and (C 1 –C 4 )-alkoxy, and

R 3 is hydrogen.

6. A process for preparing compounds as claimed in claims 1 to 5 , characterized in that

[A] compounds of the general formula (II)

 in which

R 1 and A have the meanings indicated in claim 1 , and

X is hydroxy or a suitable leaving group,

are reacted with a compound of the general formula (III)

R 3 —NH-E-R 2   (III),

in which R 2 , R 3 and E have the meanings indicated in claim 1 , or

[B] compounds of the general formula (V)

 in which

Y is a suitable leaving group, and

R 1 , R 3 , A and E have the meanings indicated in claim 1 ,

are reacted with compounds of the general formula (VI)

 in which

R 2 has the meanings indicated above, and

R 12 is hydrogen or methyl, or the two radicals together form a CH 2 CH 2 or C(CH 3 ) 2 —C(CH 3 ) 2 bridge,

in an inert solvent in the presence of a suitable catalyst and in the presence of a base, and the resulting compounds of the formula (I) are where appropriate converted with the appropriate (i) solvents and/or (ii) bases or acids into the solvates, salts and/or solvates of the salts thereof.

7. A medicament comprising at least one of the compounds as claimed in claim 1 in combination with at least one pharmaceutically acceptable, essentially nontoxic carrier or excipient.

8. A method for producing a medicament for improving perception, concentration, learning and/or memory comprising the step of mixing at least one compound as claimed in claim 1 with at least one pharmaceutically acceptable, essentially nontoxic carrier or excipient.

9. A method for the treatment of impairments of perception, concentration, learning and/or memory in humans and animals comprising administering an effective amount of at least one compound as claimed in any of claims 1 to 5 .

10. A method for the treatment of impairments of perception, concentration, learning and/or memory comprising administering to a subject an effective amount of the medicament as claimed in claim 7 .

11. The process of claim 6 , wherein X is a leaving group selected from chlorine and pentafluorophenoxy.

12. The process of claim 6 , wherein Y is a leaving group selected from triflate and halogen.

13. The process of claim 12 , wherein the halogen is bromine or iodine.