Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists
View Patent ↗The invention relates to novel benzothiophene-, benzofuran-, and indole ureas and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning, and/or memory.
1. A compound of the formula
in which
R 1 is 1-azabicyclo[2.2.2]oct-3-yl,
R 2 is hydrogen or C 1 -C 6 -alkyl,
R 3 is hydrogen, halogen, amino, hydroxy or C 1 -C 6 -alkyl,
R 4 is hydrogen or C 1 -C 6 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, trifluoromethyl, or trifluoromethoxy,
R 5 is hydrogen or C 1 -C 6 -alkyl, or
R 4 and R 5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C 1 -C 6 -alkyl, C 1 -C 4 -acyl, oxo, thioxo,
R 6 is (i) hydrogen, (ii) C 1 -C 6 -alkyl, (iii) C 3 -C 8 -cycloalkyl, (iv) C 6 -C 10 -aryl, (v) 5- to 10-membered heteroaryl, or (vi) C 6 -C 10 -arylcarbonyl, where (ii) is optionally substituted by phenyl, C 1 -C 6 -alkoxycarbonyl or C 1 -C 6 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkylamino, or C 1 -C 6 -acylamino, or
R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C 1 -C 6 -alkyl or C 1 -C 6 -hydroxyalkyl,
A is oxygen,
X is oxygen or sulfur,
the ring B is benzo which is optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
or a salt thereof.
2. A compound as claimed in claim 1 , of the formula (I) in which
R 1 is 1-azabicyclo[2.2.2]oct-3-yl,
R 2 is hydrogen or C 1 -C 6 -alkyl,
R 3 is hydrogen, halogen, amino, hydroxy or C 1 -C 6 -alkyl,
R 4 is hydrogen or C 1 -C 6 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, trifluoromethyl or trifluoromethoxy,
R 5 is hydrogen or C 1 -C 6 -alkyl, or
R 4 and R 5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C 1 -C 6 -alkyl, C 1 -C 4 -acyl, oxo, thioxo,
R 6 is (i) hydrogen, (ii) C 1 -C 6 -alkyl, (iii) C 3 -C 8 -cycloalkyl, (iv) C 6 -C 10 -aryl, or (v) 5- to 10-membered heteroaryl, where (ii) is optionally substituted by phenyl, or C 1 -C 6 -alkoxy, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkylamino, or C 1 -C 6 -acylamino, or
R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 8-membered heterocycle which is optionally substituted by C 1 -C 6 -alkyl or C 1 -C 6 -hydroxyalkyl,
A is oxygen, and
X is oxygen or sulfur, and
the ring B is benzo which is which is optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
or a salt thereof.
3. A compound as claimed in claim 1 , of the formula (I) in which
R 1 is 1-aza-bicyclo[2.2.2]oct-3-yl,
R 2 is hydrogen or C 1 -C 4 -alkyl,
R 3 is hydrogen, halogen, amino, hydroxy or C 1 -C 4 -alkyl,
R 4 is hydrogen or C 1 -C 4 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, halogen, cyano, C 1 -C 3 -alkoxy, trifluoromethyl or trifluoromethoxy,
R 5 is hydrogen or C 1 -C 4 -alkyl, or
R 4 and R 5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C 1 -C 6 -alkyl, C 1 -C 4 -acyl, oxo, thioxo,
R 6 is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, or (vi) C 6 -C 10 -arylcarbonyl, where (ii) is optionally substituted by phenyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 3 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino, or
R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C 1 -C 3 -alkyl or C 1 -C 3 -hydroxyalkyl,
A is oxygen,
X is oxygen,
the ring B is benzo which is optionally substituted by radicals from the series chlorine, fluorine, cyano, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
or a salt thereof.
4. A compound as claimed claim 1 , of the formula (I) in which
R 1 is 1-azabicyclo[2.2.2]oct-3-yl,
R 2 is hydrogen or C 1 -C 4 -alkyl,
R 3 is hydrogen, halogen, amino, hydroxy or C 1 -C 4 -alkyl,
R 4 is hydrogen or C 1 -C 4 -alkyl which is optionally substituted by a radical selected from the group of hydroxy, C 1 -C 3 -alkoxy, trifluoromethyl, trifluoromethoxy,
R 5 is hydrogen or C 1 -C 4 -alkyl, or
R 4 and R 5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C 1 -C 6 -alkyl, C 1 -C 4 -acyl, oxo, thioxo,
R 6 is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, or (v) 5- to 6-membered heteroaryl, where (ii) is optionally substituted by phenyl, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, hydroxy, chlorine, fluorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino, or
R 5 and R 6 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by C 1 -C 3 -alkyl or C 1 -C 3 -hydroxyalkyl,
A is oxygen,
X is oxygen and
the ring B is benzo which is optionally substituted by radicals from the series chlorine, fluorine, cyano, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
or a salt thereof.
5. A compound as claimed in claim 1 , of the formula (I) in which
R 1 is 1-azabicyclo[2.2.2]oct-3-yl,
R 2 to R 4 are hydrogen,
R 5 is hydrogen or C 1 -C 4 -alkyl, or
R 4 and R 5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C 1 -C 4 -alkyl, C 1 -C 4 -acyl, oxo, thioxo,
R 6 is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, (v) pyridyl, (vi) C 6 -C 10 -arylcarbonyl, where (ii) is optionally substituted by phenyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 3 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino, or
R 5 and R 6 together with the nitrogen atom to which they are bonded are a 3- to 10-membered heterocycle which is optionally substituted by C 1 -C 3 -alkyl or C 1 -C 3 -hydroxyalkyl,
A is oxygen,
X is oxygen,
the ring B is benzo,
or a salt thereof.
6. A compound as claimed in claim 1 , of the formula (I) in which
R 1 is 1-azabicyclo[2.2.2]oct-3-yl,
R 2 is hydrogen,
R 3 is hydrogen, chlorine, fluorine, amino or C 1 -C 3 -alkyl,
R 4 is hydrogen, methyl or ethyl, where methyl and ethyl are optionally substituted by a radical selected from the group of hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, or
R 4 and R 5 together with the nitrogen atom to which they are bonded are a 5- to 6-membered heterocycle which is optionally substituted by up to 2 substituents independently of one another selected from the group of C 1 -C 3 -alkyl, C 1 -C 4 -acyl, oxo, thioxo,
R 5 is hydrogen or C 1 -C 3 -alkyl,
R 6 is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) cyclopentyl, cyclohexyl, (iv) phenyl, (v) benzyl, or (vi) phenethyl, where (iv) to (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of hydroxy, chlorine, fluorine, cyano, methoxy, ethoxy, C 1 -C 4 -acyl, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 3 -alkylamino,
A is oxygen,
X is oxygen and
the ring B is benzo which is optionally substituted by radicals from the series chlorine, fluorine, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, methoxy and ethoxy,
or a salt thereof.
7. A compound of the formula
in which
R 1 to R 6 , A and X have the meanings indicated in claim 1 ,
or a salt thereof.
8. A compound of the formula
in which
R 1 to R 6 , A and X have the meanings indicated in claim 1 ,
or a salt thereof.
9. A compound of the formula
in which
R 1 to R 6 have the meanings indicated in claim 1 ,
or a salt thereof.
10. A compound of the formula
in which
R 1 to R 6 have the meanings indicated in claim 1 ,
or a salt thereof.
11. A process for preparing a compound of claim 1 , in which a compound of formula
in which R 1 to R 4 , A and B have the meanings indicated in claim 1 ,
is reacted with a compound of formula
in which X and R 6 have the meanings indicated in claim 1 ,
and the resulting compound of claim 1 is reacted, where appropriate, with an appropriate acid or base to give a salt thereof.
12. A medicament comprising at least one compound as claimed in claim 1 and at least one pharmaceutically acceptable, essentially nontoxic carrier or excipient.