2-heteroaryl carboxamides
The invention relates to novel 2-heteroaryl carboxamides 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 formula (I):
in which
R 1 is 1-azabicyclo[2.2.2]oct-3-yl, which is optionally substituted via the nitrogen atom by a radical selected from the group of C 1 -C 4 -alkyl, benzyl and oxy,
R 2 is hydrogen or C 1 -C 6 -alkyl,
R 3 is hydrogen, halogen or C 1 -C 6 -alkyl,
R 4 is hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylcarbonylamino, C 1 -C 6 -alkylaminocarbonyl, C 1 -C 4 -alkylsulphonylamino, C 3 -C 8 -cycloalkylcarbonyl-amino, C 3 -C 6 -cycloalkylaminocarbonyl, pyrrolyl, C 1 -C 6 -alkylaminocarbonylamino, hydroxyl, phenyl morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 6 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl,
where C 1 -C 6 -alkyl may optionally be substituted by hydroxyl, cyano, amino, C 1 -C 6 -alkylaminocarbonylamino, C 1 -C 6 -alkylaminocarboxyl, morpholinyl or aryl,
C 1 -C 6 -alkylaminocarbonyl may optionally be substituted by C 1 -C 6 -alkoxy or C 1 -C 6 -alkylamino, and
C 1 -C 6 -alkylcarbonylamino may optionally be substituted by C 1 -C 6 -alkoxy,
A is oxygen or sulphur,
the ring B is benzo, each of which are optionally substituted by radicals from the series halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
and
E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively may be substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkoxy and C 1 -C 6 -alkyl,
or a salt thereof.
2. The compound of formula (I) of claim 1 , 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, fluorine, chlorine, bromine or C 1 -C 4 -alkyl,
R 4 is hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylsulphonylamino, C 3 -C 6 -cycloalkylcarbonylamino, C 3 -C 6 -cycloalkylaminocarbonyl, pyrrolyl, C 1 -C 4 -alkylaminocarbonylamino, hydroxyl, phenyl morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 4 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl,
where C 1 -C 4 -alkyl may optionally be substituted by hydroxyl, cyano, amino, C 1 -C 4 -alkylaminocarbonylamino, C 1 -C 4 -alkylaminocarboxyl, morpholinyl or aryl,
C 1 -C 4 -alkylaminocarbonyl may optionally be substituted by C 1 -C 4 -alkoxy or C 1 -C 4 -alkylamino, and
C 1 -C 4 -alkylcarbonylamino may optionally be substituted by C 1 -C 4 -alkoxy,
A is oxygen or sulphur,
the ring B is benzo, each of which are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy and C 1 -C 4 -alkyl,
and
E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively may be substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 4 -alkoxy and C 1 -C 4 -alkyl,
or a salt thereof.
3. The compound of formula (I) of claim 1 , in which
R 1 is 1-azabicyclo[2.2.2]oct-3-yl,
R 2 and R 3 are hydrogen,
R 4 is hydrogen, fluorine, chlorine, bromine, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 4 -alkyl, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, C 1 -C 6 -alkylthio, C 1 -C 4 -alkylcarbonylamino, C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylsulphonylamino, C 3 -C 6 -cycloalkylcarbonylamino, C 3 -C 6 -cycloalkylaminocarbonyl, pyrrolyl, C 1 -C 4 -alkylaminocarbonylamino, hydroxyl, phenyl morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 4 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl,
where C 1 -C 4 -alkyl may optionally be substituted by hydroxyl, cyano, amino, C 1 -C 4 -alkylaminocarbonylamino, C 1 -C 4 -alkylaminocarboxyl, morpholinyl or aryl,
C 1 -C 4 -alkylaminocarbonyl may optionally be substituted by C 1 -C 4 -alkoxy or C 1 -C 4 -alkylamino, and
C 1 -C 4 -alkylcarbonylamino may optionally be substituted by C 1 -C 4 -alkoxy,
A is oxygen,
the ring B is benzo, each of which are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy and C 1 -C 4 -alkyl,
and
E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively may be substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 4 -alkoxy and C 1 -C 4 -alkyl,
or a salt thereof.
4. A compound of formula (I) of claim 1 , 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 or C 1 -C 6 -alkyl,
R 4 is hydrogen, halogen, cyano, amino, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkylamino, formyl, hydroxycarbonyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylcarbonylamino, C 1 -C 4 -alkylsulphonylamino, C 3 -C 8 -cycloalkylcarbonylamino, pyrrolyl, C 1 -C 6 -alkylaminocarbonylamino, morpholinyl, oxypiperidinyl, oxopyrrolidinyl, oxomorpholinyl, pyrrolidinyl, morpholinylcarbonyl, piperidinyl, pyridinyl, dihydropyrrolylcarbonyl, C 1 -C 4 -alkylpiperizinylcarbonyl, isoxazolecarbonylamino, tetrahydrofuranylcarbonylamino, furoylamino, piperidinylcarbonyl, or piperidinylcarbonyl,
where C 1 -C 6 -alkyl may optionally be substituted by hydroxyl, amino, C 1 -C 6 -alkylaminocarbonylamino, C 1 -C 6 -alkylaminocarboxyl, morpholinyl or aryl, and
C 1 -C 6 -alkylcarbonylamino may optionally be substituted by C 1 -C 6 -alkoxy,
A is oxygen or sulphur,
the ring B is benzo, each of which are optionally substituted by radicals from the series halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
and
E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively is optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkoxy and C 1 -C 6 -alkyl,
or a salt thereof.
5. The compound of formula (I) of claim 1 , 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 or C 1 -C 6 -alkyl,
R 4 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy morpholinyl, piperidinyl or pyrrolidinyl, where alkyl is optionally substituted by a hydroxyl radical,
A is oxygen or sulphur,
the ring B is benzo, each of which are optionally substituted by radicals from the series halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
and
E is C≡C, phenylene, thienylene, oxadizolylene, pyrrolylene, furanylene, pyrimidinylene, or pyridinylene wherein each ring system respectively 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.
6. The compound of claim 1 having the formula (Ia)
in which
R 1 is (3R)-1-azabicyclo[2.2.2]oct-3-yl,
R 2 and R 3 are, independently of one another, hydrogen or methyl,
R 4 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or morpholinyl, piperidinyl or pyrrolidinyl, where alkyl is optionally substituted by a hydroxyl radical,
and
R B is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy,
or a salt thereof.
7. The compound of claim 1 having the formula (Ib)
in which
R 1 is (3R)-1-azabicyclo[2.2.2]oct-3-yl,
R 2 and R 3 are, independently of one another, hydrogen or methyl,
R 4 is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy morpholinyl, piperidinyl or pyrrolidinyl, where alkyl is optionally substituted by a hydroxyl radical, and
R B is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy,
or a salt thereof.
8. The compound of claim 1 , wherein
R 1 is (3R)-1-azabicyclo[2.2.2]oct-3-yl,
R 2 and R 3 are hydrogen,
R 4 is hydrogen, fluorine, chlorine, bromine, trifluoromethoxy, hydroxymethyl, methoxy or morpholinyl or piperidinyl, and
R B is hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy or C 1 -C 4 -alkyl,
or a salt thereof.
9. The compound of claim 1 having the formula (Ic)
in which
E is phenylene,
R 4 is C 1 -C 6 -alkoxy, aminomethyl, hydroxycarbonyl, C 3 -C 8 -cycloalkylcarbonylamino, a group of the formula
where
R 5 is C 1 -C 6 -alkyl,
n is zero, 1, 2, 3 or 4,
or
morpholinyl, piperidinyl or pyrrolidinyl, which is optionally substituted by oxo,
A is sulphur or oxygen,
or a salt thereof.
10. The compound of claim 9
E is phenylene,
R 4 is C 1 -C 4 -alkoxy, aminomethyl, hydroxycarbonyl, C 3 -C 6 -cycloalkylcarbonylamino, a group of the formula
where
R 5 is C 1 -C 4 -alkyl,
n is zero, 1 or 2,
or
morpholinyl, piperidinyl or pyrrolidinyl, which is optionally substituted by oxo,
A is sulphur or oxygen,
or a salt thereof.
11. The compound of claim 1
or a salt thereof.
12. A process for the preparation of a compound of formula (I) of claim 1 , in which a compound of formula (II)
X 1 -E-R 4 (II),
in which
R 4 the meanings indicated in claim 1 , and
X 1 is —B(OH) 2 or
in the case where E is arylene or heteroarylene, and is hydrogen in the case where E is —C≡C—,
is reacted with a compound of the formula (III)
in which
R 1 , R 2 , R 3 , A and the ring B have the meanings indicated in claim 1 , and
X 2 is triflate or halogen, preferably chlorine, bromine or iodine,
and where appropriate
[A] the resulting compound of formula (I) is alkylated on the quinuclidine nitrogen atom with an appropriate alkylating reagent, or
[B] the resulting compound of formula (I) is oxidized on the quinuclidine nitrogen atom with a suitable oxidizing agent,
and the resulting compound of formula (I) is optionally converted to or a salt with an appropriate base or acid.
13. A process for the preparation of a compound of the formula (I) of claim 1 , in which a compound of formula (II)
X 1 -E-R 4 (II),
in which
R 4 the meanings indicated in claim 1 , and
X 1 is —B(OH) 2 or
in the case where E is arylene or heteroarylene, and is hydrogen in the case where E is —C≡C—,
is reacted with a compound of the formula (III)
in which
R 1 , R 2 , R 3 , A and the ring B have the meanings indicated in claim 1 , and
X 2 is triflate or halogen, preferably chlorine, bromine or iodine,
and the resulting compound of formula (I) is optionally converted to a salt with an appropriate base or acid.
14. A pharmaceutical composition comprising at least one compound according to any of claims 1 to 11 and at least one pharmaceutically acceptable, essentially nontoxic carrier or excipient.