Muscarinic antagonists
First Claim
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1. A compound having the structural formula ##STR41## or a stereoisomer thereof, or a pharmaceutically acceptable salt, or solvate thereof,wherein:
- Z is N;
X is --O--, --S--, --SO--, --SO2 --, --CO--, --CH2 --, --CONR20 --, --NR20 --SO2 --, --NR20 CO--, or --SO2 --NR20 --;
Q is --O--, --S--, --SO--, --SO2 --, or --CH2 --;
R is ##STR42## R1 and R21 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, phenylalkyl, and hydroxyalkyl;
R2 is cycloalkyl, cycloalkyl substituted with 1 to 3 independently selected R3 groups, cycloalkenyl, cycloalkylalkyl, ##STR43## (wherein Ry is H, alkyl, alkenyl, SO2 Rz or CORz wherein Rz is alkyl, aryl or cycloalkyl);
R3, R4, R5, R6, R22, R24, and R25 are independently selected from the group consisting of H, alkyl, halo, alkoxy, benzyloxy, benzyloxy substituted by nitro or aminoalkyl, polyhaloalkyl, nitro, hydroxy, amino, alkylamino, formyl, alkylthio, acyloxy, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl, alkylsulfinyl, --OCONH2, --OCONH-- alkyl, --OCON(alkyl)2, --NHCOO-- alkyl, --NHCO-- alkyl, phenyl, hydroxyalkyl, and 1-morpholinyl;
R8 is hydrogen, lower alkyl or cyclopropyl;
R20 is H, phenyl or alkyl; and
R27 and R28 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, mercaptoalkyl, alkylthioalkyl, and carboxyalkyl, and additionally R27 and R28 may be joined to form an alkylene group; and
n is 0 or an integer from 1 to 3.
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Abstract
Di-N-substituted piperazine or 1,4-di-substituted piperidine compounds in accordance with formula I (including all isomers, salts, esters, and solvates) ##STR1## wherein Q, n, R, R1, R2, R3, R4, R21, R27, R28, X, and Z are as defined herein are muscarinic antagonists useful for treating cognitive disorders such as Alzheimer'"'"'s disease. Pharmaceutical compositions and methods of preparation are also disclosed. Also disclosed are synergistic combinations with acetyl-cholinesterase inhibitors of compounds capable of enhancing acetylcholine release and having the above formula.
68 Citations
16 Claims
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1. A compound having the structural formula ##STR41## or a stereoisomer thereof, or a pharmaceutically acceptable salt, or solvate thereof,
wherein: -
Z is N; X is --O--, --S--, --SO--, --SO2 --, --CO--, --CH2 --, --CONR20 --, --NR20 --SO2 --, --NR20 CO--, or --SO2 --NR20 --; Q is --O--, --S--, --SO--, --SO2 --, or --CH2 --; R is ##STR42## R1 and R21 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, phenylalkyl, and hydroxyalkyl; R2 is cycloalkyl, cycloalkyl substituted with 1 to 3 independently selected R3 groups, cycloalkenyl, cycloalkylalkyl, ##STR43## (wherein Ry is H, alkyl, alkenyl, SO2 Rz or CORz wherein Rz is alkyl, aryl or cycloalkyl); R3, R4, R5, R6, R22, R24, and R25 are independently selected from the group consisting of H, alkyl, halo, alkoxy, benzyloxy, benzyloxy substituted by nitro or aminoalkyl, polyhaloalkyl, nitro, hydroxy, amino, alkylamino, formyl, alkylthio, acyloxy, alkylsulfonyl, arylsulfonyl, acyl, alkoxycarbonyl, alkylsulfinyl, --OCONH2, --OCONH-- alkyl, --OCON(alkyl)2, --NHCOO-- alkyl, --NHCO-- alkyl, phenyl, hydroxyalkyl, and 1-morpholinyl; R8 is hydrogen, lower alkyl or cyclopropyl; R20 is H, phenyl or alkyl; and R27 and R28 are independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, mercaptoalkyl, alkylthioalkyl, and carboxyalkyl, and additionally R27 and R28 may be joined to form an alkylene group; and n is 0 or an integer from 1 to 3. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16)
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13. A compound selected from the group consisting of the following formulae:
- ##STR45## wherein the methyl group attached to the piperazine ring is in the (R)-conformation.
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14. A compound selected from the group consisting of the following formulae:
- ##STR46## wherein the methyl group attached to the piperazine ring is in the (R)-conformation.
Specification