COMT inhibiting methods and compositions

A method of treating a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect, or treating symptoms associated with the neurological or psychiatric disorder, comprising administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof:

• wherein:
• X is halogen or CF3;
• Z is SO2NR2R3;
• and
• R2 and R3 together form a 3-10 membered monocyclic nitrogen-containing ring system that may be optionally substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.

A method of reducing the risk of a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect comprising administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof,

• wherein:
• X is selected from hydrogen, halogen, C≡N, CF3, and C1-C4 alkyl;
• Z is selected from SO2R1 and SO2NR2R3;
• R1 is selected from C1-C10 alkyl, C3-C10 cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl, any of which may be substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, alkoxy, nitro, amino, C1-C4 alkylamino, oxo, C3-C10 cycloalkyl, acyl, aryl, aralkyl, heterocyclyl, heteroaryl, CON(R)2, SO2R, and SO2N(R)2, where each R is independently C1-C4 alkyl or (R)2 forms a carbocyclic ring;
• R2 and R3 are independently selected from hydrogen and any of the groups as defined for R1, with the proviso that at least one of R2 and R3 is different from hydrogen;
• or R2 and R3 may together form a 3-10 membered monocyclic, bicyclic or spirocyclic nitrogen-containing ring system that contains 0-3 additional heteroatoms selected from oxygen (O), nitrogen (N), and sulfur (S), and which may be further substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl;
• with the proviso that when X is hydrogen and Z is SO2R1, R1 is not C4 alkyl, C8 alkyl, tetrahydropyran or propylcyclopropane;
• or when X is H and Z is SO2NR2R3, R2 and R3 do not together form a 1-piperidinyl ring substituted with a α-methyl group;
• or when X is C1 and Z is SO2R1, R1 is not C3 alkyl, C4 alkyl or C5-C6 cycloalkyl;
• or when X is C1 and Z is SO2NR2R3, R2 and R3 do not together form an unsubstituted, 1-pyrrolidinyl ring.

A method of reducing the risk of a neurological or psychiatric disorder for which inhibiting COMT provides a therapeutic effect, the method comprising administering to a subject in need thereof an effective amount of a COMT-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof:

• wherein:
• X is halogen or CF3;
• Z is SO2NR2R3;
• and
• R2 and R3 together form a 3-10 membered monocyclic nitrogen-containing ring system that may be optionally substituted with one or more groups selected from halogen, C≡N, CF3, OH, C1-C4 alkyl or C2-C4 alkenyl, C3-C6 cycloalkyl, alkoxy, nitro, amino, C1-C4 alkoxycarbonyl, acyl, C1-C4 alkylamino, oxo, SO2CH3, aryl, aralkyl, heterocyclyl, heteroaryl and heteroarylalkyl.