Substituted pyridines useful as modulators of acetylcholine receptors

A method for treating Parkinson's disease, said method comprising administering a therapeutically effective amount of at least one compound having structure I to a patient suffering from Parkinson's disease,

• wherein compounds having structure I have the structure:
• ##STR14## wherein:
• A is a 1, 2, 3, 4, 5 or 6 atom bridging species linking C.sup.3 of the pyridine ring with N.sup..alpha.,
• wherein A is selected from a straight chain or branched chain alkylene moiety having up to six atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to six atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to six atoms in the backbone thereof, or a substituted alkynylene moiety;
• provided, however, that N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• B is a 1, 2, 3 or 4 atom bridging species linking N.sup..alpha. with Z,
• wherein B is selected from a straight chain or branched chain alkylene moiety having up to four atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to four atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to four atoms in the backbone thereof, or a substituted alkynylene moiety;
• provided, however, that N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• Z is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, trifluoromethyl, cyano, cyanomethyl, nitro, carboxyl, carbamate, sulfonyl, sulfonamide, aryloxyalkyl, or --OR.sup.Z, wherein R.sup.Z is hydrogen, lower alkyl or aryl;
• R.sup..alpha. is selected from hydrogen or lower alkyl;
• and
• R.sup.2, R.sup.4 and R.sup.6 are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, halogen, cyano, nitro;
• --S(O)R', --S(O).sub.2 R', --S(O).sub.2 OR' or --S(O).sub.2 NHR', wherein each R' is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl;
• provided, however, that when R.sup.2, R.sup.4, R.sup.5 or R.sup.6 is --S(O)R', R' is not hydrogen;
• and further provided that when R' is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom;
• --C(O)R", wherein R" is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality;
• --OR'" or --NR'".sub.2, wherein each R'" is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, that the --OR'" or --NR'".sub.2 functionality is not conjugated with an alkenyl or alkynyl functionality;
• --SR'"", wherein R"" is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the --SR"" functionality is not conjugated with an alkenyl or alkynyl functionality;
• or
• --SiR'"".sub.3, wherein R'"" is selected from alkyl or aryl;
• R.sup.5 is selected from alkynyl, substituted alkynyl, aryl or substituted aryl;
• provided, however, that the following compounds are excluded from the definition of Formula I:
• compounds wherein A is --CH.dbd.CH--(CH.sub.2).sub.1-5 --CH.sub.2 --, B is alkyl, Z is H or absent, R.sup..alpha. is H, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are independently alkyl or halo;
• compounds wherein A is --CH.sub.2 --, B is --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --, Z is H, R.sup..alpha. is --CH.sub.3 or --CH.sub.2 --CH.sub.3, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are hydrogen;
• and compounds wherein A is --CH(CH.sub.3)-- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --, B is --CH.sub.2 --CH.sub.2 --CH(C.sub.6 H.sub.5)-- or --CH(CH.sub.3)--C.sub.6 H.sub.5, Z is phenyl or absent, R.sup..alpha. is hydrogen, and each of R.sup.2, R.sup..alpha., R.sup.5 and R.sup.6 are hydrogen.

A method for treating Alzheimer's disease, said method comprising administering a therapeutically effective amount of at least one compound having structure I to a patient suffering from Alzheimer's disease,

• wherein compounds having structure I have the structure:
• ##STR15## wherein:
• A is a 1, 2, 3, 4, 5 or 6 atom bridging species linking C.sup.3 of the pyridine ring with N.sup..alpha.,
• wherein A is selected from a straight chain or branched chain alkylene moiety having up to six atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to six atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to six atoms in the backbone thereof, or a substituted alkynylene moiety N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• B is a 1, 2, 3 or 4 atom bridging species linking N.sup..alpha. with Z,
• wherein B is selected from a straight chain or branched chain alkylene moiety having up to four atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to four atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to four atoms in the backbone thereof, or a substituted alkynylene moiety;
• provided, however, that N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• Z is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, trifluoromethyl, cyano, cyanomethyl, nitro, carboxyl, carbamate, sulfonyl, sulfonamide, aryloxyalkyl, or --OR.sup.Z, wherein R.sup.Z is hydrogen, lower alkyl or aryl;
• R.sup..alpha. is selected from hydrogen or lower alkyl;
• and
• R.sup.2, R.sup.4 and R.sup.6 are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, halogen, cyano, nitro;
• --S(O)R', --S(O).sub.2 R', --S(O).sub.2 OR' or --S(O).sub.2 NHR', wherein each R' is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl;
• provided, however, that when R.sup.2, R.sup.4, R.sup.5 or R.sup.6 is --S(O)R', R' is not hydrogen;
• and further provided that when R' is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom;
• --C(O)R", wherein R" is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality;
• --OR'" or --NR'".sub.2, wherein each R'" is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, that the --OR'" or --NR'".sub.2 functionality is not conjugated with an alkenyl or alkynyl functionality;
• --SR"", wherein R"" is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the --SR"" functionality is not conjugated with an alkenyl or alkynyl functionality;
• or
• --SIR'"".sub.3, wherein R'"" is selected from alkyl or aryl;
• R.sup.5 is selected from alkynyl, substituted alkynyl, aryl or substituted aryl;
• provided, however, that the following compounds are excluded from the definition of Formula I:
• compounds wherein A is --CH.dbd.CH--(CH.sub.2).sub.1-5 --CH.sub.2 --, B is alkyl, Z is H or absent, R.sup..alpha. is H, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are independently alkyl or halo;
• compounds wherein A is --CH.sub.2 --, B is --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --, Z is H, R.sup..alpha. is --CH.sub.3 or --CH.sub.2 --CH.sub.3, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are hydrogen;
• and compounds wherein A is --CH(CH.sub.3)-- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --, B is --CH.sub.2 --CH.sub.2 --CH(C.sub.6 H.sub.5)-- or --CH(CH.sub.3)--C.sub.6 H.sub.5, Z is phenyl or absent, R.sup..alpha. is hydrogen, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are hydrogen.

A method for treating dementia, said method comprising administering a therapeutically effective amount of at least one compound having the structure I to a patient suffering from dementia,

• wherein compounds having structure I have the structure:
• ##STR16## wherein:
• A is a 1, 2, 3, 4, 5 or 6 atom bridging species linking C.sup.3 of the pyridine ring with N.sup..alpha.,
• wherein A is selected from a straight chain or branched chain alkylene moiety having up to six atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to six atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to six atoms in the backbone thereof, or a substituted alkynylene moiety;
• provided, however, that N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• B is a 1, 2, 3 or 4 atom bridging species linking N.sup..alpha. with Z,
• wherein B is selected from a straight chain or branched chain alkylene moiety having up to four atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to four atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to four atoms in the backbone thereof, or a substituted alkynylene moiety;
• provided, however, that N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• Z is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, trifluoromethyl, cyano, cyanomethyl, nitro, carboxyl, carbamate, sulfonyl, sulfonamide, aryloxyalkyl, or --OR.sup.Z, wherein R.sup.Z is hydrogen, lower alkyl or aryl;
• R.sup..alpha. is selected from hydrogen or lower alkyl;
• and
• R.sup.2, R.sup.4 and R.sup.6 are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, halogen, cyano, nitro;
• --S(O)R', --S(O).sub.2 R', --S(O).sub.2 OR' or --S(O).sub.2 NHR', wherein each R' is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl;
• provided, however, that when R.sup.2, R.sup.4, R.sup.5 or R.sup.6 is --S(O)R', R' is not hydrogen;
• and further provided that when R' is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom;
• --C(O)R", wherein R" is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality;
• --OR'" or --NR'".sub.2, wherein each R'" is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, that the --OR'" or --NR'".sub.2 functionality is not conjugated with an alkenyl or alkynyl functionality;
• --SR"", wherein R"" is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the --SR"" functionality is not conjugated with an alkenyl or alkynyl functionality;
• or
• --SIR'"".sub.3, wherein R'"" is selected from alkyl or aryl;
• R.sup.5 is selected from alkynyl, substituted alkynyl, aryl or substituted aryl;
• provided, however, that the following compounds are excluded from the definition of Formula I:
• compounds wherein A is --CH.dbd.CH--(CH.sub.2).sub.1-5 --CH.sub.2 --, B is alkyl, Z is H or absent, R.sup..alpha. is H, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are independently alkyl or halo;
• compounds wherein A is --CH.sub.2 --, B is --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --, Z is H, R.sup..alpha. is --CH.sub.3 or --CH.sub.2 --CH.sub.3, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are hydrogen;
• and compounds wherein A is --CH(CH.sub.3)-- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --, B is --CH.sub.2 --CH.sub.2 --CH(C.sub.6 H.sub.5)-- or --CH(CH.sub.3)--C.sub.6 H.sub.5, Z is phenyl or absent, R.sup..alpha. is hydrogen, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are hydrogen.

A method for controlling pain, said method comprising administering a pain-reducing amount of at least one compound having the structure I to a patient suffering from pain,

• wherein compounds having structure I have the structure:
• ##STR17## wherein:
• A is a 1, 2, 3, 4, 5 or 6 atom bridging species linking C.sup.3 of the pyridine ring with N.sup..alpha.,
• wherein A is selected from a straight chain or branched chain alkylene moiety having up to six atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to six atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to six atoms in the backbone thereof, or a substituted alkynylene moiety;
• provided, however, that N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• B is a 1, 2, 3 or 4 atom bridging species linking N.sup..alpha. with Z,
• wherein B is selected from a straight chain or branched chain alkylene moiety having up to four atoms in the backbone thereof, or a substituted alkylene moiety, a straight chain or branched chain alkenylene moiety having up to four atoms in the backbone thereof, or a substituted alkenylene moiety, an alkynylene moiety having up to four atoms in the backbone thereof, or a substituted alkynylene moiety;
• provided, however, that N.sup..alpha. is not conjugated with an alkenyl or alkynyl moiety;
• Z is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, hydroxyalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, trifluoromethyl, cyano, cyanomethyl, nitro, carboxyl, carbamate, sulfonyl, sulfonamide, aryloxyalkyl, or --OR.sup.Z, wherein R.sup.Z is hydrogen, lower alkyl or aryl;
• R.sup..alpha. is selected from hydrogen or lower alkyl;
• and
• R.sup.2, R.sup.4 and R.sup.6 are each independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic, trifluoromethyl, halogen, cyano, nitro;
• --S(O)R', --S(O).sub.2 R', --S(O).sub.2 OR' or --S(O).sub.2 NHR', wherein each R' is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl;
• provided, however, that when R.sup.2, R.sup.4, R.sup.5 or R.sup.6 is --S(O)R', R' is not hydrogen;
• and further provided that when R' is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom;
• --C(O)R", wherein R" is selected from hydrogen, alkyl, substituted alkyl, alkoxy, alkylamino, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, arylamino, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality;
• --OR'" or --NR'".sub.2, wherein each R'" is independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, that the --OR'" or --NR'".sub.2 functionality is not conjugated with an alkenyl or alkynyl functionality;
• SR"", wherein R"" is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the --SR"" functionality is not conjugated with an alkenyl or alkynyl functionality;
• or
• --SiR'"".sub.3, wherein R'"" is selected from alkyl or aryl;
• R.sup.5 is selected from alkynyl, substituted alkynyl, aryl or substituted aryl;
• provided, however, that the following compounds are excluded from the definition of Formula I:
• compounds wherein A is --CH.dbd.CH--(CH.sub.2).sub.1-5 --CH.sub.2 --, B is alkyl, Z is H or absent, R.sup..alpha. is H, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are independently alkyl or halo;
• compounds wherein A is --CH.sub.2 --, B is --CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --, Z is H, R.sup..alpha. is --CH.sub.3 or --CH.sub.2 --CH.sub.3, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are hydrogen;
• and compounds wherein A is --CH(CH.sub.3)-- or --CH.sub.2 --CH.sub.2 --CH.sub.2 --, B is --CH.sub.2 --CH.sub.2 --CH(C.sub.6 H.sub.5)-- or --CH(CH.sub.3)--C.sub.6 H.sub.5, Z is phenyl or absent, R.sup..alpha. is hydrogen, and each of R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are hydrogen.