Patent ID: 6486172
Filing Date: 2002-11-26
Classification: A61P,C07D

Abstract:
A method for treating a disease or condition in a mammal in need thereof, wherein the &agr;7 nicotinic acetylcholine receptor is implicated, wherein the disease or condition is cognitive and attention deficit symptoms of Alzheimer's, neurodegeneration associated with diseases such as Alzheimer's disease, pre-senile dementia (mild cognitive impairment), or senile dementia comprising administering to the mammal a therapeutically effective amount of a compound according Formula I: or pharmaceutically acceptable salts thereof, wherein X is O or S;R1 is independently selected from the group consisting of â€”H, alkyl, cycloalkyl, halogenated alkyl, and aryl; Alkyl is both straight- and branchedâ€”chain moieties having from 1-6 carbon atoms; Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+1) substituent(s) independently selected from â€”F, â€”Cl, â€”Br, or â€”I where n is the maximum number of carbon atoms in the moiety; Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms; Aryl is phenyl, substituted phenyl, naphthyl, or substituted naphthyl; Substituted phenyl is a phenyl either having 1-4 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I, or having 1 substituent selected from â€”R12 and 0-3 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I; Substituted naphthyl is a naphthalene moiety either having 1-4 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I, or having 1 substituent selected from â€”R12 and 0-3 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I, where the substitution can be independently on either only one ring or both rings of said naphthalene moiety; R2 is â€”H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, benzyl, substituted benzyl, or aryl; Substituted alkyl is an alkyl moiety from 1-6 carbon atoms and having 0-3 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I and further having 1 substituent selected from â€”OR10, â€”SR10, â€”NR10R10, â€”C(O)R10, â€”C(O)NR10R10, â€”CN, â€”NR10C(O)R10, â€”S(O)2NR10R10, â€”NR10S(O)2R10, â€”NO2, â€”R7, â€”R9, phenyl, or substituted phenyl; Substituted benzyl is a benzyl either having 1-4 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I, or having 1 substituent selected from â€”R12 and 0-3 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I, provided that all substitution is on the phenyl ring of the benzyl; R3 is selected from the group consisting of â€”H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, aryl, â€”R7, â€”R9, â€”OR8, â€”SR8, â€”F, â€”Cl, â€”Br, â€”I, â€”NR8R8, â€”C(O)R8, â€”CN, â€”C(O)NR8R8, â€”NR8C(O)R8, â€”S(O)R8, â€”OS(O)2R8, â€”NR8S(O)2R8, â€”NO2, and â€”N(H)C(O)N(H)R8; Alkenyl is straight- and branchedâ€”chain moieties having from 2-6 carbon atoms and having at least one carbon-carbon double bond; Halogenated alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 1 to (2nâˆ’1) substituent(s) independently selected from â€”F, â€”Cl, â€”Br, or â€”I where n is the maximum number of carbon atoms in the moiety; Substituted alkenyl is an unsaturated alkenyl moiety having from 2-6 carbon atoms and having 0-3 substituents independently selected from â€”F, or â€”Cl, and further having 1 substituent selected from â€”R7, â€”R9, â€”OR10, â€”SR10, â€”NR10R10, â€”C(O)R10, â€”C(O)NR10R10, â€”NR10C(O)R10, â€”S(O)2NR10R10, â€”NR10S(O)2R10, â€”CN, phenyl, or substituted phenyl; Alkynyl is straight- and branchedâ€”chained moieties having from 2-6 carbon atoms and having at least one carbon-carbon triple bond; Halogenated alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 1 to (2nâˆ’3) substituent(s) independently selected from â€”F, â€”Cl, â€”Br, or â€”I where n is the maximum number of carbon atoms in the moiety; Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from â€”F, or â€”Cl, and further having 1 substituent selected from â€”R7, â€”R9, â€”OR10, â€”SR10, â€”NR10R10, â€”C(O)R10, â€”C(O)NR10R10, â€”NR10C(O)R10, â€”S(O)2NR10R10, â€”NR10S(O)2R10, â€”CN, phenyl, or substituted phenyl; Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 1-4 substituents independently selected from â€”F, or â€”Cl; Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atoms and having 0-3 substituents independently selected from â€”F, or â€”Cl, and further having 1 substituent selected from â€”OR10, â€”SR10, â€”NR10R10, â€”C(O)R10, â€”CN, â€”C(O)NR10R10, â€”NR10C(O)R10, â€”S(O)2NR10R10, â€”NR10S(O)2R10, â€”NO2, phenyl, or substituted phenyl; Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2 atoms within the ring being â€”S-, â€”N(R3)-, or â€”O-; Halogenated heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being â€”S-, â€”N(R3)-, or â€”O-, and having 1-4 substituents independently selected from â€”F, or â€”Cl; Substituted heterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being â€”S-, â€”N(R3)-, or â€”O- and having 0-3 substituents independently selected from â€”F, or â€”Cl, and further having 1 substituent selected from â€”OR10, â€”SR10, â€”NR10R10, â€”C(O)R10, â€”C(O)NR10R10, â€”CN, â€”NR10C(O)R10, â€”NO2, â€”S(O)2NR10R10, â€”NR10S(O)2R10, phenyl, or substituted phenyl; R4 is selected from the group consisting of â€”Oâ€”R5, â€”Sâ€”R5, â€”S(O)â€”R5, â€”C(O)â€”R5, and alkyl substituted on the &ohgr; carbon with R5 where said &ohgr; carbon is determined by counting the longest carbon chain of the alkyl moiety with the C-1 carbon being the carbon attached to the phenyl ring of the core molecule and the &ohgr; carbon being the carbon furthest from said C-1 carbon; R5 is selected from aryl, R7, or R9; R7 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of â€”0-, &boxH;N-, â€”N(R14)-, and â€”S-, and having 0-1 substituent selected from â€”R12 and 0-3 substituents independently selected from â€”F, â€”Cl, â€”Br, or â€”I, or R7 is a 9-membered fused-ring moiety having a 6-membered ring fused to a 5-membered ring and having the formula wherein E is O, S, or NR14, wherein E and G are independently selected from CR18, O, S, or NR14, and A is CR18 or N, or wherein E and G are independently selected from CR18, O, S, or NR14, and A is CR18 or N, each 9-membered fused-ring moiety having 0-1 substituent selected from â€”R12 and 0-3 substituent(s) independently selected from â€”F, â€”Cl, â€”Br, or â€”I, and having a bond directly or indirectly attached to the core molecule where valency allows in either the 6-membered or the 5-membered ring of the fused-ring moiety; Each R8 is independently selected from â€”H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R7, R9, phenyl, or substituted phenyl; R9 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from &boxH;N- and having 0-1 substituent selected from â€”R12 and 0-3 substituent(s) independently selected from â€”F, â€”Cl, â€”Br, or â€”I, or 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from &boxH;N-, including quinolinyl or isoquinolinyl, each 10-membered fused- ring moiety having 0-1 substituent selected from â€”R12 and 0-3 substituent(s) independently selected from â€”F, â€”Cl, â€”Br, or â€”I and having a bond directly or indirectly attached to the core molecule where valency allows; Each R10 is independently selected from â€”H, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituent selected from R13, cycloalkyl substituted with 1 substituent selected from R13, heterocycloalkyl substituted with 1 substituent selected from R13, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, or substituted phenyl; Each R11 is independently selected from â€”H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl; R12 is selected from â€”OR11, â€”SR11, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, â€”NR11R11, â€”C(O)R11, â€”NO2, â€”C(O)NR11R11, â€”CN, â€”NR11C(O)R11, â€”S(O)2NR11R11, or â€”NR11S(O)2R11; R13 is selected from â€”OR11, â€”SR11, â€”NR11R11, â€”C(O)R11, â€”C(O)NR11R11, â€”CN, â€”CF3, â€”NR11C(O)R11, â€”S(O)2NR11R11, â€”NR11S(O)2R11, or â€”NO2; R14 is selected from â€”H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, phenyl, or substituted phenyl; Each R15 is independently selected from alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R7, R9, phenyl, or substituted phenyl; Each R16 is independently selected from cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R7, R9, phenyl, or substituted phenyl; R17, is selected from cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, or substituted heterocycloalkyl; and Each R18 is independently selected from â€”H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, â€”OR11, â€”SR11, â€”NR11R11, â€”C(O)R11, â€”NO2, â€”C(O)NR11R11, â€”CN, â€”NR11C(O)R11, â€”S(O)2NR11R11, or â€”NR11S(O)2R11, â€”F, â€”Cl, â€”Br, or â€”I, or a bond directly or indirectly attached to the core molecule, provided that there is only one said bond to the core molecule within the 9-membered fused-ring moiety, further provided that the fused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, â€”OR11, â€”SR11, â€”NR11R11, â€”C(O)R11, â€”NO2, â€”C(O)NR11R11, â€”CN, â€”NR11C(O)R11, â€”S(O)2NR11R11, or â€”NR11S(O)2R11, and further provided that the fused-ring moiety has 0-3 substituent(s) selected from â€”F, â€”Cl, â€”Br, or â€”I.