US 5,705,512 A · Modulators of acetylcholine receptors

Abstract

The present invention provides a class of pyridine compounds which are modulators of acetylcholine receptors, i.e., compounds which displace acetylcholine receptor ligands from their binding sites. Invention compounds may act as agonists, partial agonists, antagonists or allosteric modulators of acetylcholine receptors, and are useful for a variety of therapeutic applications, such as the treatment of Alzheimer's disease and other disorders involving memory loss and/or dementia; disorders of attention and focus; disorders of extrapyramidal motor function; mood and emotional disorders; substance abuse including withdrawal syndromes and substitution therapy; neuroendocrine disorders and dysregulation of food intake, including bulimia and anorexia; disorders of nociception and control of pain; autonomic disorders including dysfunction of gastrointestinal motility and function; pheochromocytoma; cardiovascular dysfunction including hypertension and cardia arrhythmias, comedication in surgical procedures, and the like.

A method for treating cognitive dysfunction, said method comprising administering a therapeutically effective amount of a compound having the structure I to a patient suffering from cognitive dysfunction, wherein structure I is as follows:

##STR11## wherein:
A is a 1, 2 or 3 atom bridging species which forms part of a saturated or monounsaturated 5-, 6- or 7-membered ring including N.sup.7, C.sup.8, C.sub.9 and B;
B is selected from --O--, --S--, --NR.sup.10 --, wherein R.sup.10 is selected from hydrogen, lower alkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl;
--C.sup.10 HR.sup.10a --, wherein R.sup.10a is selected from hydrogen, lower alkyl, hydroxyalkyl, aryl, aryloxyalkyl, fluoro, trifluoromethyl, cyano, cyanomethyl, --OR', --NR'.sub.2, or --SR', wherein each R' is independently hydrogen, lower alkyl, alkenyl, alkynyl or aryl, provided, however, that neither the --NR'.sub.2 nor the --SR' functionality is conjugated with an alkenyl or alkynyl functionality;
or B is .dbd.C.sup.10 R.sup.10a -- or .dbd.N--, provided there is no double bond in the ring between A and B, or between B and C.sup.9 when there is a double bond between N.sup.7 and C.sup.8, and provided that B is not a heteroatom when A is a 1 atom bridging species;
R.sup.2, R.sup.4, R.sup.5 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, heterocyclic, substituted heterocyclic, trifluoromethyl, halogen, cyano, nitro;
--S(O)R', --S(O).sub.2 R' or --S(O).sub.2 NHR', wherein each R' is as defined above, 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, alkenyl or alkynyl, and provided that when R.sup.2, R.sup.4, R.sup.5 or R.sup.6 is S(O).sub.2 NHR', R' is not alkenyl or alkynyl;
--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, heterocyclic, substituted heterocyclic or trifluoromethyl, provided, however, that the carbonyl functionality is not conjugated with an alkenyl or alkynyl functionality;
--OR'", wherein R'" is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, aroyl, substituted aroyl, heterocyclic, substituted heterocyclic, acyl, trifluoromethyl, alkylsulfonyl or arylsulfonyl, provided, however, that the --OR'" functionality is not conjugated with an alkenyl or alkynyl functionality;
--NR'".sub.2, wherein each R'" is independently as defined above, or each R'" and the N to which they are attached can cooperate to form a 4-, 5-, 6- or 7-membered ring;
provided, however, that the --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, 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.7 is selected from hydrogen, lower alkyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, or R.sup.7 is absent when there is a double bond between N.sup.7 and C.sup.8 ;
and
R.sup.9 and R.sup.9a are each independently selected from hydrogen, lower alkyl, hydroxyalkyl, aryl, aryloxyalkyl, fluoro, trifluoromethyl, cyano, cyanomethyl, --OR', --NR'.sub.2, or --SR', wherein each R' is as defined above, provided, however, that neither the --NR'.sub.2 nor the --SR' functionality is conjugated with an alkenyl or alkynyl functionality;
provided, however, that the following compounds are excluded from the definition of Formula I:
nicotine, nornicotine, anabasine, N-methyl anabasine, anabaseine, anatabine, N-methyl-2-oxoanabasine, myosmine, cotinine, the compounds wherein A=--CH.sub.2 --, B=--CH.sub.2 --, R.sup.2 =H or Br, R.sup.4, R.sup.6, R.sup.9 and R.sup.9a =H, R.sup.5 =H or methyl, and R.sup.7 =methyl;
compounds wherein A=--CH.sub.2 --, B=--CH.sub.2 --, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 =H or alkyl, R.sup.7 is alkyl and R.sup.9 and R.sup.9a =hydrogen;
compounds wherein A=--CH.sub.2 --, --C(O)-- or --CH(CH.sub.2 F)--, B=--CHR.sup.10a -- (wherein R.sup.10a is H, lower alkyl, hydroxyalkyl, F, cyano, cyanomethyl or --OR', wherein R'=hydrogen or methyl), R.sup.2, R.sup.4, R.sup.5 and R.sup.6 =H, R.sup.7 is methyl and R.sup.9 and R.sup.9a =hydrogen, methyl, fluorine, cyanomethyl, cyano or hydroxyalkyl;
compounds wherein A=--CH.sub.2 --, --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.dbd., B=--CH.sub.2 -- or --CH.dbd., R.sup.2 and R.sup.6 =lower alkyl or arylalkyl, R.sup.4, R.sup.5, R.sup.9 and R.sup.9a =H and R.sup.7 =hydrogen or methyl;
compounds wherein A=--CH.sub.2 --, B=--CH.sub.2 --, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 =H, R.sup.7 and R.sup.9 are methyl and R.sup.9a =hydrogen or methyl;
compounds wherein A=--CH.sub.2 --, B=--CH.sub.2 --, R.sup.2, R.sup.4 and R.sup.6 =H or methyl, R.sup.5, R.sup.9 and R.sup.9a are hydrogen, and R.sup.7 =methyl;
compounds wherein A=--CH.sub.2 -- or --C(O)--, B=--CH.sub.2 --, R.sup.2, R.sup.5, R.sup.6, R.sup.9 and R.sup.9a are hydrogen, R.sup.4 =--NH.sub.2 and R.sup.7 =methyl;
compounds wherein A=--CH.sub.2 --, B=--CH.sub.2 --, R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.9 and R.sup.9a are hydrogen and R.sup.5 -bromine;
compounds wherein A=--CH.sub.2 --, B=--CH.sub.2 --, R.sup.2, R.sup.4, R.sup.6, R.sup.9 and R.sup.9a are hydrogen, R.sup.5 =fluorine, chlorine, bromine, iodine, or --NH.sub.2, and R.sup.7 =hydrogen or methyl;
compounds wherein A=--CH.sub.2 -- or --CH.sub.2 CH.sub.2 --, B=--CH.sub.2 --, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are alkyl or halogen, R.sup.7 =H or alkyl, and R.sup.9 and R.sup.9a are alkyl;
and compounds wherein A=--CH.sub.2 CH.sub.2 --, B=--CH.sub.2 --, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 are H or lower alkyl, R.sup.7 =absent or H if the pyrrolidone ring contains no unsaturation, and R.sup.9 and R.sup.9a are H or lower alkyl.

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Modulators of acetylcholine receptors

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Modulators of acetylcholine receptors

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Abstract

Claims22