Pyridyl ethers and thioethers as ligands for nicotinic acetylcholine receptor and its therapeutic application

A method for treating a condition or disease the pathogenesis of which may be regulated by modulation of the nicotinic acetylcholine receptor which comprises the step of administering to a patient suffering from such a condition or disease an effective amount of a compound of the general formula:

• wherein
• m is selected from 0, 1 or 2;
• p is selected from 0 or 1;
• Y is selected from the group consisting of O, S, S(O) and S(O)2;
• R1 is independently selected from the group consisting of H—, HO—, O—, C1-6alkyl—, C2-6alkenyl—, C2-6alkynyl—, C3-6cycloalkylC1-3alkyl—, phenylC1-3alkyl—, —C(O)C1-6alkyl, —C(O)phenyl, —C(O)C1-6alkylphenyl, —C(O)OC1-6alkyl, —C(O)Ophenyl, —C(O)NHC1-6alkyl, —C(O)N(C1-6alkyl)2 and —C(O)NHphenyl;
• wherein R1 is optionally substituted on a carbon atom with one to three Ra substituents;
• wherein Ra is independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxyC1-4alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F;
• R2 is independently selected from the group consisting of H, C1-6alkyl, phenyl and heteroaryl;
• wherein heteroaryl is as defined below;
• R3 is selected from the group consisting of H, C1-6alkyl, Cl, Br and F;
• with the proviso that if m is 0, then R3 is not Cl, Br or F;
• and
• R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen and at least one is a selected radicals;
• wherein the radicals are selected from the group consisting of:
• g) a sulfur radical:
• —(S═(O)n)R2;
• wherein n is selected from 0, 1 or 2 and Rs is as defined previously;
• Rs is a group selected from the group consisting Of C1-4 alkyl, phenyl and heteroaryl (each of which is optionally mono- or di-substituted with Rq, as defined previously;
• wherein
• heteroaryl is a monocyclic aromatic hydrocarbon group) having five or six ring atoms, having at least one carbon atom which is the point of attachment, having from one to three carbon atoms replaced by N in the case of six ring atoms, having one carbon atom replaced by O, S or N in the case of five ring atoms and, optionally, having up to three additional carbon atoms replaced by N;
• Rq is selected from the group consisting of —OH, —OCH3, —CN, —C(O)NH2, —OC—(O)NH2, CHO, —OC(O)N(CH3)2, —SO2NH2, SO2N(CH3)2, —SOCH3, SO2CH3, —F, —CF3, —COOMa (wherein Ma is selected from the group consisting of hydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by Ma, as defined Previously) and —SO3Mb (wherein Mb is selected from the group consisting of hydrogen and an alkali metal);
• h) a sulfamoyl group:
• —SO2N(Ry)Rz;
• wherein Ry and Rz are as defined previously;
• Ry and Rz are independently selected from the group consisting of H, C1-4alkyl (optionally mono- or di-substituted by Rq, as defined Previously), a three to five membered diradical to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously) and a two to five membered diradical interrupted by —O—, —S—, —S(O)— or —S(O)2— to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously);
• n) a sulfonamido group:
• —(N—Rt)SO2Rs;
• wherein Rs and Rt are as defined previously;
• Rt is selected from the group consisting of H and C1-4alkyl;
• wherein the alkyl chain is optionally mono- or di-substituted by Rq, as defined previously;
• v) a thiocarbamoyl group:
• —(C═S)N(Ry)Rz;
• wherein Ry and Rz are as defined previously;
• x) a thiocyanate radical:
• —SCN;
• y) a trifluoromethylthio radical:
• —SCF3;
• z) a tetrazolyl radical;
• wherein the point of attachment is the carbon atom of the tetrazole ring and any one nitrogen atom is mono-substituted by a substituent selected from the group consisting of hydrogen, an alkali metal and a C1-4alkyl radical;
• wherein the C1-4alkyl radical is optionally mono- or di-substituted by Rq, as defined previously;
• ac) a C2-C4 alkenyl radical;
• wherein the radical is mono-substituted by a substituent selected from the group consisting of any one of g), h), n), x), y) and z )or is mono-substituted by substituents selected from the group consisting of phenyl, pyridyl, quinoline and isoquinoline;
• wherein each phenyl, pyridyl, quinoline or isoquinoline substituent is optionally mono- or di-substituted by Rq, as defined previously;
• ae) a C1-C4 alkyl mono-substituted by a substituent selected from the group consisting of any one of g), h), n), x), y) and z);
• ag) a C2-C4 alkynyl radical;
• wherein the radical is mono-substituted by a substituents selected from the group consisting of any one of g), h), n), x), y) and z) and trialkylsilyl;
• ah) phenyl radicals
• ai) bicyclic radicals;
• wherein the radical is independently selected from the group consisting of naphthyl, biphenyl, quinoline, indolizine, indole, isoindole, indoline, benzofuran, indazole, benzimidazole, purine, quinolizine, cinnoline, quinoxaline, phthalazine and quinazoline;
• aj) heterocyclic radicals;
• wherein the radical is independently selected from the group consisting of furyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl and isoquinolinyl;
• and
• ak) aryl and heteroaryl radicals;
• wherein the radical is independently selected from the group consisting of any one of ah) through aj);
• wherein the radical is substituted with one or two substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxy, C1-C6 thioalkyl, halogen, cyano, hydroxy, amino, nitro and C1-C6alkylamino, in which any terminal carbon atom may be replaced by a group selected from the group consisting of carboxyl and C2-C6alkoxycarbonyl;
• and pharmaceutically acceptable salts and esters thereof.

A pharmaceutical composition for treating a condition or a disease the pathogenesis of which may be regulated by modulation of the nicotinic acetylcholine receptor which comprises a biologically acceptable carrier or diluent and an effective amount of a compound of the following formula effective to treat a patient suffering from the condition or disease:

• wherein
• m is selected from 0, 1 or 2;
• p is selected from 0 or 1;
• Y is selected from the group consisting of O, S, S(O) and S(O)2;
• R1 is independently selected from the group consisting of H—, HO—, O—, C1-6alkyl—, C2-6alkenyl—, C2-6alkynyl—, C3-6cycloalkylC1-3alkyl—, phenylC1-3alkyl—, —C(O)C1-6alkyl, —C(O)phenyl, —C(O)C1-6alkylphenyl, —C(O)OC1-6alkyl, —C(O)Ophenyl, —C(O)NHC1-6alkyl, —C(O)N(C1-6alkyl)2 and —C(O)NHphenyl;
• wherein R1 is optionally substituted on a carbon atom with one to three Ra substituents;
• wherein Ra is independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxyC1-4alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F;
• R2 is independently selected from the group consisting of H, C1-6alkyl, phenyl and heteroaryl;
• wherein heteroaryl is as defined below;
• R3 is selected from the group consisting of H, C1-6alkyl, Cl, Br and F;
• with the proviso that if m is 0, then R3 is not Cl, Br or F;
• and
• R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen and at least one is a selected radicals;
• wherein the radicals are selected from the group consisting of:
• g) a sulfur radical:
• —(S═(O)n)—Rs;
• wherein n is selected from 0, 1 or 2 and Rs is as defined previously;
• Rs is a group selected from the group consisting of C1-4alkyl, phenyl and heteroaryl (each of which is optionally mono- or di-substituted with Rq, as defined previously);
• wherein
• heteroaryl is a monocyclic aromatic hydrocarbon group having five or six ring atoms, having at least one carbon atom which is the point of attachment, having from one to three carbon atoms replaced by N in the case of six ring atoms, having one carbon atom replaced by O, S or N in the case of five ring atoms and, optionally, having up to three additional carbon atoms replaced by N;
• Rq is selected from the group consisting of —OH, —OCH3, —CN, —C(O)NH2, —OC—(O)NH2, CHO, —OC(O)N(CH3)2, —SO2NH2, SO2N(CH3)2, —SOCH3, SO2CH3, —F, —CF3, —COOMa (wherein Ma is selected from the group consisting of hydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by Ma, as defined previously) and —SO3Mb (wherein Mb is selected from the group consisting of hydrogen and an alkali metal);
• h) a sulfamoyl group:
• —SO2N(Ry)Rz;
• wherein Ry and Rz are as defined previously;
• Ry and Rz are independently selected from the group consisting of H, C1-4alkyl (optionally mono- or di-substituted by Rq, as defined previously), a three to five membered diradical to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously) and a two to five membered diradical interrupted by —O—, —S—, —S(O)— or —S(O)2— to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously);
• n) a sulfonamido group:
• —(N—Rt)SO2Rs;
• wherein Rs and Rt are as defined previously;
• Rt is selected from the group consisting of H and C1-4alkyl;
• wherein the alkyl chain is optionally mono- or di-substituted by Rq, as defined previously;
• v) a thiocarbamoyl group:
• —(C═S)N(Ry)Rz;
• wherein Ry and Rz are as defined previously;
• x) a thiocyanate radical:
• —SCN;
• y) a trifluoromethylthio radical:
• —SCF3;
• z) a tetrazolyl radical;
• wherein the point of attachment is the carbon atom of the tetrazole ring and any one nitrogen atom is mono-substituted by a substituent selected from the group consisting of hydrogen, an alkali metal and a C1-4alkyl radical;
• wherein the C1-4alkyl radical is optionally mono- or di-substituted by Rq, as defined previously;
• ac) a C2-C4 alkenyl radical;
• wherein the radical is mono-substituted by a substituent selected from the group consisting of any one of g), h), n), x), y) and z) or is mono-substituted by substituents selected from the group consisting of phenyl, pyridyl, quinoline and isoquinoline;
• wherein each phenyl, pyridyl, quinoline or isoquinoline substituent is optionally mono- or di-substituted by Rq, as defined previously;
• ae) a C1-C4 alkyl mono-substituted by a substituent selected from the group consisting of any one of g), h), n), x), y) and z);
• ag) a C2-C4 alkynyl radical;
• wherein the radical is mono-substituted by a substituents selected from the group consisting of any one of g), h), n), x), y) and z) and trialkylsilyl;
• ah) phenyl radicals
• ai) bicyclic radicals;
• wherein the radical is independently selected from the group consisting of naphthyl, biphenyl, quinoline, indolizine, indole, isoindole, indoline, benzofuran, indazole, benzimidazole, purine, quinolizine, cinnoline, quinoxaline, phthalazine and quinazoline;
• aj) heterocyclic radicals;
• wherein the radical is independently selected from the group consisting of furyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl and isoquinolinyl;
• and
• ak) aryl and heteroaryl radicals;
• wherein the radical is independently selected from the group consisting of any one of ah) through aj);
• wherein the radical is substituted with one or two substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxy, C1-C6 thioalkyl, halogen, cyano, hydroxy, amino, nitro and C1-C6alkylamino, in which any terminal carbon atom may be replaced by a group selected from the group consisting of carboxyl and C2-C6alkoxycarbonyl;
• and pharmaceutically acceptable salts and esters thereof.