Tris-Quaternary Ammonium Salts and Methods for Modulating Neuronal Nicotinic Acetylcholine Receptors

A method for preventing and/or treating substance use and/or abuse

• comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound of Formula (I):
• wherein the substance use and/or abuse is selected from the group consisting of nicotine abuse, nicotine intoxication, cocaine abuse, and alcohol abuse;
• wherein the three side chains attached to the phenyl ring may be connected to the 1, 2, and 3 positions;
• the 1, 2, and 4 positions;
• or the 1, 3 and 5positions of the phenyl ring;
• wherein m1, m2 and m3 are each independently 0, 1, 2, 3, 4 or 5;
• wherein n1, n2, and n3 are each independently 1, 2, 3, 4, or 5;
• wherein X1 ⊖, X2⊖, and X3 ⊖are each independently an organic or inorganic anion;
• wherein L1, L2 and L3 are each independently chosen from the group consisting of —CH2—CH2—, cis —CH═CH—, trans —CH═CH—, —C≡C—, —CH2—S—, —S—CH2—, —Se—CH2—, —CH2—Se—, —CH2—O—, —O—CH2—, —CH2—NH—, —NH—CH2—, —CH2—NR — where R is a branched or straight chain alkyl group of one to four carbons, —NR—CH2— where R is a branched or straight chain alkyl group of one to four carbons, —CH═N—, —N═CH—, and —N═N—;
• wherein R1, R2, and R3 are each independently five or six membered nitrogen containing rings as shown in formulas (IIA) and (IIB)
• wherein A1 is carbon or nitrogen, provided that when A1 joins a ring atom with an unsaturated bond or is a nitrogen, R9 is absent, and when A1 joins a ring atom with an unsaturated bond and is a nitrogen, both R4 and R9 are absent;
• wherein A2 is carbon or nitrogen, provided that when A2 joins a ring atom with an unsaturated bond or is a nitrogen, R10is absent, and when A2 joins a ring atom with an unsaturated bond and is a nitrogen, both R5 and R10 are absent;
• wherein A3 is carbon or nitrogen, provided that when A3 joins a ring atom with an unsaturated bond or is a nitrogen, R11 is absent, and when A3 joins a ring atom with an unsaturated bond and is a nitrogen, both R6 and R11 are absent;
• wherein A4 is carbon or nitrogen, provided that when A4 joins a ring atom with an unsaturated bond or is a nitrogen, R12 is absent, and when A4 joins a ring atom with an unsaturated bond and is a nitrogen, both R7 and R12 are absent;
• wherein A5 is carbon or nitrogen, provided that when A5 joins a ring atom with an unsaturated bond or is a nitrogen, R13 is absent, and when A5 joins a ring atom with an unsaturated bond and is a nitrogen, both R8 and R13 are absent;
• wherein A6 is carbon or nitrogen, provided that when A6 joins a ring atom with an unsaturated bond or is a nitrogen, R19 is absent, and when A6 joins a ring atom with an unsaturated bond and is a nitrogen, both R15 and R19 are absent;
• wherein A7 is carbon or nitrogen, provided that when A7 joins a ring atom with an unsaturated bond or is a nitrogen, R20 is absent, and when A7 joins a ring atom with an unsaturated bond and is a nitrogen, both R16 and R20 are absent;
• wherein A8 is carbon or nitrogen, provided that when A8 joins a ring atom with an unsaturated bond or is a nitrogen, R21 is absent, and when A8 joins a ring atom with an unsaturated bond and is a nitrogen, both R17 and R21 are absent;
• wherein A9 is carbon or nitrogen, provided that when A9 joins a ring atom with an unsaturated bond or is a nitrogen, R22 is absent, and when A9 joins a ring atom with an unsaturated bond and is a nitrogen, both R18 and R22 are absent;
• wherein R14 or R23 is absent when any of the bonds to the ammonium nitrogen is unsaturated, and R14 or R23 is a straight chain or branched alkyl group of four carbons or fewer when all of the bonds to the ammonium nitrogen are saturated;
• wherein R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 or R15, R16, R17, R18, R19, R20, R21, and R22, when present, 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;
• halo;
• cyano;
• nitro;
• SOY1, SO2Y1, SO2OY1 or SO2NHY1, where Y1 is selected from hydrogen, lower alkyl, alkenyl, alkynyl or aryl, and where Y1 is not hydrogen in SOY1 and if Y1 is alkenyl or alkynyl, the site of unsaturation is not conjugated with a heteroatom;
• COY2, where Y2 is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y2 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the carbonyl group;
• OY3, where Y3 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, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, acyl, substituted acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y3 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the oxygen;
• NY4Y5, where Y4 and Y5 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, acyl, substituted acyl, alkylsulfonyl, arylsulfonyl, heterocyclic, or substituted heterocyclic, where if Y4 or Y5 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the nitrogen;
• SY6, where Y6 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, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heterocyclic, or substituted heterocyclic, and where if Y6 comprises alkenyl or alkynyl, the site of unsaturation is not conjugated with the sulfur;
• or R4 and R5 together with A1 and A2, or R5 and R6 together with A2 and A3, or R15 and R16 together with A6 and A7, or R16 and R17 together with A7 and A8 independently form a three to eight member cyclolkane, substituted cycloalkane, cycloalkene, substituted cycloalkene, aryl, substituted aryl, heterocycle with one to three hetero atoms in the ring, or substituted heterocycle with one to three hetero atoms in the ring.