N- and O-substituted 4-[2-(diphenylmethoxy)-ethyl]-1- (phenyl) methyl) piperidine analogs and methods of treating CNS disorders therewith
N- and O-substituted 4[2-diaromaticmethoxy and methylamino)alkyl]piperidines exhibit high CNS activity with respect to the dopamine transporter (DAT) and serotonin transporter (SERT). Preferred compounds exhibit highly differential behavior as between the DAT and SERT and between the DAT and the norepinephrine transporter (NET). The compounds have utility in treating CNS disorders, including but not limited to cocaine addiction, depression, and Parkinson's disease.
1. The compound having the structure:
and where X is selected from the group consisting of —NH—, —NR 4 —, and —O—;
R 4 is C 1-4 alkyl, NH 2 , C 1-4 hydroxyalkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 hydroxyalkenyl, halogenated C 2-4 alkenyl, C 2-4 and alkynyl;
Y is —H, —NH 2 , —OH, ═O, or —O—C(O)—R 5 ;
o is 0, 1, 2, 3, or 4;
p is 0, 1, 2, 3, or 4;
R and R 1 are selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO 2 , NH 2 , OR 5 , wherein R 5 is C 1-8 alkyl, C 5-6 cycloalkyl, or C 2-8 alkenyl or R 2 is a 5 or 6 membered heterocycle,
and where any carbon of CH 2 m may be substituted by OR 7 where R 7 is C 1-18 alkyl or C 2-18 alkylene, or
where R 8 is C 1-18 alkyl or C 2-18 alkylene,
and pharmaceutically acceptable salts and derivatives thereof.
2. The compound having the structure:
and where X is selected from the group consisting of —NH—, —NR 4 —, and —O—;
R 4 is C 1-4 alkyl, NH 2 , C 1-4 hydroxyalkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 hydroxyalkenyl, halogenated C 2-4 alkenyl, C 2-4 and alkynyl, andC 2-4 halogenated alkynyl;
Y is —H, —NH 2 , —OH, ═O, or —O—C(O)—R 5 ;
wherein R 5 is C 1-8 alkyl, C 5-6 cycloalkyl, or C 2-8 alkenyl or R 5 is a 5 or 6 membered heterocycle;
m is 1 or 2;
p is 0, 1, 2, 3, or 4;
R 1 is selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO 2 , NH 2 , OR 5 , and where any carbon of CH 2 m may be substituted by OR 7 where R 7 is C 1-18 alkyl or C 2-18 alkylene, or
where R 8 is C 1-18 alkyl or C 2-18 alkylene,
and pharmaceutically acceptable salts and derivatives thereof.
3. The compound having the structure:
R and R 2 are selected from the group consisting of H, F, Cl, Br, I, CN, COOEt, OH, NO 2 , NH 2 , OR 3 , wherein R 5 is C 1-8 alkyl, C 5-6 cycloalkyl, or C 2-8 alkenyl or R 3 is a 5 or 6 membered heterocycle,
and where the carbon of —(CH 2 )— linking group between N and B may be substituted by OR 7 where R 7 is C 1-18 alkyl or C 2-18 alkylene, or
where R 8 is C 1-18 alkyl or C 2-18 alkylene,
wherein R 9 is
wherein R 10 is C 6-20 alkyl, and pharmaceutically acceptable salts and derivatives thereof.