Pharmaceutical compositions and methods for use

Abstract

Patients susceptible to or suffering from conditions and disorders, such as central nervous system disorders, are treated by administering to a patient in need thereof aryloxyalkylamines and arylthioalkylamines, including pyridyloxylalkylamines, phenoxyalkylamines, pyridylthiolalkylamines and phenylthioalkylamines. Exemplary compounds include (2-(5-bromo(3-pyridylthio))ethyl)methylamine, (2-(5-bromo(3-pyridylthio))isopropyl)methylamine, (2-(5-bromo(3-pyridylthio))propyl)methylamine, (3-(5-bromo(3-pyridylthio))propyl)methylamine, 3-((3S)-3-pyrrolidinyloxy)pyridine, 3-(4-piperidinyloxy)pyridine, 3-(1-methyl-4-piperidinyloxy)pyridine, (3-benzo[3,4-d]1,3-dioxolan-5-yloxypropyl)methylamine, and methyl(3-tricyclo[7.3.1.0<5,13>]tridec-2-yloxypropyl)amine.

That which is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       where X is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value between about −0.3 and about 0.75; X′ are individually nitrogen, N—O or carbon bonded to a substituent species characterized as having a sigma m value between about −0.3 and about 0.75; m is an integer and n is an integer such that the sum of m plus n is 1, 2, 3, 4, 5, 6, 7, or 8; Z′ and Z″ individually represent hydrogen or lower alkyl; E, E I , E II  and E III  individually represent hydrogen or a non-hydrogen substituent; or E and E I  or E II  and E III  and their associated carbon atom combine to form a ring structure; or E III  and E I , when located on immediately adjacent carbon atoms, and their associated carbon atoms combine to form a ring structure; A, A I  or A II  are individually hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and substituted arylalkyl functionalities; or adjacent substituents of A, A I  or A II , when X or X′ are carbon bonded to a substituent component, combine to form one or more saturated or unsaturated, carbocyclic or heterocyclic rings; and B′ is oxygen or sulfur.  
     
     
         2 . The compound of    claim 1   , wherein X′ is C—NR′R″, C—OR′ or C—NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, lower alkyl, aromatic group containing species and substituted aromatic group containing species.  
     
     
         3 . The compound of    claim 1   , wherein X′ is C—NH 2 , C—NHCH 2  or C—N(CH 3 ) 2 .  
     
     
         4 . The compound of    claim 1   , wherein zero, one or two of the substituents designated as E, E′, E″ and E′″ are non-hydrogen substituents.  
     
     
         5 . The compound of    claim 1   , wherein X′ is nitrogen.  
     
     
         6 . The compound of    claim 1   , wherein X is CH, CBr or COR.  
     
     
         7 . The compound of    claim 1   , wherein A, A′ and A″ are all hydrogen.  
     
     
         8 . The compound of    claim 1   , wherein E, E′, E″ and E′″ individually are hydrogen or lower alkyl.  
     
     
         9 . The compound of    claim 1   , wherein at least one of Z′ and Z″ are hydrogen.  
     
     
         10 . The compound of    claim 9   , wherein Z′ is hydrogen and Z″ is methyl.  
     
     
         11 . The compound of    claim 1   , selected from the group consiting of dimethyl(3-(3-pyridyloxy)propyl)amine, 2-(3-pyridyloxy)ethylamine, methyl(2-(3-pyridyloxy)ethyl)amine, dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, methyl(4-(3-pyridyloxy)butyl)amine, (3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine, methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine, (3-(5-chloro(3-pyridyloxy))propyl)methylamine, methyl(3-(6-methyl(3-pyridyloxy))propyl)amine, methyl(3-(2-methyl(3-pyridyloxy))propyl)amine, cyclopropyl(3-(3-pyridyloxy)propyl)amine, 3-(5-chloro-3-pyridyloxy)propylamine, methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine, ethyl(3-(3-pyridyloxy)propyl)amine, methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine, (methylethyl)(3-(3-pyridyloxy)propyl)amine, methyl(1-methyl-3-(3-pyridyloxy)propyl)amine, (3-(3-aminophenoxy)propyl)methylamine, methyl(3-(3-nitrophenoxy)propyl)amine, 3-(3-pyridyloxy)propylamine, 1-(3-chloropropoxy)-3-nitrobenzene, benzyl(3-(3-pyridyloxy)propyl)amine, dimethyl(3-(3-(methylamino)propoxy)phenyl)amine.  
     
     
         12 . The compound of    claim 1   , wherein carbon atoms associated with E and E′, E″ and E′″ or E′ and E′″ combine to form a ring structure selected from the group consisting of cyclopentyl, cyclohexyl, and cyclopentyl.  
     
     
         13 . A method of treating a central nervous system disorder comprising administering to a subject in need thereof, an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       where X is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value between about −0.3 and about 0.75; X′ are individually nitrogen, N—O or carbon bonded to a substituent species characterized as having a sigma m value between about −0.3 and about 0.75; m is an integer and n is an integer such that the sum of m plus n is 1, 2, 3, 4, 5, 6, 7, or 8; Z′ and Z″ individually represent hydrogen or lower alkyl; E, E I , E II  and E III  individually represent hydrogen or a non-hydrogen substituent; or E and E I  or E II  and E III  and their associated carbon atom combine to form a ring structure; or E III  and E I , when located on immediately adjacent carbon atoms, and their associated carbon atoms combine to form a ring structure; A, A I  or A II  are individually hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and substituted arylalkyl functionalities; or adjacent substituents of A, A I  or A II , when X or X′ are carbon bonded to a substituent component, combine to form one or more saturated or unsaturated, carbocyclic or heterocyclic rings; and B′ is oxygen or sulfur.  
     
     
         14 . The method of    claim 13   , whereby X′ is C—NR′R″, C—OR′ or C—NO 2  whereby R′ and R″ are selected from the group consisting of hydrogen, lower alkyl, aromatic group containing species and substituted aromatic-group containing species.  
     
     
         15 . The method of    claim 13   , whereby X′ is C—NH 2 , C—NHCH 2  or C—N (CH 3 ) 2 .  
     
     
         16 . The method of    claim 13   , whereby zero, one or two of the substituents designated as E, E′, E″ and E′″ are non-hydrogen substituents.  
     
     
         17 . The method of    claim 13   , whereby X′ is nitrogen.  
     
     
         18 . The method of    claim 13   , whereby X is CH, CBr or COR.  
     
     
         19 . The method of    claim 13   , whereby A, A′ and A″ are all hydrogen.  
     
     
         20 . The method of    claim 13   , whereby E, E′, E″ and E′″ individually are hydrogen or lower alkyl.  
     
     
         21 . The method of    claim 13   , whereby at least one of Z′ and Z″ are hydrogen.  
     
     
         22 . The method of    claim 21   , whereby Z′ is hydrogen and Z″ is methyl.  
     
     
         23 . The method of    claim 13   , the compound selected from the group consiting of dimethyl(3-(3-pyridyloxy)propyl)amine, 2-(3-pyridyloxy)ethylamine, methyl(2-(3-pyridyloxy)ethyl)amine, dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, methyl(4-(3-pyridyloxy)butyl)amine, (3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine, methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine, (3-(5-chloro(3-pyridyloxy))propyl)methylamine, methyl(3-(6-methyl(3-pyridyloxy))propyl)amine, methyl(3-(2-methyl(3-pyridyloxy))propyl)amine, cyclopropyl(3-(3-pyridyloxy)propyl)amine, 3-(5-chloro-3-pyridyloxy)propylamine, methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine, ethyl(3-(3-pyridyloxy)propyl)amine, methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine, (methylethyl)(3-(3-pyridyloxy)propyl)amine, methyl(1-methyl-3-(3-pyridyloxy)propyl)amine, (3-(3-aminophenoxy)propyl)methylamine, methyl(3-(3-nitrophenoxy)propyl)amine, 3-(3-pyridyloxy)propylamine, 1-(3-chloropropoxy)-3-nitrobenzene, benzyl(3-(3-pyridyloxy)propyl)amine, and dimethyl(3-(3-(methylamino)propoxy)phenyl)amine.  
     
     
         24 . The method of    claim 13   , whereby carbon atoms associated with E, E′, E″ and E′″ or E′ and E′″ combine to form a ring structure selected from the group consisting of cyclopentyl, cyclohexyl, and cyclopentyl.  
     
     
         25 . A pharmaceutical composition incorporating a compound of the formula:  
       
         
           
           
               
               
           
         
       
       where X is nitrogen or carbon bonded to a substituent species characterized as having a sigma m value between about −0.3 and about 0.75; X′ are individually nitrogen, N—O or carbon bonded to a substituent species characterized as having a sigma m value between about −0.3 and about 0.75; m is an integer and n is an integer such that the sum of m plus n is 1, 2, 3, 4, 5, 6, 7, or 8; Z′ and Z″ individually represent hydrogen or lower alkyl; E, E I , E II  and E III  individually represent hydrogen or a non-hydrogen substituent; or E and E I  or E II  and E III  and their associated carbon atom combine to form a ring structure; or E III  and E I , when located on immediately adjacent carbon atoms, and their associated carbon atoms combine to form a ring structure; A, A I  or A II  are individually hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and substituted arylalkyl functionalities; or adjacent substituents of A, A I  or A II , when X or X′ are carbon bonded to a substituent component, combine to form one or more saturated or unsaturated, carboxycyclic or heterocyclic rings; and B′ is oxygen or sulfur.  
     
     
         26 . The pharmaceutical composition of    claim 25   , wherein X′ is C—NR′R″, C—OR′ or C—NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, lower alkyl, aromatic group containing species and substituted aromatic-group containing species.  
     
     
         27 . The pharmaceutical composition of    claim 25   , wherein X′ is C—NH 2 , C—NHCH 2  or C—N(CH 3 ) 2 .  
     
     
         28 . The pharmaceutical composition of    claim 25   , wherein zero, one or two of the substituents designated as E, E′, E″ and E′″ are non-hydrogen substituents.  
     
     
         29 . The pharmaceutical composition of    claim 25   , wherein X′ is nitrogen.  
     
     
         30 . The pharmaceutical composition of    claim 25   , wherein X is CH, CBr or COR.  
     
     
         31 . The pharmaceutical composition of    claim 25   , wherein A, A′ and A″ are all hydrogen.  
     
     
         32 . The pharmaceutical composition of    claim 25   , wherein E, E′, E″ and E′″ individually are hydrogen or lower alkyl.  
     
     
         33 . The pharmaceutical composition of    claim 25   , wherein at least one of Z′ and Z″ are hydrogen.  
     
     
         34 . The pharmaceutical composition of    claim 33   , wherein Z′ is hydrogen and Z″ is methyl.  
     
     
         35 . The pharmaceutical composition of    claim 25   , the compound selected from the group consiting of dimethyl(3-(3-pyridyloxy)propyl)amine, 2-(3-pyridyloxy)ethylamine, methyl(2-(3-pyridyloxy)ethyl)amine, dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, methyl(4-(3-pyridyloxy)butyl)amine, (3-(5-chloro(3-pyridyloxy))-1-methylpropyl)methylamine, methyl(3-(5-(phenylmethoxy)(3-pyridyloxy))propyl)amine, (3-(5-chloro(3-pyridyloxy))propyl)methylamine, methyl(3-(6-methyl(3-pyridyloxy))propyl)amine, methyl(3-(2-methyl(3-pyridyloxy))propyl)amine, cyclopropyl(3-(3-pyridyloxy)propyl)amine, 3-(5-chloro-3-pyridyloxy)propylamine, methyl(3-(5-methoxy-3-pyridyloxy)propyl)amine, ethyl(3-(3-pyridyloxy)propyl)amine, methyl(3-(5-isopropoxy-3-pyridyloxy)propyl)amine, (methylethyl)(3-(3-pyridyloxy)propyl)amine, methyl(1-methyl-3-(3-pyridyloxy)propyl)amine, (3-(3-aminophenoxy)propyl)methylamine, methyl(3-(3-nitrophenoxy)propyl)amine, 3-(3-pyridyloxy)propylamine, 1-(3-chloropropoxy)-3-nitrobenzene, benzyl(3-(3-pyridyloxy)propyl)amine, and dimethyl(3-(3-(methylamino)propoxy)phenyl)amine.  
     
     
         36 . The pharmaceutical composition of    claim 25   , wherein carbon atoms associated with E, E′, E″ and E′″ or E′ and E′″ combine to form a ring structure selected from the group consisting of cyclopentyl, cyclohexyl, and cyclopentyl.