Pharmaceutical compositions and methods for use

Abstract

Pharmaceutical compositions include aryl substituted amine compounds, and in particular, carbon-linked aromatic azabicyclo compounds, and in particular, aromatic alkylene azabicyclo compounds and aromatic alkyl azabicyclo compounds.

That which is claimed is:  
     
         1 . A compound having a structure of the formula:  
       
         
           
           
               
               
           
         
       
       where the wavy line in the structure indicates that the bond can be a C—C or C═C bond; the dashed line in the structure indicates that the bond can be a C—C or C═C bond; and at least one of the wavy or dashed lines is a C—C bond; X, X ′  and X″ are individually nitrogen or carbon bonded to a species hereinafter defined as A ″ ; A, A ′  and A″ are individually substituent species characterized as having a sigma m value which is between about −0.3 and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E′, E″ and E′″ individually represent hydrogen, alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl; either E and E′ or E″ and E′″ and their associated carbon atom can combine to form a ring structure; either E and E″ or E′ and E′″ and their associated carbon atoms can combine to form a ring structure; j is an integer from 0 to 3; and Z represents a non-hydrogen substitutent.  
     
     
         2 . The compound of  claim 1  wherein X″ is nitrogen or carbon bonded to A″ wherein A″ is selected from the group consisting of NR′R″OR′ and NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic heterocyclic ring and an aromatic group-containing species.  
     
     
         3 . The compound of  claim 2  wherein A″ is selected from the group consisting of NH 2 , NHCH 3  or NC(CH 3 ) 2 .  
     
     
         4 . The compound of  claim 1  wherein A and A′ are selected from the groups consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR′, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl or an aromatic group-containing species.  
     
     
         5 . The compound of  claim 1  wherein the dashed line is a C═C bond.  
     
     
         6 . The compound of  claim 1  wherein the wavy line is a C═C bond and the compounds have E and Z forms.  
     
     
         7 . A compound having a structure of the formula:  
       
         
           
           
               
               
           
         
       
       where the wavy line in the structure indicates that the bond can be a C—C or C═C bond; the dashed line in the structure indicates that the bond can be a C—C or C═C bond; and at least one of the wavy or dashed lines is a C—C bond; X, X′ and X″ are individually nitrogen or carbon bonded to a species hereinafter defined as A″ A, A′ and A″ are individually substituent species characterized as having a sigma m value which is between about −0.3 and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E′, E″ and E′″ individually represent hydrogen, alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl; either E and E′ or E″ and E′″ and their associated carbon atom can combine to form a ring structure; either E and E″ or E′ and E′″ and their associated carbon atoms can combine to form a ring structure; j is an integer from 0 to 3; Z represents a non-hydrogen substitutent, t is 0, 1 or 2; w is an integer from 0 to 3; A IV  is a non-hydrogen substituent selected from the group consisting of alkyl, alkenyl, substituted alkenyl heterocyclyl, substituted heterocyclyl, cycloalkenyl, substituted cycloalkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl or an aromatic containing species.  
     
     
         8 . The compound of  claim 7  wherein X″ is nitrogen or carbon bonded to A″ wherein A″ is selected from the group consisting of NR′R″, OR′ and NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic heterocyclic ring and an aromatic group-containing species.  
     
     
         9 . The compound of  claim 8  wherein A″ is selected from the group consisting of NH 2 , NHCH 3  or NC(CH 3 ) 2 .  
     
     
         10 . The compound of  claim 7  wherein A and A′ are selected from the groups consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR′, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl or an aromatic group-containing species.  
     
     
         11 . The compound of  claim 7  wherein the dashed line is a C═C bond.  
     
     
         12 . The compound of  claim 7  wherein the wavy line is a C═C bond and the compounds have E and Z forms.  
     
     
         13 . A pharmaceutical composition incorporating a nicotinic antagonist, said composition comprising an amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       in association with a pharmaceutically acceptable carrier, wherein said amount is effective to interact with relevant nicotinic receptor sites of a patient where the wavy line in the structure indicates that the bond can be a C—C or C═C bond; the dashed line in the structure indicates that the bond can be a C—C or C═C bond; and at least one of the wavy or dashed lines is a C—C bond; X, X′ and X″ are individually nitrogen or carbon bonded to a species hereinafter defined as A″; A, A′ and A″ are individually substituent species characterized as having a sigma m value which is between about −0.3 and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E′, E″ and E′″ individually represent hydrogen, alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl; either E and E′ or E″ and E′″ and their associated carbon atom can combine to form a ring structure; either E and E″ or E′ and E′″ and their associated carbon atoms can combine to form a ring structure; j is an integer from 0 to 3; and Z represents a non-hydrogen substitutent.  
     
     
         14 . The pharmaceutical composition of  claim 13  wherein X″ is nitrogen or carbon bonded to A″ wherein A″ is selected from the group consisting of NR′R″, OR′ and NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic heterocyclic ring and an aromatic group-containing species.  
     
     
         15 . The pharmaceutical composition of  claim 14  wherein A″ is selected from the group consisting of NH 2 , NHCH 3  or NC(CH 3 ) 2 .  
     
     
         16 . The pharmaceutical composition of  claim 13  wherein A and A′ are selected from the groups consisting of H 1 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR′, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q  C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl or a non-aromatic heterocyclic ring, or an aromatic group-containing species.  
     
     
         17 . The pharmaceutical composition of  claim 13  wherein the dashed line is a C═C bond.  
     
     
         18 . The pharmaceutical composition of  claim 13  wherein the wavy line is a C═C bond and the compounds have E and Z forms.  
     
     
         19 . A pharmaceutical composition incorporating a nicotinic antagonist, said composition comprising an amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       in association with a pharmaceutically acceptable carrier, wherein said amount is effective to interact with relevant nicotinic receptor sites of a patient where the wavy line in the structure indicates that the bond can be a C—C or C═C bond; the dashed line in the structure indicates that the bond can be a C—C or C═C bond; and at least one of the wavy or dashed lines is a C—C bond; X, X I  and X II  are individually nitrogen or carbon bonded to a species hereinafter defined as A II ; A, A I  and A II  are individually substituent species characterized as having a sigma m value which is between about −0.3 and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E′, E″ and E′″ individually represent hydrogen, alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl; either E and E′ or E″ and E′″ and their associated carbon atom can combine to form a ring structure; either E and E″ or E′ and E′″ and their associated carbon atoms can combine to form a ring structure; j is an integer from 0 to 3; and Z represents a non-hydrogen substitutent, t is 0, 1 or 2, w is an integer from 0 to 3; A IV  is a non-hydrogen substituent selected from the group consisting of alkyl, alkenyl, substituted alkenyl heterocyclyl, substituted heterocyclyl, cycloalkenyl, substituted cycloalkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR′, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl or an aromatic group containing species.  
     
     
         20 . The pharmaceutical composition of  claim 19  wherein X″ is nitrogen or carbon bonded to A″ wherein A″ is selected from the group consisting of NR′R″OR′ and NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic heterocyclic ring and an aromatic group-containing species.  
     
     
         21 . The pharmaceutical composition of  claim 20  wherein A″ is selected from the group consisting of NH 2 , NHCH 3  or NC(CH 3 ) 2 .  
     
     
         22 . The pharmaceutical composition of  claim 19  wherein A and A′ are selected from the groups consisting of H 1 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl, a non-aromatic heterocyclic ring, or an aromatic group-containing species.  
     
     
         23 . The pharmaceutical composition of  claim 19  wherein the dashed line a is C═C bond.  
     
     
         24 . The pharmaceutical composition of  claim 19  wherein the wavy line is a C═C bond and the compounds have E and Z forms.  
     
     
         25 . A method of treating a disorder comprising administering to a subject having a disorder characterized by an alteration in normal neurotransmitter release an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       where the wavy line in the structure indicates that the bond can be a C—C or C═C bond; the dashed line in the structure indicates that the bond can be a C—C or C═C bond; and at least one of the wavy or dashed lines is a C—C bond; X, X′ and X″ are individually nitrogen or carbon bonded to a species hereinafter defined as A″; A, A′ and A″ are individually substituent species characterized as having a sigma m value which is between about −0.3 and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E′, E″ and E′″ individually represent hydrogen, alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl; either E and E′ or E″ and E′″ and their associated carbon atom can combine to form a ring structure; either E and E″ or E′ and E′″ and their associated carbon atoms can combine to form a ring structure; j is an integer from 0 to 3; and Z represents a non-hydrogen substitutent.  
     
     
         26 . The method of treating a disorder of  claim 25  whereby X″ is nitrogen or carbon bonded to A″ wherein A″ is selected from the group consisting of NR′R″, OR′ and NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic heterocyclic ring and an aromatic group-containing species.  
     
     
         27 . The method of treating a disorder of  claim 26  whereby A″ is selected from the group consisting of NH 2 , NHCH 3  or NC(CH 3 ) 2 .  
     
     
         28 . The method of treating a disorder of  claim 25  whereby A and A′ are selected from the groups consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR′, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl, a non-aromatic heterocyclic ring, or an aromatic group-containing species.  
     
     
         29 . The method of  claim 25  whereby the dashed line is a C═C bond.  
     
     
         30 . The method of  claim 25  whereby the wavy line is C═C bond and the compounds have E and Z forms.  
     
     
         31 . A method of treating a disorder comprising administering to a subject having a disorder characterized by an alteration in normal neurotransmitter release an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       where the wavy line in the structure indicates that the bond can be a C—C or C═C bond; the dashed line in the structure indicates that the bond can be a C—C or C═C bond; and at least one of the wavy or dashed lines is a C—C bond; X, X′ and X″ are individually nitrogen or carbon bonded to a species hereinafter defined as A″; A, A′ and A″ are individually substituent species characterized as having a sigma m value which is between about −0.3 and about 0.75; n is an integer from 0 to 3; m is 0, 1 or 2; p is 1 or 2; E, E′, E″ and E′″ individually represent hydrogen, alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl; either E and E′ or E″ and E′″ and their associated carbon atom can combine to form a ring structure; either E and E″ or E′ and E′″ and their associated carbon atoms can combine to form a ring structure; j is an integer from 0 to 3; and Z represents a non-hydrogen substitutent, t is 0 1  1 or 2, w is an integer from 0 to 3; A IV  is a non-hydrogen substituent selected from the group consisting of alkyl, alkenyl, substituted alkenyl heterocyclyl, substituted heterocyclyl, cycloalkenyl, substituted cycloalkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2 R′, OR′, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R′, (CR′R″) q C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen or alkyl.  
     
     
         32 . The method of treating a disorder of  claim 31  whereby X″ is nitrogen or carbon bonded to A″ wherein A″ is selected from the group consisting of NR′R″, OR′ and NO 2  wherein R′ and R″ are selected from the group consisting of hydrogen, alkyl, cycloalkyl, a non-aromatic heterocyclic ring and an aromatic group-containing species.  
     
     
         33 . The method of treating a disorder of  claim 32  whereby A″ is selected from the group consisting of NH 2 , NHCH 3  or NC(CH 3 ) 2 .  
     
     
         34 . The method of treating a disorder of  claim 31  whereby A and A′ are selected from the groups consisting of H 1 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, F, Cl, Br, I, NR′R″, CF 3 , OH, CN, NO 2 , C 2 R′, SH, SR′, N 3 , SO 2  R′, OR′, (CR′R″) q OR′, O—(CR′R″) q C 2 R′, SR′, C(═O)NR′R″, NR′C(═O)R″, C(═O)R″, (CR′R″) q  C 2 R′, C(═O)OR′, OC(═O)R′, OC(═O)NR′R″ and NR′C(═O)OR″ where q is an integer from 1 to 6 and R′ and R″ are individually hydrogen, alkyl, cycloalkyl, a non-aromatic heterocyclic ring, or an aromatic group-containing species.  
     
     
         35 . The method of treating a disorder of  claim 31  wherein the dashed line is a C═C bond.  
     
     
         36 . The method of treating a disorder of  claim 31  wherein the wavy line is a C═C bond and the compounds have E and Z forms.