Therapeutic compounds

Abstract

This invention to antagonists that inhibit transporters and receptors. The invention also relates to partial inhibitors of transporters and receptors that allow partial transport or partial binding of a compound to the transporter or receptor. The invention also relates to compounds that differentially prevent transport or binding through a transporter or to a receptor. The invention also relates to the use of these compounds for treating certain diseases and disorders.

1 . A compound comprising
 a) a ligand for a transporter or receptor and   b) a linker-acceptor moiety connected to the ligand, comprising
 1) an acceptor moiety that binds the transporter or receptor and 
 2) a linker which attaches the ligand to the acceptor moiety. 
   
   
   
       2 . The compound of  claim 1  wherein the linker comprises a cleavable bond, cleavage of which produces at least two components, (1) a barb comprised of the acceptor moiety and (2) the ligand, wherein the ligand is released from the compound. 
   
   
       3 . The compound of  claim 2  wherein the cleavable bond is an ether, thioether or amino or bond. 
   
   
       4 . The compound of  claim 1  wherein the acceptor moiety is a radical acceptor. 
   
   
       5 . The compound of  claim 1  wherein the acceptor moiety is an epoxide or an alkenyl moiety. 
   
   
       6 . (canceled) 
   
   
       7 . The compound of  claim 1 , wherein the transporter is a monoamine transporter and the acceptor moiety binds the monoamine transporter. 
   
   
       8 . The compound of  claim 1  wherein the compound comprises a ligand for at least one transporter selected from the dopamine, norepinephrine and serotonin transporters. 
   
   
       9 . The compound of  claim 1  in which the ligand binds at least one receptor selected from the dopamine, norepinephrine and serotonin receptors. 
   
   
       10 . The compound of  claim 1  wherein the ligand comprises a tropane and the monoamine transporter is the dopamine transporter. 
   
   
       11 . The compound of  claim 1  wherein the ligand comprises a tropane moiety and the monoamine transporter is the serotonin transporter. 
   
   
       12 .- 14 . (canceled) 
   
   
       15 . The compound of  claim 1  wherein the monoamine transporter is DAT. 
   
   
       16 .- 17 . (canceled) 
   
   
       18 . The compound of  claim 1 , wherein the ligand has the following Formula 1: 
     
       
         
         
             
             
         
       
     
     Where:
 the 2-, 3-, 6-, or 7-positions are α or β; 
 the compounds are racemic or 1R- or 1S-configured; 
 X═O, NR 3 , NR 9 , CHR 3 , CHR 1 , CH 2 , CHW 1 , CW 1 W 1 , CO, S, SO, SO 2 , NSO 2 R 3 , NSO 2 R 1  or CX 2 W, with the N, C, O or S atom being a member of the ring; 
 Ar=Phenyl or 1-naphththyl or 2-naphthyl, unsubstituted or substituted with one or more group selected from: —H; —Br; —Cl; —I; —F; —OH; —CH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —C(CH 2 )CH 3 , (CH 2 ) q CH 3 , where q=0-6; —COCH 3 ; alkyl; alkenyl; alkynyl; allyl; isopropyl; isobutyl; wherein each substitutent can be at the 2, 3 and/or 4 position of the ring; 
 W or X 2 ═H, OH, OCH 3 , OAc, OCOR 4 , CH 3 , (CH 2 ) n CH 3 , R 4 ; 
 W 1 ═H, Br, Cl, I, F, OH, OCH 3 , CF 3 , NO 2 , NH 2 , CN, NHCOCH 3 , N(CH 3 ) 2 , (CH 2 ) n CH 3 , COCH 3 , or C(CH 3 ) 3 ; 
 X 1 ═NR 3 , CH 2 , CHR 4 , CR 3 R 4 , CO, O, S; SO, SO 2 , NSO 2 R 1 , or NSO 2 R 3 ; 
 R 1 ═H, COOCH 3 , COOR 4 , COR 4 , CH 2 OH, (CH 2 ) n OH, (CH 2 ) n OR 4 , CR 3 ═NOR 3 , CH═NR 3 ; 
 R 2 ═H, OH, OCOR 4 , OCOR 5 , where R 5  is not F, Cl; 
 R 3 ═H, CH 3 , CH 2 Ar, (CH 2 ) n Ar, Ar, lower alkyl, lower alkenyl or lower alkynyl; CH 2 CH═CHZ, (CH 2 ) n OH, (CH 2 ) n OR 4 , CH═CHZ; CH 2 J-Maleimide, CH 2 JN-Maleimide where J=CH 2  or O; (CH 2 ) n OCOCH 3 ; (CH 2 ) n OCOCH 2 OCH 3 ; (CH 2 ) n -morpholine; (CH 2 ) n -piperidine; (CH 2 ) n -piperazine; 
 R 4 ═CH 3 , CH 2 CH 3 , alkyl, alkenyl, alkynyl, allyl, isopropyl, isobutyl; 
 R 9 ═H, COOCH 3 , COOR 4 , COR 4 , CH 2 OH, (CH 2 ) n OH, (CH 2 ) n OR 4 ; 
 n=0-4; 
 m=0-4; and 
 Z=F, Cl, I or Br. 
 
   
   
       19 . The compound of  claim 1 , where the linker-acceptor moiety is selected from the following: (CH 2 ) n OCH 2 CH═CH 2 ; COD(CH 2 ) n CH═CH 2 ; (CH 2 ) n D(CH 2 ) m CH═CH 2 ; (CH 2 ) n SCH 2 CH═CH 2 ; (CH 2 ) n OCH 2 (CH 2 ) n CH═CH 2 ; (CH 2 ) n CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH—(O:epoxide)-CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCO(CH 2 ) m OCH 3 ; (CH 2 ) n OCOCH(CH 3 ) 3 ; (CH 2 ) n OCO(CH 2 ) m CH(CH 3 ) 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCOCH 2 CH(R 2 ) 2 ; (CH 2 ) n OCOCHR 4 CH(R 2 ) 2 ; (CH 2 ) n OCOCHCHR 2 ; (CH 2 ) n OCHCH(R 2 ) 2 ; (CH 2 ) n J-Maleimide, (CH 2 ) n JN-Maleimide; COO(CH 2 ) m -Maleimide; (CH 2 ) n OCOCH 3 ; (CH 2 ) n OCOCH 2 OCH 3 ; 
     
       
         
         
             
             
         
       
     
     or a linker acceptor construct comprising Linker and Acceptor; where D=CH 2 , (CH 2 ) p , O, S, NH, SO and SO 2 ; J=CH 2  or O; n=0-4; m=0-4; p=0-3. 
   
   
       20 . The compound of  claim 18 , where the linker-acceptor moiety is selected from the following: (CH 2 ) n OCH 2 CH═CH 2 ; COD(CH 2 ) n CH═CH 2 ; (CH 2 ) n D(CH 2 ) m CH═CH 2 ; (CH 2 ) n SCH 2 CH═CH 2 ; (CH 2 ) n OCH 2 (CH 2 ) n CH═CH 2 ; (CH 2 ) n CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH—(O:epoxide)-CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCO(CH 2 ) m OCH 3 ; (CH 2 ) n OCOCH(CH 3 ) 3 ; (CH 2 ) n OCO(CH 2 ) m CH(CH 3 ) 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCOCH 2 CH(R 2 ) 2 ; (CH 2 ) n OCOCHR 4 CH(R 2 ) 2 ; (CH 2 ) n OCOCHCHR 2 ; (CH 2 ) n OCHCH(R 2 ) 2 ; (CH 2 ) n J-Maleimide, (CH 2 ) n JN-Maleimide; COO(CH 2 ) m -Maleimide; (CH 2 ) n OCOCH 3 ; (CH 2 ) n OCOCH 2 OCH 3 ; 
     
       
         
         
             
             
         
       
     
     or a linker acceptor construct comprising Linker and Acceptor; where D=CH 2 , (CH 2 ) p , O, S, NH, SO and SO 2 ; J=CH 2  or O; n=0-4; m=0-4; p=0-3; wherein the linker-acceptor moiety is at one or two of R 1 , R 2 , R 3 , R 4 , or Ar; 
   
   
       21 . The compound according to  claim 1 , wherein the Linker comprises 
     
       
         
         
             
             
         
       
       A and/or B are each individually ═—(CH 2 ) n -D-(CH 2 ) m —; 
       D=CH 2 , (CH 2 ) p , O, S, NH, SO and SO 2 ; 
       where R 5 , R 6  and R 7  are each individually H, CH 3 , (CH 3 ) 2 , (CH 2 ) n SO 3 Q, alkyl, (alkyl) 2 , alkenyl, alkynyl, Ar, F, Cl, OCH 3 ; 
       Q=K + , Na + , Li + , Ca 2+ , NH 4   + , RNH 3   + , or other pharmaceutically acceptable salts; 
       n=0-4; 
       m=0-4; and 
       p=0-3. 
     
   
   
       22 . The compound according to  claim 1 , wherein the Linker is selected from —(CH 2 ) n —O—(CH 2 ) m —, —(CH 2 ) n OCO(CH 2 ) m —, —(CH 2 ) n COO(CH 2 ) m —, —(CH 2 ) n S(CH 2 ) m —, where n and m=0-4. 
   
   
       23 . The compound of  claim 1 , wherein the Acceptor is selected from the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where A is —(CH 2 ) n -D-(CH 2 ) m —;
 D=CH 2 , (CH 2 ) p , O, S, NH, SO and SO 2 ; 
 R 5  is H, CH 3 , (CH 3 ) 2 , (CH 2 ) n SO 3 Q, alkyl, (alkyl) 2 , alkenyl, alkynyl, Ar, F, Cl, OCH 3 ; and Q=K + , Na + , Li + , Ca 2+ , NH 4   + , RNH 3   + , or other pharmaceutically acceptable salts. 
 
   
   
       24 . The compound of  claim 1 , wherein the Acceptor is selected from the following structures: —CH 2 CH═CH 2 ; 
     
       
         
         
             
             
         
       
     
   
   
       25 . The compound of  claim 1 , having the following structure: 
     
       
         
         
             
             
         
       
     
     Where:
 the 2-, 3-, 6-, or 7-positions are α or β; 
 the compounds are racemic or 1R- or 1S-configured; 
 X═O, NR 3 , NR 9 , CHR 3 , CHR 1 , CH 2 , CHW 1 , CW 1 W 1 , CO, S, SO, SO 2 , NSO 2 R 3 , NSO 2 R 1  or CX 2 W, with the N, C, O or S atom being a member of the ring; 
 Ar=Phenyl or 1-naphththyl or 2-naphthyl, unsubstituted or substituted with one or more group selected from: —H; —Br; —Cl; —I; —F; —OH; —OR 4 ; —CH 3 ; —CF 3 ; —NO 2 ; —NH 2 ; —CN; —NHCOCH 3 , —C(CH 3 ) 3 , —C(CH 2 )CH 3 , (CH 2 ) q CH 3 , where q=0-6; —COCH 3 ; alkyl; alkenyl; alkynyl; allyl; isopropyl; isobutyl; wherein each substitutent can be at the 2, 3 and/or 4 position of the ring; 
 W or X 2 ═H, OH, OCH 3 , OAc, OCOR 4 , CH 3 , (CH 2 ) n CH 3 , R 4 ; 
 W 1 ═H, Br, Cl, I, F, OH, OCH 3 , CF 3 , NO 2 , NH 2 , CN, NHCOCH 3 , N(CH 3 ) 2 , (CH 2 ) n CH 3 , COCH 3 , or C(CH 3 ) 3 ; 
 X 1 ═NR 3 , CH 2 , CHR 4 , CR 3 R 4 , CO, O, S; SO, SO 2 , NSO 2 R 1 , or NSO 2 R 3 ; 
 R 1 ═H, COOCH 3 , COOR 4 , COR 4 , CH 2 OH, (CH 2 ) n OH, (CH 2 ) n OR 4 , CR 3 ═NOR 3 , CH═NR 3 ,R 8 ; 
 R 2 ═H, OH, OCOR 4 , R 8 , OCOR 5 , where R 5  is not F, Cl; 
 R 3 ═H, CH 3 , CH 2 Ar, (CH 2 ) n Ar, R 8 , Ar, lower alkyl, lower alkenyl or lower alkynyl; CH 2 CH═CHZ, (CH 2 ) n OH, (CH 2 ) n OR 4 , CH═CHZ; CH 2 J-Maleimide, CH 2 JN-Maleimide where J=CH 2  or O; (CH 2 ) n OCOCH 3 ; (CH 2 ) n OCOCH 2 OCH 3 ; (CH 2 ) n -morpholine; (CH 2 ) n -piperidine; (CH 2 ) n -piperazine; 
 R 4 ═CH 3 , CH 2 CH 3 , alkyl, alkenyl, alkynyl, allyl, isopropyl, isobutyl, R 8 ; 
 R 9 ═H, COOCH 3 , COOR 4 , COR 4 , CH 2 OH, (CH 2 ) n OH, (CH 2 ) n OR 4 , R 8 ; 
 
     R 8 ═(CH 2 ) n OCH 2 CH═CH 2 ; COD(CH 2 ) n CH═CH 2 ; (CH 2 ) n D(CH 2 ) m CH═CH 2 ; (CH 2 ) n SCH 2 CH═CH 2 ; (CH 2 ) n OCH 2 (CH 2 ) n CH═CH 2 ; (CH 2 ) n CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH═CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH—(O:epoxide)-CH 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCO(CH 2 ) m OCH 3 ; (CH 2 ) n OCOCH(CH 3 ) 3 ; (CH 2 ) n OCO(CH 2 ) m CH(CH 3 ) 2 ; (CH 2 ) n OCO(CH 2 ) m CH 3 ; (CH 2 ) n OCOCH 2 CH(R 2 ) 2 ; (CH 2 ) n OCOCHR 4 CH(R 2 ) 2 ; (CH 2 ) n OCOCHCHR 2 ; (CH 2 ) n OCHCH(R 2 ) 2 ; (CH 2 ) n J-Maleimide, (CH 2 ) n JN-Maleimide; COO(CH 2 ) m -Maleimide; (CH 2 ) n OCOCH 3 ; (CH 2 ) n OCOCH 2 OCH 3 ; 
     
       
         
         
             
             
         
       
     
     or a linker acceptor construct comprising Linker and Acceptor;
 D=CH 2 , (CH 2 ) p , O, S, NH, SO and SO 2 ; 
 Wherein R 8  is at one or two of R 1 , R 2 , R 3 , R 4 , or Ar; 
 n=0-4; m=0-4; p=0-3; and 
 Z=F, Cl, I or Br. 
 
   
   
       26 .- 31 . (canceled) 
   
   
       32 . The compound according to  claim 1 , wherein the Linker is selected from the following structures: 
     
       
         
         
             
             
         
       
     
     where A and B are each individually ═—(CH 2 ) n -D-(CH 2 ) m —;
 D=CH 2 , (CH 2 ) p , O, S, NH, SO and SO 2 ; 
 
     and the Acceptor is selected from the following structures: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where R 5 , R 6  and R 7  are each individually H, CH 3 , (CH 3 ) 2 , (CH 2 ) n SO 3 Q, alkyl, (alkyl) 2 , alkenyl, alkynyl, Ar, F, Cl, OCH 3 ;
 Q=K + , Na + , Li + , Ca 2+ , NH 4   + , RNH 3   + , or other pharmaceutically acceptable salts; 
 n=0-4; 
 m=0-4; and 
 p=0-3. 
 
   
   
       33 . The compound according to  claim 18  wherein Ar is a phenyl substituted with 3,4-diCl; 3-Cl,4-C(CH 2 )CH 3 ; 3-Br,4-C(CH 2 )CH 3 ; 3-I,4-C(CH 2 )CH 3 ; 4-Cl,3-C(CH 2 )CH 3 ; 4-Br,3-C(CH 2 )CH 3 ; 4-I,3-C(CH 2 )CH 3 ; 3,4-diOH; 3,4-diOAc; 3,4-diOCH 3 ; 3-OH,4-Cl; 3-OH,4-F; 3-Cl,4-OH; or 3-F,4-OH. 
   
   
       34 . (canceled) 
   
   
       35 . The compound of  claim 1  wherein the compound has Formula 1 and X is selected from N—R 3  or O. 
   
   
       36 . (canceled) 
   
   
       37 . (canceled) 
   
   
       38 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
     pent-4-enoic acid-(3α-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]oct-2β-yl)lmethyl ester (O-1893); 
     2β-carbomethoxy-3β-(4-fluorophenyl)-8-[2-(3-oxiranylpropionyloxy)ethyl)-8-azabicyclo[3.2.1]octane (O-1899); 
     3α-(3,4-dichlorophenyl)-2β-pent-4-enyloxymethyl-8-oxabicyclo[3.2.1]octane (O-2153); 
     3-Methylbutanoic acid-[3α-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]oct-2′-yl]methyl ester (O-2059); 
     Pentanoic acid-[3α-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]oct-2β-yl]methyl ester (O-2102); 
     3-Oxiranyl-propionic acid [3α-(3,4-dichlorophenyl)-8-oxabicyclo[3.2.1]oct-3β-yl[methyl ester (O-1834); 
     2β-Carbomethoxy-3β-(4-fluorophenyl)-8-(3-methoxy acetoxypropyl)-8-azabicyclo[3.2.1]octane (O-1071); 
     2β-Carbomethoxy-3β-(4-fluorophenyl)-8-(2-acetoxyethyl)-8-azabicyclo[3.2.1]octane (O-1103); and 
     2β-Carbomethoxy-3β-(4-fluorophenyl)-8-(2-maleimidoethyl)-8-azabicyclo[3.2.1]octane (O-1233). 
   
   
       39 .- 46 . (canceled) 
   
   
       47 . (canceled) 
   
   
       48 . The compound of  claim 1 , wherein the linker-acceptor construct is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       where R 5 , R 6 , and R 7  are each selected from H, CH 3 , (CH 3 ) 2 , alkyl, (alkyl) 2 , alkenyl, alkynyl, aryl (Ar), F, Cl, OCH 3 ; 
       n=0-4; 
       m=0-4. 
     
   
   
       49 . The compound according to  claim 1 , wherein the linker acceptor comprises: —(CH 2 ) n CH═CH 2 ; —CH 2 —O—(CH 2 ) n CH═CH 2 ; —CH 2 OCO(CH 2 ) n CH═CH 2 ; 
     
       
         
         
             
             
         
       
     
   
   
       50 . A method of affecting a patient's response to a substance that acts at a transporter or a receptor, the method comprising administering to the patient 1) an effective amount of a compound according to  claim 1   2) a pharmaceutically acceptable carrier.   
   
   
       51 . A pharmaceutical composition comprising a compound according to  claim 1  in a pharmaceutically acceptable carrier. 
   
   
       52 . A method of inhibiting binding of cocaine to the DAT comprising administering an effective amount of a compound according to  claim 1 , wherein the transport of dopamine is not completely inhibited. 
   
   
       53 . A method of controlling the binding of serotonin to the SERT comprising administering an effective amount of a compound according to  claim 1  in a pharmaceutically acceptable carrier, wherein the transport of serotonin is not completely inhibited. 
   
   
       54 . A method of treating depression comprising administering an effective amount of a compound according to  claim 1  in a pharmaceutically acceptable carrier wherein the compound alters the transport of serotonin which is not completely inhibited. 
   
   
       55 . A method of inhibiting transport of neurotoxins by the DAT comprising administering an effective amount of a compound according to  claim 1 , wherein the ligand is released from the compound, wherein the transport of dopamine is not inhibited. 
   
   
       56 . A method of treating Parkinsonism comprising administering an effective amount of a compound according to  claim 1  in a pharmaceutically acceptable carrier, wherein the compound inhibits transport of neurotoxins by the DAT and the transport of dopamine is minimally inhibited. 
   
   
       57 . A method of treating attention deficit disorder, attention deficit hyperactivity disorder or autism comprising administering an effective amount of a compound according to  claim 1  in a pharmaceutically acceptable carrier, wherein the compound alters the transport of serotonin which is not completely inhibited. 
   
   
       58 . A method of treating obsessive compulsive disorder comprising administering an effective amount of a compound according to  claim 1  in a pharmaceutically acceptable carrier, wherein the compound alters the transport of serotonin which is not completely inhibited.