Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects

Abstract

The present invention provides compositions and methods of using stereospecific benzodiazepine derivatives, their salts and prodrugs for the treatment of anxiolytic or convulsant disorders having the side effects of reduced alcohol craving in human alcoholics and a concomitant reduced sedative, hypnotic, muscle relaxant and ataxic side-effects. The invention further provides pharmaceutical compositions for treatment of anxiolytic and convulsant disorders in subjects in need thereof, comprising a compound, prodrug or a salt having a chemical structure represented by any one of Formula I-IV, VI-XI, XV-XVIII and XX-XXI and a pharmaceutically-acceptable carrier.

1 . A compound of formula I, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  is one of H, CH 3 , C 2 H 4 N(C 2 H 5 ) 2 , CH 2 CF 3 , CH 2 CCH or an alkyl cyclopropyl; R 2  is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position; R 3  is R or S and is CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3 , or COOC 2 H 5 . 
   
   
       2 . The compound of  claim 1  wherein the compound is of formula XX, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where R is H, Si(CH 3 ) 3 ; X′ is F, Cl, Br, or NO 2  and R 3  is R or S and one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       3 . A compound of formula II, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  is one of H, CH 3 , C 2 HN(C 2 H 5 ) 2 , CH 2 CF 3 , CH 2 CCH or an alkyl cyclopropyl; R 2  is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position and R 3  is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       4 . A compound of formula III, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
 R 2  is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position and R 3  is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
 
   
   
       5 . A compound of formula IV, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  is one of H, CH 3 , C 2 H 4 N(C 2 H 5 ) 2 , CH 2 CF 3 , CH 2 CCH, or an alkyl cyclopropyl; R 2  is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position and R 3  is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 ; and A is an ethoxide or a propoxide. 
   
   
       6 . A compound of formula VI, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
 R 1  is one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , or cyclopropyl; R 2  is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position; R 6  is a branched or straight chain C 1  to C 4  alkyl or a methyl cyclopropyl; R 7  (R and/or S) is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
 
   
   
       7 . A compound of formula VII, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where the compound has E or Z isomers; and where Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si (CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 2  is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position; R 3  is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       8 . A compound of formula VIII, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where X is N or CH; Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  is H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3 , or cyclopropyl; R 2  is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position and R 3  is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       9 . The compound of  claim 8  wherein the compound is of formula XXI, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where R is H, Si(CH 3 ) 3 ; X′ is F, Cl, Br, or NO 2  and R 3  is R or S and one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       10 . A compound of formula IX, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where n is 0 to 4; Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl;
 Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8)′ position with at least the substituent 
 —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CF 3 , CH 2 CH 3 , or cyclopropyl; R 2  and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position and R 3  or R′ 3  (R and/or S) is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
 
   
   
       11 . A compound of formula X, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8)′ position with at least the substituent
 —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3  or cyclopropyl; R 2  and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position; B is O or NH and wherein —BCH 2 B— is optionally replaced with —N(R 7 )—N(R 7 )—, where R 7  is one of H, CH 3 , alkyl, or cycloalkyl and R 3  or R′ 3  is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
 
   
   
       12 . A compound of formula XI, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where n is 1 or 2; Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent —C≡C—R, where R is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; Y′ and Z′ are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8)′ position with at least the substituent
 —C≡C—R′, where R′ is H, Si(CH 3 ) 3 , t-butyl, isopropyl, methyl, or cyclopropyl; R 1  and R 1 ′ are independently one of H, CH 3 , CF 3 , CH 2 CH 3 , CH 2 CF 3  or cyclopropyl; R 2  and R 2 ′ are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO 2  at the 2′-position; B is O, NH, or —N(R 7 )—N(R 7 )—, where R 7  is one of H, CH 3 , alkyl, or cycloalkyl and R 3  or R′ 3  is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
 
   
   
       13 . A compound of formula XV, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where n is 1 or 2; R is H, SiMe 3 , tBu, CH 3 , methyl cyclopropyl, CF 3 , CCl 3 , CBr 3 ; Ar is phenyl, 2′-fluorophenyl, 2′-chlorophenyl, 2′-thienyl, 3′-thienyl, 2′-pyridyl, 2′-pyridyl N—O; X is N or CH; R′ is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       14 . A compound of formula XVI, or salt or prodrug thereof, 
     Formula XVI 
     
       
         
         
             
             
         
       
     
     where R is H, SiMe 3 , tBu, CH 3 , methyl cyclopropyl, CF 3 , CCl 3 , CBr 3 ; Ar is phenyl, 2′-fluorophenyl, 2′-chlorophenyl, 2′-thienyl, 3′-thienyl, 2′-pyridyl, 2′-pyridyl N—O; X is N or CH; R′ is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       15 . A compound of formula XVII, or salt or prodrug thereof, 
     Formula XVII 
     
       
         
         
             
             
         
       
     
     where R is H, SiMe 3 , tBu, CH 3 , methyl cyclopropyl, CF 3 , CCl 3 , CBr 3 ; Ar is phenyl, 2′-fluorophenyl, 2′-chlorophenyl, 2′-thienyl, 3′-thienyl, 2′-pyridyl, 2′-pyridyl N—O; Y is O, S, NHCH 3 ; R′ is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       16 . A compound of formula XVIII, or salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     where n is 0 or 1; R is H, SiMe 3 , tBu, CH 3 , methyl cyclopropyl, CF 3 , CCl 3 , CBr 3 ; Ar is phenyl, 2′-fluorophenyl, 2′-chlorophenyl, 2′-thienyl, 3′-thienyl, 2′-pyridyl, 2′-pyridyl N—O; Y is O, S, NHCH 3 ; R′ is R or S and is one of CH 3 , OH, OAc, OCON(CH 3 ) 2 , COOCH 3  or COOC 2 H 5 . 
   
   
       17 . A pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of compounds having a chemical structure of any one of Formulas I-IV, VI-XI, XV-XVIII and XX-XXI; and a pharmaceutically-acceptable carrier. 
   
   
       18 . A method of reducing anxiety in a subject in need thereof comprising of administering an effective amount of a benzodiazepine analog compound having a structure of any one of Formula I-IV, VI-XI, XV-XVIII and XX-XXI; a salt or prodrug thereof. 
   
   
       19 . A method of reducing convulsant disorders in a subject in need thereof comprising of administering an effective amount of a benzodiazepine analog compound having a structure of any one of Formula I-IV, VI-XI, XV-XVIII and XX-XXI; a salt or prodrug thereof. 
   
   
       20 . A method of reducing alcoholism in a subject in need thereof comprising of administering an effective amount of a benzodiazepine analog compound having a structure of any one of Formula I-IV, VI-XI, XV-XVIII and XX-XXI; a salt or prodrug thereof.