Benzothiophene compounds having antiinfective activity

Abstract

Benzothiophene compounds such as are DNA binding compounds exhibiting antibacterial activity.

1 . A compound of the formula 
       
         
           
           
               
               
           
         
         or the pharmaceutically acceptable salts thereof, 
         wherein 
         each R 5  is independently H, F, Cl, Br, I, CN, OH, NH 2 , a substituted or unsubstituted (C 1 -C 12 )alkyl group, a substituted or unsubstituted (C 1 -C 12 )alkoxy group, or a substituted or unsubstituted (C 1 -C 12 )heteroalkyl group; 
         m is an integer from 1 to 25, inclusive; 
         each Y is independently a branched or unbranched, substituted or unsubstituted (C 1 -C 5 )alkylene group or a substituted or unsubstituted, aromatic or heteroaromatic ring system, wherein the ring system comprises a 5- or 6-member aromatic or heteroaromatic ring or fused 6,6 or 6,5 aromatic or heteroaromatic rings, with the proviso that at least one Y is a substituted or unsubstituted aromatic or heteroaromatic ring system; 
         Z is either O or N; 
         n is 1 if Z is O and 2 if Z is N; and 
         each R 2  is independently H, a substituted or unsubstituted (C 1 -C 12 )alkyl group, or a substituted or unsubstituted (C 1 -C 12 )heteroalkyl group. 
       
     
     
         2 . A compound according to  claim 1 , having a basic group having a pK b  of 12 or less or a quaternized nitrogen group. 
     
     
         3 . A compound according to  claim 2 , wherein the residue Z(R 2 ) n  contains a basic group having a pK b  of 12 or less or a quaternized nitrogen group. 
     
     
         4 . A compound according to  claim 1 , wherein at least one Y is a 5- or 6-member heteroaromatic ring. 
     
     
         5 . A compound according to  claim 1 , wherein the residue 
       
         
           
           
               
               
           
         
         is 
       
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound according to  claim 5 , wherein each R 5  is H. 
     
     
         7 . A compound according to  claim 1 , wherein the residue 
       
         
           
           
               
               
           
         
         is 
       
       
         
           
           
               
               
           
         
         wherein the two R 6 's are both OH or OCH 3  or combine to form O—(CH(R 7 )) t —O, where t is 1 or 2 and each R 7  is independently H or a C 1 -C 6  alkyl, alkenyl, alkynyl, or acyl group. 
       
     
     
         8 . A compound according to  claim 1 , wherein the residue 
       
         
           
           
               
               
           
         
         is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound of the formula 
       
         
           
           
               
               
           
         
         or the pharmaceutically acceptable salts thereof, 
         wherein 
         m is an integer from 1 to 25, inclusive; 
         each moiety —(NH—Y—CO) m — is independently selected from the group consisting of 
         (a) moieties M 1  of the formula 
       
       
         
           
           
               
               
           
         
         wherein one of X 1 , X 2 , and X 3  is a ring vertex selected from the group consisting of —O—, —S—, and —NR 2 —, and the other two of X 1 , X 2 , and X 3  are ring vertices selected from the group consisting of ═N— and ═CR 1 —; 
         (b) moieties M 2  of the formula 
       
       
         
           
           
               
               
           
         
         wherein x is 0 or 1 and each R 15  is independently H, OH, NH 2 , or F; 
         (c) moieties M 3  of the formula 
       
       
         
           
           
               
               
           
         
         wherein each L is independently a divalent moiety separating —NH— and —(C═O)— by 3 or 4 atoms; and 
         (d) moieties M 4  of the formula 
       
       
         
           
           
               
               
           
         
         with the proviso that at least one moiety —(NH—Y—CO)— is a moiety M 1  or M 4 ; 
         Z is O or N; 
         n is 1 if Z is O and 2 if Z is N; 
         wherein in the preceding formulae 
         each R 1  is independently H, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , a substituted or unsubstituted (C 1 -C 12 )alkyl group, a substituted or unsubstituted (C 1 -C 12 )alkoxy group, or a substituted or unsubstituted (C 1 -C 12 )heteroalkyl group; 
         each R 2  is independently H, a substituted or unsubstituted (C 1 -C 12 )alkyl group, or a substituted or unsubstituted (C 1 -C 12 )heteroalkyl group; and 
         each R 5  is independently H, F, Cl, Br, I, CN, OH, NH 2 , a substituted or unsubstituted (C 1 -C 12 )alkyl group, or a substituted or unsubstituted (C 1 -C 12 )heteroalkyl group; 
         said compound having a basic group having a pK b  of 12 or less or a quaternized nitrogen group. 
       
     
     
         10 . A compound according to  claim 9 , wherein the residue Z(R 2 ) n  contains a basic group having a pK b  of 12 or less or a quaternized group. 
     
     
         11 . A compound according to  claim 9 , wherein at least one moiety —(NH—Y—CO)— is a moiety M 1 . 
     
     
         12 . A compound according to  claim 11 , wherein a moiety M 1  has a basic group having a pK b  of 12 or less or a quaternized nitrogen group. 
     
     
         13 . A compound according to  claim 9 , wherein the residue 
       
         
           
           
               
               
           
         
         is 
       
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound according to  claim 13 , wherein each R 5  is H. 
     
     
         15 . A compound according to  claim 9 , wherein the residue 
       
         
           
           
               
               
           
         
         is 
       
       
         
           
           
               
               
           
         
         wherein the two R 6 's are both OH or OCH 3  or combine to form O—(CH(R 7 )) t —O, where t is 1 or 2 and each R 7  is independently H or a C 1 -C 6  alkyl, alkenyl, alkynyl, or acyl group. 
       
     
     
         16 . A compound according to  claim 9 , wherein the residue 
       
         
           
           
               
               
           
         
         is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound according to  claim 9 , of the formula 
       
         
           
           
               
               
           
         
         wherein M 2 , M 3 , R 2 , R 5 , Z and n have the meanings assigned in  claim 5 ; each A is independently M 1  or M 4 ; each of a, c, e, g and h is an integer independently from 0 to 5, inclusive; and each of b, d, and f is independently 0 or 1, with the sum of a, c, e and g being at least 2. 
       
     
     
         18 . A compound according to  claim 9 , of the formula 
       
         
           
           
               
               
           
         
         wherein X 1 , X 2 , X 3 , R 2 , R 5 , Z, and n have the meanings assigned in  claim 5  and i is an integer from 2 to 4, inclusive. 
       
     
     
         19 . A compound according to  claim 18 , of the formula 
       
         
           
           
               
               
           
         
         wherein one R 8  is H and the other R 8  is H, F, CH 3 , NO 2 , or N(CH 3 ) 2 . 
       
     
     
         20 . A compound according to  claim 18 , of the formula 
       
         
           
           
               
               
           
         
         wherein R 9  is H or Cl. 
       
     
     
         21 . A compound according to  claim 18 , of the formula 
       
         
           
           
               
               
           
         
         wherein R 10  is Cl or H. 
       
     
     
         22 . A compound according to  claim 9 , of the formula 
       
         
           
           
               
               
           
         
         wherein M 1 , M 4 , R 2 , R 5 , Z and n are as assigned in  claim 5  and k is an integer from 0 to 2, inclusive. 
       
     
     
         23 . A compound according to  claim 9 , of the formula 
       
         
           
           
               
               
           
         
         wherein M 3 , R 2 , R 5 , Z and n have the meanings assigned in  claim 5 ; each B is independently M 1  or M 2 ; and p and q are independently integers from 1 to 7, inclusive. 
       
     
     
         24 . A compound according to  claim 9 , of the formula 
       
         
           
           
               
               
           
         
         wherein X 1 , X 2 , X 3 , M 2 , R 2 , R 5 , Z, and n have the meanings assigned in  claim 5  and each of r and s is independently 1 or 2. 
       
     
     
         25 . A method of treating a bacterial infection in a mammal, comprising administering to a patient in need of such treatment an effective amount of a compound according to  claim 1 . 
     
     
         26 . A method according to  claim 25 , wherein the bacterial infection is an infection by Gram-positive bacteria. 
     
     
         27 . A method according to  claim 25 , wherein the bacterial infection is an infection by drug resistant bacteria. 
     
     
         28 . A method according to  claim 27 , wherein the drug resistant bacteria is MRSA, MRSE, PRSP, or VSE. 
     
     
         29 . A method of treating a bacterial infection in a mammal, comprising administering to a patient in need of such treatment an effective amount of a compound according to  claim 9 . 
     
     
         30 . A method according to  claim 29 , wherein the bacterial infection is an infection by Gram-positive bacteria. 
     
     
         31 . A method according to  claim 29 , wherein the bacterial infection is an infection by drug resistant bacteria. 
     
     
         32 . A method according to  claim 29 , wherein the drug resistant bacteria is MRSA, MRSE, PRSP, or VSE. 
     
     
         33 . The use of a compound in accordance with  claim 1  for the preparation of a medicament for the treatment of a bacterial infection in a mammal. 
     
     
         34 . The use of a compound in accordance with  claim 9  for the preparation of a medicament for the treatment of a bacterial infection in a mammal.