Pyrrolobenzodiazepines

Abstract

A compound with formula (I) where R 10 is a therapeutically removable nitrogen protecting group; R 2 and R 3 are independently selected from: H, R, OH, OR, ═O, ═CH—R, ═CH 2 , CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 —R, CO 2 R, COR and CN; R 6 , R 7 and R 9 are independently selected from H, R, OH, OR, halo, amino, nitro, Me 3 Sn; X is S, O or NH; R 11 is either H or R; and where there is optionally a double bond between C1 and C2 or C2 and C3; and R 8 is selected from H, R, OH, OR, halo, amino, nitro, Me 3 Sn, or R 7 and R 8 together form a group —O—(CH 2 ) p —O—, where p is 1 or 2. Such compounds may be used in methods of ADEPT, GDEPT, NPEPT or PDT.

1 . A compound with the formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 10  is a therapeutically removable nitrogen protecting group;  
 R 2  and R 3  are independently selected from: H, R, OH, OR, ═O, ═CH—R, ═CH 2 , CH 2 —CO 2 R, CH 2 —CO 2 H, CH 2 —SO 2 R, O—SO 2 —R, CO 2 R, COR and CN; R 6 , R 7  and R 9  are independently selected from H, R, OH, OR, halo, amino, nitro, Me 3 Sn; or R 7  and R 8  together form a group —O—(CH 2 )—O—, where p is 1 or 2.  
 X is S, O or NH;  
 R 11  is either H or R;  
 where R is a lower alkyl group having 1 to 10 carbon atoms, or an aralkyl group, of up to 12 carbon atoms, whereof the alkyl group optionally contains one or more carbon-carbon double or triple bonds, which may form part of a conjugated system, or an aryl group, of up to 12 carbon atoms; and is optionally substituted by one or more halo, hydroxy, amino, or nitro groups, and optionally contains one or more hetero atoms, which may form part of, or be, a functional group;  
 and where there is optionally a double bond between C1 and C2 or C2 and C3;  
 and R 8  is selected from H, R, OH, OR, halo, amino, nitro, Me 3 Sn, where R is as defined above, or the compound is a dimer with each monomer being the same or different and being of formula I, where the R 8  groups of the monomers form together a bridge having the formula -T-R′-T- linking the monomers, where R′ is an alkylene chain containing from 3 to 12 carbon atoms, which chain may be interrupted by one or more hetero atoms and/or aromatic rings, and may contain one or more carbon-carbon double or triple bonds, and each T is independently selected from O, S or N.  
 
     
     
         2 . A compound according to  claim 1 , wherein R 10  is of the formula II:  
       
         
           
           
               
               
           
         
       
       wherein n is 0 to 3, R (I)  is H or R, and R (II)  is one or more optional substituents independently selected from NO 2 , OR, or R, where R is as defined in  claim 1 , and if two substituents R (II)  are on adjacent atoms, they may together be of the formula —O—(CH 2 ) m —O— where m is 1 or 2.  
     
     
         3 . A compound according to either  claim 1  or  claim 2 , wherein R 10  is a photolabile protecting group.  
     
     
         4 . A compound according to  claim 3 , wherein R 10  is cleavable by light with a wavelength of 250 to 550 nm.  
     
     
         5 . A compound according to either  claim 1  or  claim 2  wherein R 10  is an enzyme labile group.  
     
     
         6 . A compound according to  claim 5 , wherein R 10  is a nitroreductase labile group.  
     
     
         7 . A compound according to  claim 5 , wherein R 10  is a penicillin V/G amidase labile group.  
     
     
         8 . A compound according to  claim 5 , wherein R 10  is a L-γ-glutamyl transpeptidase labile group.  
     
     
         9 . A compound according to  claim 5 , wherein R 10  is a glutathione transferase labile group.  
     
     
         10 . A compound according to  claim 6 , wherein R 10  is of the formula III:  
       
         
           
           
               
               
           
         
       
       wherein n is 0 to 3, R (I)  is H or R, and R (III)  is one or more optional substituents independently selected from NO 2 O, OR, or R, where R is as defined in  claim 1 , and if two substituents R (III)  are on adjacent atoms, they may together be of the formula —O—(CH 2 ) m —O— where m is 1 or 2.  
     
     
         11 . A compound according to  claim 9 , wherein R 10  is of the formula XI:  
       
         
           
           
               
               
           
         
       
       wherein R is as defined in  claim 1 , and n is 0 to 3.  
     
     
         12 . A compound according to  claim 11 , wherein R in the group formula XI is a substituted or unsubstituted phenyl group.  
     
     
         13 . A compound according to any one of the preceding claims, wherein X is O.  
     
     
         14 . A compound according to any one of the preceding claims, wherein R 11  is H.  
     
     
         15 . A compound according to any one of the preceding claims, wherein R 6  and R 9  are H.  
     
     
         16 . A compound according to  claim 15 , wherein R 7  and R 8  are independently selected from H, OH, and OR, where R is as defined in  claim 1 .  
     
     
         17 . A compound according to any one of the preceding claims, wherein the compound is a C8 dimer, wherein R 6  and R 9  are H, and R 7  is independently selected from H, OH, and OR, where R is as defined in  claim 1 .  
     
     
         18 . A compound according to any one of the preceding claims, wherein the compound is a C8 dimer, and R′ is —O—(CH 2 ) P —O—, where p is from 1 to 12.  
     
     
         19 . A method of preparing a compound of formula I as defined in any one of  claims 1  to  18  wherein XR 11 ≠OH from a compound of formula Ia:  
       
         
           
           
               
               
           
         
       
       wherein the substituents of the compound of formula Ia are the same as for the compound of formula I to be prepared.  
     
     
         20 . A method of preparing a compound of formula Ia as defined in  claim 19  by the oxidation of a compound of formula IVa:  
       
         
           
           
               
               
           
         
       
       wherein the substituents of the compound of formula IVa are the same as for the compound of formula Ia to be prepared.  
     
     
         21 . A method according to  claim 20 , wherein the oxidation is a Swern oxidation.  
     
     
         22 . A method of preparing a compound of formula IVa as defined in  claim 20 , by reacting a compound of formula Va:  
       
         
           
           
               
               
           
         
       
       with a compound of formula VI:  
       Y—R 10    (VI)  
       wherein the substituents of the compounds of formulae Va and VI are the same as for the compound of formula IVa to be prepared, and Y is a halogen atom.  
     
     
         23 . A method of preparing a compound of formula IVa according to  claim 20 , wherein the compound of formula VI is a haloformate of the formula Y-A, where A is a group of formula II as defined in  claim 2 .  
     
     
         24 . A method of making a compound of formula IVa as defined in  claim 20 , by reacting a compound of formula VII:  
       
         
           
           
               
               
           
         
       
       with a compound of formula VI:  
       Y—R 10    (VI)  
       to form a compound of formula VIII:  
       
         
           
           
               
               
           
         
       
       and then reacting the compound of formula VIII with a compound of formula IXa:  
       
         
           
           
               
               
           
         
       
       via the formation of an acid chloride, wherein the substituents for compounds of formulae VI, VII, VIII and IXa are the same as for the compound of formula Va to be prepared, and where Y is a halogen atom.  
     
     
         25 . A method of preparing a compound of formula Ia as defined in  claim 19  by the unmasking of a compound of formula IVb:  
       
         
           
           
               
               
           
         
       
       wherein the substituents of the compound of formula IVb are the same as for the compound of formula Ia to be prepared, Q is either O or S and R (IV)  is Me or Et, or together form —(CH 2 ) q — where q is 2 or 3.  
     
     
         26 . A method according to claim 25, wherein Q is S, R (iv)  is Et and the unmasking is mercury-mediated unmasking.  
     
     
         27 . A method according to  claim 25 , wherein Q is O, R (iv)  is Me and the unmasking is palladium-mediated unmasking.  
     
     
         28 . A method of preparing a compound of formula IVb as defined in  claim 25 , by reacting a compound of formula Vb:  
       
         
           
           
               
               
           
         
       
       with a compound of formula VI:  
       Y—R 10    (VI)  
       wherein the substituents of the compounds of formulae Vb and VI are the same as for the compound of formula IVb to be prepared, and Y is a halogen atom.  
     
     
         29 . A method of preparing a compound of formula IVb according to  claim 28 , wherein the compound of formula VI is a haloformate of the formula Y-A, where A is a group of formula II as defined in  claim 2 .  
     
     
         30 . A method of making a compound of formula IVb as defined in  claim 25 , by reacting a compound of formula VII:  
       
         
           
           
               
               
           
         
       
       with a compound of formula VI:  
       Y—R 10    (VI)  
       to form a compound of formula VIII:  
       
         
           
           
               
               
           
         
       
       and then reacting the compound of formula VIII with a compound of formula IXb:  
       
         
           
           
               
               
           
         
       
       via the formation of an acid chloride, wherein the substituents for compounds of formulae VI, VII, VIII and IXb are the same as for the compound of formula Vb to be prepared, and where Y is a halogen atom.  
     
     
         31 . A method of making a compound of formula X:  
       
         
           
           
               
               
           
         
       
       by the cleavage of the therapeutically removable protecting group R 10  of a compound of formula I as defined in any one of  claims 1  to  18 , wherein the substituent groups of the compound of formula X are the same as the substituent groups of compound I used.  
     
     
         32 . The use of a compound of formula I as defined in any one of  claims 5  to  8  or  10  in conjunction with an appropriate enzyme in methods of ADEPT or GDEPT therapy.  
     
     
         33 . The use of compounds of formula I as defined in any one of  claims 2  to  4  in conjunction with light of wavelengths between 250 and 550 nm in methods of PDT.  
     
     
         34 . The use of compounds of formula I as defined in  claim 9  or II in methods of NPEPT.  
     
     
         35 . A pharmaceutical composition comprising a compound of formula I as defined in any one of  claims 1  to  18  and a pharmaceutically acceptable carrier or diluent.  
     
     
         36 . The use of a compound of formula I as defined in any one of  claims 1  to  18  to prepare a medicament for the treatment of a neoplastic disease.  
     
     
         37 . The use of a compound of formula I as defined in any one of  claims 1  to  18  to prepare a medicament for the treatment of a bacterial, viral or parasitic infection.