Hif hydroxylase inhibitors

Abstract

The invention provides a compound of one of the formulae (A), (B), (C), (D), (E), (F) as herein defined, or a salt thereof, for use in the treatment of a condition associated with increased or decreased HIF levels or activity, or a condition in which an increase or decrease in HIF levels or activity may be beneficial.

1 . A compound of one of the formulae  
       
         
           
           
               
               
           
         
       
       where each of R 1  and R 5  is independently H, OH, SH, a branched or straight C 1  to C 6  alkyl chain optionally containing 1 or more N, S, O or P chain atoms, which can be functionalised, any amino acid side chain, a 4 to 7 membered heterocyclic ring optionally containing 1 or 2 N, S, O or P atoms or a 5 or 6 membered aromatic ring, optionally containing 1 or 2 N, O or S atoms which may be fused to another ring or a said alkyl chain substituted by a said aromatic ring, A 1  is CH 2  or O, and each of R 2  and R 3  is independently H, OH, a branched or straight C 1  to C 6  alkyl chain optionally containing 1 or more N, S, O or P chain atoms which can be functionalised, optionally with 1, 2, 3, 4 or 5 halo substitutions, a 4 to 7 membered heterocyclic ring optionally containing 1 or 2 N, S, O or P atoms, or a 5 or 6 membered aromatic ring, optionally containing 1 or 2 N, O or S atoms which may be fused to another ring or a said alkyl chain substituted by said aromatic ring,  
       
         
           
           
               
               
           
         
       
       wherein R 2  is as defined above,  
       
         
           
           
               
               
           
         
       
       is a single bond and T is CH 2  or C═O, or  
       
         
           
           
               
               
           
         
       
       is a double bond and T is CH; A 2  is H or —XCO 2 R 4 ; X is a single bond or a branched or straight C 1  to C 6  alkyl chain optionally containing 1 or more N, S, O or P chain atoms, and optionally substituted by halo, OH, OR 4 , NRR 2  or NHCOR 4  where R 2 , R 3  and R 4  are as defined above and R 4  represents H, a branched or straight chain C 1  to C 6  alkyl group, a 4 to 7 membered heterocyclic ring, optionally containing 1 or 2 N, S, O or P atoms, or a 5 or 6 membered aromatic ring, optionally containing 1 or 2 N, O or S atoms, which may be fused to another ring,  
       
         
           
           
               
               
           
         
       
       where each X which may be the same or different is NH, NR″, where R″ is OH, a branched or straight C 1  to C 6  alkyl chain optionally containing 1 or more eg. 2 N, S, O or P chain atoms which can be functionalised, or 0, each Y, which may be the same or different, is O or S and each R 1 , which may be the same or different, is as defined above,  
         Q-(CH 2 ) m —COOH  (D)  
       where m is 0 or 1, Q represents (CR 1 R 6 ) x Z where x is 0, 1 or 2, R 1  is as defined above and R 6  is as defined for R 1  and Z is P═O(OH) 2 , B(OH) 2  or SO 3 H, or a salt thereof, or  
       
         
           
           
               
               
           
         
       
       where each R 1 , which are the same or different, is as defined above; R 11  represents OH or R 10 NH where R 10  is HO, R 1 CO or HOOC(X) x  wherein R 1  is as defined above, x is 0 or 1 and X is R 1 R 1 C wherein each R 1 , which are the same or different, is as defined above; or R 10  is an amino acid residue H 2 N(R 1 R 1 C)CO— wherein each R 1 , which are the same or different, is as defined above; n is 1 or 2 and R 12  is H or straight or branched C 1  to C 6  alkyl; or a salt thereof,  
       
         
           
           
               
               
           
         
       
       wherein each of Z 1  and Z 2  is independently hydrogen, SH or an electron withdrawing group, and R 12  is as defined above, or a salt thereof for use in the treatment of a condition associated with increased or decreased HIF levels or activity, or a condition in which an increase or decrease in HIF levels or activity may be beneficial.  
     
     
         2 . A compound according to  claim 1  which is of formula (A) where R 1  is aryloxymethyl, R 2  is hydrogen and R 3  is hydrogen.  
     
     
         3 . A compound according to  claim 2  wherein R 1  is phenyloxymethyl, benzyloxymethyl or p-hydroxybenzylmethyl.  
     
     
         4 . A compound according to  claim 1  of formula (B) where X is a single bond or methyl, R 2  is H or phenyl alkyl and R 4  is H or methyl.  
     
     
         5 . A compound according to  claim 1  of formula (C) wherein X is O and R 1  is H or methyl.  
     
     
         6 . A compound according to  claim 1  of formula (D) wherein x is 1, and R 1  and R 6  are both hydrogen.  
     
     
         7 . A compound according to  claim 1  of formula (E) wherein R 1  is H and R 12  is H or ethyl.  
     
     
         8 . A compound according to  claim 7  wherein R 11  represents R 10 NH and R 10  is H an acyl group of a natural amino acid, acetyl or benzoyl.  
     
     
         9 . A compound according to  claim 7  wherein R 11  is HOOC(X)x.  
     
     
         10 . A method for the treatment of a condition associated with increased or decreased HIF levels or activity, or a condition in which an increase or decrease in HIF levels or activity may be beneficial, comprising administering the compound of  claim 1  to an individual in need thereof in an amount sufficient to increase or decrease HIF levels or activity.  
     
     
         11 . (canceled)  
     
     
         12 . A pharmaceutical composition which comprises a compound as defined in  claim 1  together with a pharmaceutically acceptable excipient vehicle or carrier.  
     
     
         13 . (canceled)