Treatment or prophylaxis of proliferative conditions

Abstract

The invention relates to novel compounds for use in the treatment or prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express cytochrome P450 1B1 (CYP1B1) and allelic variants thereof. The invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapy, for example in the treatment of prophylaxis of cancers or other proliferative conditions, as well as methods for treating cancers or other conditions in human or non-human animal patients. The invention also provides methods for identifying novel compounds for use in the treatment of prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express CYP1 B1 and allelic variants thereof. The invention also provides a method for determining the efficacy of a compound of the invention in treating cancer.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       (wherein:
 X 1  is such that —X 1 —X 2  is —O—X 2 , —S—X 2 , —SO 2 —O—X 2 , —SO 2 NZ 10 —X 2 , conjugated alkenemethyloxy or conjugated alkenemethylthio, conjugated alkenemethylSO 2 —O, conjugated alkenemethyl-SO 2 NZ 10  or of the formula: 
 
       
         
           
           
               
               
           
         
         —X 2  is absent or is such that X 1 -X 2 -Effector is one of 
       
       
         
           
           
               
               
           
         
         each n and m is independently 0 or 1; 
         p is 0, 1 or 2; 
         X 3  is oxygen or sulfur and additionally, when m=0, may be SO 2 —O, SO 2 NZ 10 , conjugated alkenemethyloxy, conjugated alkenemethylthio, conjugated alkenemethyl-SO 2 —O or conjugated alkenemethyl-SO 2 NZ 10    
         each of Y 1 , Y 2  and Y 3  is independently carbon or nitrogen, wherein if Y 1  is nitrogen, Z 1  is absent, if Y 2  is nitrogen, Z 3  is absent and if Y 3  is nitrogen, Z 5  is absent; 
         Y 4  is an oxygen, carbon or nitrogen atom, sulfoxide or sulfone; 
         —Y 5 — is either (i) a single bond, (ii) ═CH—, wherein the double bond ═ in ═CH— is connected to Y 4 , or (iii) —CH 2 — or —CH 2 CH 2 —, or one of (ii) to (iii) wherein the hydrogen atom in (ii) is or one or more hydrogen atoms in (iii) are replaced with a substituent Z 11 , wherein Z 11  is selected independently from alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthioxy, alkenylthioxy, alkynylthioxy, arylthioxy, aralkylthioxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro and cyano; 
         each of Z 1 -Z 4 , where present, are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthioxy, alkenylthioxy, alkynylthioxy, arylthioxy, aralkylthioxy, amino, hydroxy, thio, halo, carboxy, formyl, nitro and cyano; and Z 5 , where present, is independently selected from hydrogen alkyl, alkenyl, alkynyl, aryl, aralkyl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, aralkyloxy, alkylthioxy, alkenylthioxy, alkynylthioxy, arylthioxy, aralkylthioxy, amino, hydroxy, thio, carboxy, formyl, nitro and cyano, or one of Z 2  & Z 3 , Z 3  & Z 4  and Z 4  and Z 5  together with the atoms to which they are connected form an aromatic ring fused to the remainder of the compound, provided that at least one of Z 1 , Z 2  and Z 4  is hydrogen; 
         Z 6  is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and aralkyl; 
         none, one or two of Y 6  may be nitrogen atoms with the remainder being carbon atoms; 
         each Z 7  is independently hydrogen, alkyl or aryl; 
         each Z 8  is independently selected from hydrogen, an electron withdrawing group, unsubstituted C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, unsubstituted C 1 -C 6  alkoxy, and substituted C 1 -C 6  alkoxy where the substituted alkyl or alkoxy are substituted with one or more groups selected from ether, amino, mono- or di-substituted amino, cyclic C 1 -C 5  alkylamino, imidazolyl, C 1 -C 6  alkylpiperazinyl, morpholino, thiol, thioether, tetrazole, carboxylic acid, ester, amido, mono- or di-substituted amido, N-connected amide, N-connected sulfonamide, sulfoxy, sulfonate, sulfonyl, sulfoxy, sulfinate, sufinyl, phosphonooxy, phosphate and sulfonamide; 
         each Z 9  is independently oxygen or sulfur; 
         Z 10  is hydrogen or alkyl, for example a C 1-4  alkyl; 
         Effector is a molecule having a pharmacological or diagnostic function), or a pharmaceutically acceptable salt, ester, amide or solvate thereof.