Treatment or prophylaxis of proliferative conditions

Abstract

The disclosure 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. Also provided are 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. Provided are 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 CYP1B1 and allelic variants thereof. Finally, provided is a method for determining the efficacy of a compound as described herein 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-4 alkyl; 
         Effector is a molecule having a pharmacological or diagnostic function), 
       
       or a pharmaceutically acceptable salt, ester, amide or solvate thereof. 
     
     
         2 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein the or each Z 7  is hydrogen. 
     
     
         3 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein X 1  is oxygen. 
     
     
         4 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Y 2  and Y 3  are each carbon. 
     
     
         5 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Z 3  and Z 5  are each alkoxy or amino. 
     
     
         6 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Z 3  and Z 5  are each C 1-6 alkoxy. 
     
     
         7 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 6 , wherein Z 3  and Z 5  are each methoxy. 
     
     
         8 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Y 1  is carbon. 
     
     
         9 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Z 1  is alkoxy or amino. 
     
     
         10 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Z 1  is hydrogen. 
     
     
         11 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of any one of  claims 1  to  10 , wherein Z 2  and/or Z 4  is hydrogen. 
     
     
         12 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Y 4  is nitrogen, oxygen or sulfur. 
     
     
         13 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 12 , wherein Y 4  is oxygen or sulfur and p=0. 
     
     
         14 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 13 , wherein Y 4  is oxygen. 
     
     
         15 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein —Y 5 — is a single bond. 
     
     
         16 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Z 3  is 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. 
     
     
         17 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein X 1  is such that —X 1 -X 2  is —O—X 2 , —S—X 2 , —SO 2 —OX 2  or —SO 2 NZ 10 —X 2 . 
     
     
         18 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 17 , wherein X 1  is such that —X 1 -X 2  is —O—X 2 . 
     
     
         19 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein X 2  is present. 
     
     
         20 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein X 2  is absent or X 1 -X 2 -Effector is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 19  or  claim 20 , wherein one of n and m is 0 or both n and m are 0. 
     
     
         22 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 19 , wherein the or each Z 9  is oxygen. 
     
     
         23 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 19 , wherein none or one of Y 6  are nitrogen. 
     
     
         24 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein X 2  is absent. 
     
     
         25 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 1 , wherein Effector is a cytotoxic or cyclostatic agent. 
     
     
         26 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 25  wherein Effector is connected to the remainder of the compound through an oxygen or sulfur atom and -Effector is of formula (II): 
       
         
           
           
               
               
           
         
       
       (wherein:
 Z 12  is oxygen or sulfur; 
 each X 4  is independently oxygen, sulfur or NZ 13  wherein each —Z 13  is independently —(CH 2 ) 2 —Z 14 , -alkyl or -hydrogen; and 
 each Z 14  is independently chloro, bromo, iodo, or mesylate). 
 
     
     
         27 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 26  wherein Z 12  is oxygen. 
     
     
         28 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 26 , wherein each X 4  is NZ 13 . 
     
     
         29 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 28 , wherein each Z 13  is hydrogen. 
     
     
         30 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 26 , wherein each Z 14  is bromo or chloro. 
     
     
         31 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate of  claim 30 , wherein each Z 14  is bromo. 
     
     
         32 . A composition comprising a compound, or pharmaceutically acceptable salt, ester, amide or solvate, as defined in  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         33 - 35 . (canceled) 
     
     
         36 . The compound of  claim 1 , wherein said Effector is a molecule having a diagnostic function. 
     
     
         37 . The compound of  claim 36 , wherein said Effector is a fluorophore. 
     
     
         38 . The compound of  claim 37 , wherein said fluorophore is selected from the group consisting of coumarins, resorufins, fluoresceins, and rhodamines. 
     
     
         39 . The compound of  claim 38 , wherein said fluorophore is a coumarin. 
     
     
         40 - 46 . (canceled)