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 - 49 . (canceled) 
     
     
         50 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer thereof, wherein:
 X 1  is such that —X 1 -X 2  is —O—X 2 , —S—X 2 , —SO 2 —O—X 2 , —SO2NZ 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, sulfur, carbon, 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 (iv) —CH 2 CH 2 —, wherein the one or more hydrogen atoms in (ii), (iii) or (iv) are optionally 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 2  and 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; 
           Z 3 , where present, is selected 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; 
           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 , where present, 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, 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, wherein the electron withdrawing group is selected from halo, —CN, haloalkyl, amide, nitro, —COR, akenyl, alkynyl, N + R 3 , ester, —CONR 2 , —NR—C(═O)—R, —NR—S(═O) 2 R, —S(═O) 2 OH, —S(═O) 2 OR, —S(═O) 2 R, —S(═O) 2 ONR 2 , wherein each R is independently selected from a C 1 -C 6  alkyl group, a C 3 -C 20  heterocyclic group, or a C 3 -C 20  aryl group, unsubstituted C 1 -C 6  alkoxy, and substituted C 1 -C 6  alkoxy, wherein 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, amide, mono- or di-substituted amide, —NR—C(═O)—R, —NR—S(═O) 2 —R, —S(═O) 2 OH, —S(═O) 2 OR, —S(═O) 2 R, —S(═O)OH, —S(═O)OR, —S(═O)R, —OP(═O)(OH) 2 , OP(═O)(OR) 2 , and S(═O) 2 —NR 2 , wherein each R is independently selected from a C 1 -C 6  alkyl group, a C 3 -C 20  heterocyclic group, or a C 3 -C 20  aryl group; each Z 9  is independently oxygen or sulfur; 
           Z 10  is hydrogen or alkyl, for example a C 1-4  alkyl; and 
         
         Effector is a moiety, which when released from the compound of formula (I), provides a fluorophore or cytotoxic agent selected from cyclophosphamides, gemcitabine, cytarabine, 5-fluorouracil, 6-mercaptopurine, camptothecin, topotecan, doxorubicin, daunorubicin duocarmycin, etoposide, duetoposide, combretastatin A-4, vinblastine, vincristine, AQ4N, hydroxyurea, maytansines, enediyenes, epothilones, taxanes, bleomycins, calicheamicins, colchicine, dacarbazine, dactinomycin, epirubicin, epirubicin derivatives, fludarabine, hydroxyureapentatostatin, methotraxate, mitomycin, mitoxantrone, carboplatin, cisplatin, taxels, 6-thioguanine, vinca alkaloids, platinum coordination complexes, anthracenediones, substituted ureas, methyl hydrazine derivatives. 
       
     
     
         51 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein each Z 7  is hydrogen. 
     
     
         52 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein X 1  is oxygen. 
     
     
         53 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein Z 3  and Z 5  are each C 1-6 alkoxy. 
     
     
         54 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein Z 3  and Z 5  are each methoxy. 
     
     
         55 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein Z 1  is hydrogen. 
     
     
         56 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein Z 2  and/or Z 4  is hydrogen. 
     
     
         57 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein Y 4  is oxygen or sulfur and p=0. 
     
     
         58 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein Y 4  is oxygen, —Y 5 — is a single bond, and Y 2  and Y 3  are each carbon. 
     
     
         59 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein X 1  is such that —X 1 -X 2  is —O—X 2 . 
     
     
         60 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein X 2  is present. 
     
     
         61 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein X 2  is absent or X 1 -X 2 -Effector is of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         62 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 63 , wherein one of n and m is 0 or both n and m are 0, and wherein each Z 9  is oxygen. 
     
     
         63 . The compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer of  claim 50 , wherein the Effector is gemcitabine. 
     
     
         64 . The compound, or pharmaceutically acceptable salt, ester, amide solvate or stereoisomer of  claim 50 , wherein the Effector is a fluorophore selected from the group consisting of coumarins, resorufins, fluoresceins, and rhodamines. 
     
     
         65 . The compound, or pharmaceutically acceptable salt, ester, amide or solvate, of  claim 50  wherein Y 1 , Y 2  and Y 3  are carbon, Y 4  is oxygen with p being zero, and Y 5  is a single bond, and having the structure: 
       
         
           
           
               
               
           
         
       
     
     
         66 . A compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer thereof, selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         67 . A compound, which is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer thereof. 
     
     
         68 . A composition comprising a compound, or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer, of  claim 50 , together with a pharmaceutically acceptable carrier. 
     
     
         69 . A composition comprising a compound, which is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer, together with a pharmaceutically acceptable carrier. 
     
     
         70 . A method of treatment or prophylaxis of a proliferative condition, said method comprising administering a therapeutically or prophylactically useful amount of a compound according to  claim 50 , or pharmaceutically acceptable salt, ester, amide, solvate or stereoisomer thereof, to a subject in need thereof. 
     
     
         71 . The method according to  claim 70 , wherein the proliferative condition is pre-malignant or malignant cellular proliferation, a cancer, a leukemia, psoriasis, a bone disease, a fibroproliferative disorder or atherosclerosis. 
     
     
         72 . The method according to  claim 70 , wherein the proliferative condition is selected from bladder, brain, breast, colon, head and neck, kidney, lung, liver, ovarian, prostate and skin cancer.