Diarylhydantoin compounds

Abstract

The present invention relates to diarylhydantoin compounds, including diarylthiohydantoins, and methods for synthesizing them and using them in the treatment of hormone lefiactory prostate cancer.

1 . A compound having the formula 
       
         
           
           
               
               
           
         
         wherein X is selected from the group consisting of trifluoromethyl and iodo, 
         wherein W is selected from the group consisting of H and NR5, 
         wherein R5 is selected from the group consisting of H, methyl, and 
       
       
         
           
           
               
               
           
         
         wherein D is S or O and E is N or O and G is alkyl, aryl, substituted alkyl or substituted aryl; or 
         D is S or O and E-G together are C1-C4 lower alkyl, 
         wherein R1 and R2 together comprise eight or fewer carbon atoms and are selected from the group consisting of alkyl, substituted alkyl including haloalkyl, and, together with the carbon to which they are linked, a cycloalkyl or substituted cycloalkyl group, 
         wherein R3 is selected from the group consisting of hydrogen, halogen, methyl, C1-C4 alkoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methoxycarbonyl, acetamido, methanesulfonamino, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, and C1-C6 alkyl or alkenyl optionally substituted with hydroxyl, methoxycarbonyl, cyano, amino, amido, nitro, carbamoyl, or substituted carbamoyl including methylcarbamoyl, dimethylcarbamoyl, and hydroxyethylcarbamoyl,
 wherein R4 is selected from the group consisting of hydrogen, halogen, alkyl, and haloalkyl, 
 
         wherein R3 is not methylaminomethyl or dimethylaminomethyl. 
       
     
     
         2 . The compound of  claim 1 , wherein R5 is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         wherein R3 is selected from the group consisting of hydroxy, methylcarbamoyl, methylcarbamoylpropyl, methylcarbamoylethyl, methylcarbamoylmethyl, methylsulfonecarbamoylpropyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, carbamoylmethyl, carbamoylethyl, carboxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoylpropyl, carboxypropyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, methoxycarbonyl, 3-cyano-4-trifluoromethylphenylcarbamoyl, hydroxyethylcarbamoylethyl, and hydroxyethoxycarbonylethyl, and 
         wherein R10 and R11 are both H or, respectively, F and H, or H and F. 
       
     
     
         4 . The compound of  claim 3 , wherein R10 and R11 are both H. 
     
     
         5 . The compound of  claim 3 , wherein R10 and R11 are, respectively, F and H. 
     
     
         6 . The compound of  claim 3 , wherein R3 is methylcarbamoyl. 
     
     
         7 . The compound of  claim 3 , wherein R3 is methylcarbamoyl and R10 and R11 are, respectively, F and H. 
     
     
         8 . The compound of  claim 1 ,
 wherein R1 and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms, and   R3 is selected from the group consisting of carbamoyl, alkylcarbamoyl, carbamoylalkyl, and alkylcarbamoylalkyl, and R4 is H or F.   
     
     
         9 . The compound of  claim 8 , wherein R4 is 3-fluoro. 
     
     
         10 . The compound of  claim 1 ,
 wherein R1 and R2 are independently methyl or, together with the carbon to which they are linked, a cycloalkyl group of 4 to 5 carbon atoms,   R3 is selected from the group consisting of cyano, hydroxy, methylcarbamoyl, methylcarbamoyl-substituted alkyl, methylsulfonecarbamoyl-substituted alkyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, methoxycarbonyl, acetamido, methanesulfonamido, carbamoyl-substituted alkyl, carboxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoyl-substituted alkyl, carboxy-substituted alkyl, 4-(1,1-dimethylethoxy)carbonyl)-1-piperazinyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, hydroxyethoxycarbonyl-substituted alkyl, and 3-cyano-4-trifluoromethylphenylcarbamoyl, and R4 is F.   
     
     
         11 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
         wherein R3 is selected from the group consisting of methylcarbonyl, methoxycarbonyl, acetamido, and methanesulfonamido, and R4 is selected from the group consisting of F and H. 
       
     
     
         12 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
       wherein R4 is selected from the group consisting of F and H. 
     
     
         13 . A compound according to  claim 1 , wherein R1 and R2 together with the carbon to which they are linked are 
       
         
           
           
               
               
           
         
       
     
     
         14 . A compound selected from the compounds of Tier 1 and Tier 2. 
     
     
         15 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1 , having the formula 
       
         
           
           
               
               
           
         
       
     
     
         20 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of  claims 1 - 19  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         23 . A method for treating a hyperproliferative disorder comprising administering a pharmaceutical composition of  claim 20  to a subject in need of such treatment, thereby treating the hyperproliferative disorder. 
     
     
         24 . The method of  claim 23 , wherein the composition is administered at a dosage of the compound in the range of from about 0.001 mg per kg body weight per day to about 100 mg per kg body weight per day. 
     
     
         25 . The method of  claim 23 , wherein the composition is administered at a dosage of the compound in the range of from about 0.01 mg per kg body weight per day to about 100 mg per kg body weight per day. 
     
     
         26 . The method of  claim 23 , wherein the composition is administered at a dosage of the compound in the range of from about 0.1 mg per kg body weight per day to about 10 mg per kg body weight per day. 
     
     
         27 . The method of  claim 23 , wherein the composition is administered at a dosage of the compound of about 1 mg per kg body weight per day. 
     
     
         28 . A method for treating a hyperproliferative disorder comprising administering a composition according to  claim 21  to a subject in need of such treatment, thereby treating the hyperproliferative disorder. 
     
     
         29 . The method of  claim 28 , wherein the composition is administered at a dosage of the compound in the range of from about 0.1 mg per kg body weight per day to about 10 mg per kg body weight per day. 
     
     
         30 . The method of  claim 28 , wherein the composition is administered at a dosage of the compound of about 1 mg per kg body weight per day. 
     
     
         31 . The method of  claim 23 , wherein the hyperproliferative disorder is hormone refractory prostate cancer. 
     
     
         32 . The method of  claim 23 , wherein the compound is administered by intravenous injection, by injection into tissue, intraperitoneally, orally, or nasally. 
     
     
         33 . The method of  claim 28 , wherein the composition is administered orally. 
     
     
         34 . The method of  claim 23 , wherein the composition has a form selected from the group consisting of a solution, dispersion, suspension, powder, capsule, tablet, pill, time release capsule, time release tablet, and time release pill. 
     
     
         35 . The method of  claim 28 , wherein the composition has a form selected from the group consisting of a capsule, tablet, and pill. 
     
     
         36 . The method of  claim 28 , wherein the compound is selected from the group consisting of RD 162′, RD 162″, RD 169, or RD 170, or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 28 , wherein the compound is N-methyl-4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]-2-fluorobenzamide [RD162] or a pharmaceutically acceptable salt thereof. 
     
     
         38 . A method of synthesizing a diaryl compound of formula: 
       
         
           
           
               
               
           
         
         in a first polar solvent to form a mixture, 
         heating the mixture, 
         adding a second polar solvent, the same as or different from the first polar solvent, and an aqueous acid to the mixture, 
         refluxing the mixture, 
         cooling the mixture and combining with water, and 
         separating the diaryl compound from the mixture, 
         wherein R51 comprises an alkyl chain of from 1 to 4 carbon atoms, R52 is selected from the group consisting of cyano, hydroxy, methylcarbamoyl, methylcarbamoyl-substituted alkyl, methylsulfonecarbamoyl-substituted alkyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, methoxycarbonyl, 3-cyano-4-trifluoromethylphenylcarbamoyl, carbamoyl-substituted alkyl, carboxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoyl-substituted alkyl, carboxy-substituted alkyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, and hydroxyethoxycarbonyl-substituted alkyl, and R53 is selected from the group consisting of F and H. 
       
     
     
         39 . The method of  claim 38 , wherein R51 comprises an alkyl chain of from 1 to 2 carbon atoms, R52 is selected from the group consisting of carbamoyl and methylcarbamoyl, and R53 is F. 
     
     
         40 . A method of synthesizing a compound of formula: 
       
         
           
           
               
               
           
         
       
       comprising
 mixing 4-isothiocyanato-2-trifluoromethylbenzonitrile and N-methyl-4-(1-cyanocyclobutylamino)-2-fluorobenzamide in dimethylformamide to form a first mixture, 
 heating the first mixture to form a second mixture, 
 adding alcohol and acid to the second mixture to form a third mixture, 
 refluxing the third mixture to form a fourth mixture, 
 cooling the fourth mixture, 
 combining the fourth mixture with water and extracting an organic layer; 
 isolating the compound from the organic layer. 
 
     
     
         41 . A method of synthesizing the compound of  claim 16  [RD162′], comprising
 mixing N-Methyl-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide and 4-Isothiocyanato-2-trifluoromethylbenzonitrile in DMF and heating to form a first mixture; 
 adding an alcohol and an acid to the first mixture to form a second mixture; 
 refluxing the second mixture; 
 cooling the second mixture, 
 combining the second mixture with water and extracting an organic layer; 
 isolating the compound from the organic layer. 
 
     
     
         42 . A method of synthesizing the compound of  claim 17  [RD162″], comprising
 mixing N-Methyl-2-fluoro-4-(1-cyanocyclopentyl)aminobenzamide, 4-isothiocyanato-2-trifluoromethyl benzonitrile, and DMF and heating under reflux to form a first mixture; 
 adding an alcohol and an acid to the first mixture to form a second mixture; 
 refluxing the second mixture; 
 cooling the second mixture; 
 combining the second mixture with water and extracting an organic layer; 
 isolating the compound from the organic layer. 
 
     
     
         43 . A method of synthesizing the compound of  claim 18  [RD169], comprising
 mixing N,N-Dimethyl 4-[4-(1-cyanocyclobutylamino)phenyl]butanamide, 4-isothiocyanato-2-trifluoromethyl benzonitrile, and DMF and heating under reflux to form a first mixture; 
 adding an alcohol and an acid to the first mixture to form a second mixture; 
 refluxing the second mixture; 
 cooling the second mixture; 
 combining the second mixture with water and extracting an organic layer; 
 isolating the compound from the organic layer. 
 
     
     
         44 . A method of synthesizing the compound of  claim 19  [RD170], comprising
 mixing DMSO, dichloromethane, and oxalyl chloride to form a first mixture, 
 adding 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide to the first mixture to form a second mixture; 
 adding triethylamine to the second mixture to form a third mixture; 
 warming the third mixture and quenching with aqueous NH 4 Cl to form a fourth mixture; 
 extracting an organic layer from the fourth mixture; 
 isolating the compound from the organic layer. 
 
     
     
         45 . A compound having the formula 
       
         
           
           
               
               
           
         
         wherein R 5  is CN or NO 2  or SO 2 R 11 , 
         wherein R 6  is CF 3 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated akynyl, halogen, 
         wherein A is sulfur (S) or oxygen (O), 
         wherein B is O or S or NR 8 , 
         wherein R 8  is selected from the group consisting of H, methyl, aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, SO 2 R 11 , NR 11 R 12 , (CO)OR 11 , (CO)NR 11 R 12 , (CO)R 11 , (CS)R 11 , (CS)NR 11 R 12 , (CS)OR 11 , 
       
       
         
           
           
               
               
           
         
         wherein D is S or O and E is N or O and G is alkyl, aryl, substituted alkyl or substituted aryl; or 
         D is S or O and E-G together are C1-C4 lower alkyl, 
         wherein R1 and R2 are independently alkyl, haloalkyl, hydrogen, aryl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkenyl, halogenated akynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocylic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, or R 1  and R 2  are connected to form a cycle which can be heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, 
       
       
         
           
           
               
               
           
         
         wherein X is carbon or nitrogen and can be at any position in the ring, and 
         wherein R3, R4, and R7 are independently selected from the group consisting of hydrogen, halogen, methyl, methoxy, formyl, haloacetoxy, trifluoromethyl, cyano, nitro, hydroxyl, phenyl, amino, methylcarbamoyl, methylcarbamoyl-substituted alkyl, dimethylcarbamoyl-substituted alkyl, methoxycarbonyl, acetamido, methanesulfonamino, carbamoyl-substituted alkyl, methanesulfonyl, 4-methanesulfonyl-1-piperazinyl, piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, hydroxyl-substituted alkyl, hydroxyl-substituted alkenyl, carbamoyl-substituted alkenyl, methoxycarbonyl-substituted alkyl, cyano-substituted alkyl, 
       
       
         
           
           
               
               
           
         
          aryl, substituted aryl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkenyl, halogenated alkynyl, SO 2 R 11 , NR 11 R 12 , NR 12 (CO)OR 11 , NH(CO)NR 11 R 12 , NR 12  (CO)R 11 , O(CO)R 11 , O(CO)OR 11 , O(CS)R 11 , NR 12 (CS)R 11 , NH(CS)NR 11 R 12 , NR 12 (CS)OR 11 , arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, substituted cycloalkyl, haloalkyl, methylsulfonecarbamoyl-substituted alkyl, methylaminomethyl, dimethylaminomethyl, methylsulfonyloxymethyl, methoxycarbonyl, acetamido, methanesulfonamido, carbamoyl-substituted alkyl, carboxymethyl, methoxycarbonylmethyl, methanesulfonyl, 4-cyano-3-trifluoromethylphenylcarbamoyl-substituted alkyl, carboxy-substituted alkyl, 4-(1,1-dimethylethoxy)carbonyl)-1-piperazinyl, hydroxyethylcarbamoyl-substituted alkyl, hydroxyethoxycarbonyl-substituted alkyl, 3-cyano-4-trifluoromethylphenylcarbamoyl, 
         wherein R 11  and R 12  are independently hydrogen, aryl, aralkyl, substituted aralkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic or non-aromatic, cycloalkyl, or substituted cycloalkyl, or R 11  and R 12  can be connected to form a cycle which can be heterocyclic aromatic or non-aromatic, substituted heterocyclic aromatic, cycloalkyl, or substituted cycloalkyl. 
       
     
     
         46 . The compound of  claim 45 , wherein the compound has substantial androgen receptor antagonist activity and no substantial agonist activity on hormone refractory prostate cancer cells. 
     
     
         47 . A method comprising:
 providing at least one compound according to  claim 45 ;   measuring inhibition of androgen receptor activity for the compound and determining if the inhibition is above a first predetermined level,   measuring stimulation of androgen receptor activity in hormone refractory cancer cells for the compound and determining if the stimulation is below a second predetermined level,   selecting the compound if the inhibition is above the first predetermined level and the stimulation is below the second predetermined level.   
     
     
         48 . The method of  claim 47 , wherein the predetermined levels are those of bicalutamide. 
     
     
         49 . The method of  claim 47 , wherein the step of measuring inhibition comprises measuring inhibitory concentration (IC50) in an AR response reporter system or a prostate specific antigen secreting system. 
     
     
         50 . The method of  claim 47 , wherein the step of measuring stimulation comprises measuring fold induction by increasing concentrations in an AR response reporter system or a prostate specific antigen secreting system. 
     
     
         51 . The method of  claim 47 , wherein the steps of measuring inhibition and/or stimulation comprise measuring an effect of the compound on tumor growth in an animal.