Cytotoxic agents and methods of use

Abstract

Disclosed are compounds that inhibit proteasomic activity in cells. Also disclosed are pharmaceutical compositions comprising such compounds as well as methods to treat conditions, particularly cell proliferative conditions, such as cancer and inflammatory conditions.

1 . A method for treating a proliferative disorder in a mammalian patient, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 X and X′ are independently selected from the group consisting of oxygen, sulfur and NR 3  where R 3  is independently selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, aryloxy, alkylamino, arylamino, and acylamino; 
 Y, Y′ and Y″ are independently selected from the group consisting of —O—, —N(R 3 )—, —S— and —C(R 4 )(R 5 )— where R 3  is as defined above and R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, substituted aryloxy, acyloxy, amino, substituted amino, acylamino, alkylthio, arylthio, and acylthio or R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted cycloalkyl group or further R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted vinyl group; or prodrugs, isomers and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . The method of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 Y, Y′ and Y″ are independently selected from the group consisting of —O—, —N(R 3 )—, —S— and —C(R 4 )(R 5 ) where 
 R 3  is independently selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, aryloxy, alkylamino, arylamino, and acylamino; 
 R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, substituted aryloxy, acyloxy, amino, substituted amino, acylamino, alkylthio, arylthio, and acylthio or R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted cycloalkyl group or further R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted vinyl group; or prodrugs, isomers and pharmaceutically acceptable salts thereof. 
 
     
     
         3 . The method of  claim 1 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, substituted aryloxy, acyloxy, amino, substituted amino, acylamino, alkylthio, arylthio, and acylthio or R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted cycloalkyl group or further R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted vinyl group; 
 Y′ and Y″ are independently selected from the group consisting of —O—, —N(R 3 )—, —S— and —C(R 4 )(R 5 )— where R 3  is independently selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, aryloxy, alkylamino, arylamino, and acylamino; and R 4  and R 5  are as defined above; or prodrugs, isomers and pharmaceutically acceptable salts thereof. 
 
     
     
         4 . A method for treating a proliferative disorder in a mammalian patient, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IV: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, substituted aryloxy, acyloxy, amino, substituted amino, acylamino, alkylthio, arylthio, and acylthio or R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted cycloalkyl group or further R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted vinyl group; 
 R 6  is selected from the group consisting of hydrogen, hydroxyl, amino, substituted amino, acylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, and substituted aryloxy, or 
 prodrugs, isomers and pharmaceutically acceptable salts thereof 
 
     
     
         5 . A compound method for treating a proliferative disorder in a mammalian patient, comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula V: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl substituted alkynyl, aryl and substituted aryl; 
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, substituted aryloxy, acyloxy, amino, substituted amino, acylamino, alkylthio, arylthio, and acylthio or R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted cycloalkyl group or further R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted vinyl group; 
 R 6  is selected from the group consisting of hydrogen, hydroxyl, amino, substituted amino, acylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, and substituted aryloxy; 
 R 7  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl; or 
 prodrugs, isomers and pharmaceutically acceptable salts thereof 
 
     
     
         6 . The method according to  claim 1 , wherein R 1  is selected from the group consisting of methyl, trifluoromethyl, methoxymethyl, ethyl, 2-methoxyethyl, n-propyl, iso-propyl, iso-butyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, vinyl, ethynyl, allyl, benzyl, and phenyl. 
     
     
         7 . The method according to  claim 1 , wherein R 2  is selected from the group consisting of 1-hydroxyl-2-methylpropane-1-yl, and 1-hydroxyl-1-cyclohexylmethane-1-yl. 
     
     
         8 . The method according to  claim 1 , wherein Y″ is >NR 3 . 
     
     
         9 . The method according to  claim 8 , wherein R 3  is hydrogen or methoxy. 
     
     
         10 . The method according to  claim 1 , wherein Y is >CR 4 R 5 . 
     
     
         11 . The method of  claim 10 , wherein R 4  is selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, halogen, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, phenoxy, (C 1 -C 6 )alkylamino, and (C 1 -C 6 )acylamino. 
     
     
         12 . The method of  claim 10 , wherein R 5  is selected from the group consisting of hydrogen, fluoro, and chloro. 
     
     
         13 . The method of  claim 10 , wherein R 4  and R 5  are joined to form a group selected from a cycloalkyl group, a vinyl group and a substituted vinyl group. 
     
     
         14 . A method according to  claim 5 , wherein R 7  is selected from the group consisting of (C 3 -C 6 )alkyl, cycloalkyl, and cycloalkenyl. 
     
     
         15 . A method according to  claim 5 , wherein R 8  is hydrogen. 
     
     
         16 - 18 . (canceled) 
     
     
         19 . The method of  claim 1  in combination with an effective amount of at least one anti-neoplastic agent. 
     
     
         20 . A method for treating a proliferative disorder in a mammalian patient which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a mixture thereof; 
       wherein:
 R 1  is selected from the group consisting of alkyl substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 X and X′ are independently selected from the group consisting of oxygen, sulfur and NR 3  where R 3  is independently selected from the group consisting of hydrogen, hydroxyl, amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, aryloxy, alkylamino, arylamino, and acylamino; 
 Y, Y′ and Y″ are independently selected from the group consisting of —O—, —N(R 3 )—, —S— and —C(R 4 )(R 5 )— where R 3  is as defined above and R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, substituted aryloxy, acyloxy, amino, substituted amino, acylamino, alkylthio, arylthio, and acylthio or R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted cycloalkyl group or further R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted vinyl group; 
 R 6  is selected from the group consisting of hydrogen, hydroxyl, amino, substituted amino, acylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, substituted alkoxy, aryloxy, and substituted aryloxy R 7  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 8  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl and substituted aryl; or prodrugs, isomers and pharmaceutically acceptable salts thereof; 
 
       in combination with at least one anti-neoplastic agent. 
     
     
         21 . (canceled) 
     
     
         22 . A method for inducing cytotoxic activity in a mammalian patient suffering from a condition characterized by cell proliferation, comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; 
 X and X′ are independently selected from the group consisting of oxygen, sulfur and NR 3  where R 3  is independently selected from the group consisting of hydrogen, hydroxylamino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkoxy, aryloxy, alkylamino, arylamino, and acylamino; 
 Y, Y′ and Y″ are independently selected from the group consisting of —O—, —N(R 3 )—, —S— and —C(R 4 )(R 5 )— where R 3  is as defined above and R 4  and R 5  are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, aryloxy, substituted aryloxy, acyloxy, amino, substituted amino, acylamino, alkylthio, arylthio, and acylthio or R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted cycloalkyl group or further R 4  and R 5  together with the carbon atom pendent thereto form an optionally substituted vinyl group; or prodrugs, isomers and pharmaceutically acceptable salts thereof. 
 
     
     
         23 . The method of  claim 1 , wherein the proliferative disorder is cancer. 
     
     
         24 . The method of  claim 1 , wherein the proliferative disorder is an inflammatory disorder; and wherein the compound is administered in combination with an anti-inflammatory agent.