Lactacystin analogs

Abstract

Compounds related to lactacystin and lactacystin β-lactone, pharmaceutical compositions containing the compounds, and methods of use.

1 . A method of treating cancer, comprising administering to a subject an effective anti-cancer amount of a pharmaceutical composition having the formula:  
       
         
           
           
               
               
           
         
         wherein Z 1  is O, S, SO 2 , NH, or NR a , R a  being C 1-6  alkyl;  
         X 1  is O, S, CH 2 , two singly bonded H, CH(R b ) in the E or Z configuration, or C(R b )(R c ) in the E or Z configuration, each of R b  and R d , independently, being C 1-6  alkyl, C 6-12  aryl, C 3-8  cycloalkyl, C 3-8  heteroaryl, C 3-8  heterocyclic radical, or halogen, X 1  being two singly bonded H when Z 1  is SO 2 ;  
         Z 2 is O, S, NH, NR d , CHR 1 , or CHOR 1  in the (R) or (S) configuration, wherein R d  is C 1-6  alkyl and R 1  is H, halogen, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, NR d R e  (except where Z 2  is CHOR 1 ), or the side chain of any naturally occurring α-amino acid, or R 1  and R 2  taken together are a bivalent moiety, provided that when R 1  and R 2  are taken together, Z 1  is NH or NR a  and Z 2  is CHR 1 ; R e  being H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, or C 2-6  alkynyl, and the bivalent moiety forming a C 3-8  cycloalkyl, C 3-8  heteroaryl, C 3-8  heterocyclic radical, or C 6-12  aryl, where the H in CHR 1  is deleted when R 1  and R 2  taken together form a C 3-8  heteroaryl or C 6-12  aryl;  
         R 2  is C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, azido, C 2-6  alkynyl, halogen, OR f , SR f , NR f R g , —ONR f R g , —NR g (OR f ), or —NR g (SR f ) (each of R f  and R g , independently, being H, C 1-6 , alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, or C 2-6  alkynyl), or R 1  and R 2  taken together are a bivalent moiety, the bivalent moiety forming a C 3-8  cycloalkyl, C 3-8  heteroaryl, C 3-8  heterocyclic radical, or C 6-12  aryl, where the H in CHR 1  is deleted when R 1  and R 2  taken together form a C 3-8  heteroaryl or C 6-12  aryl;  
         A 1  is H, the side chain of any naturally occurring α-amino acid, or is of the following formula,  
           —(CH 2 ) m —Y—(CH 2 ) n —R 3 X 3    
         wherein Y is O, S, C═O, C═S, —(CH═CH)—, vinylidene, —C═NOR h , —C═NNR i R i′ , sulfonyl, methylene, CHX 4  in the (R) or (S) configuration, or deleted, X 4  being halogen, methyl, halomethyl, OR h , SR h , NR i R i′ , —NR i (OR h ), or —NR i (NR i R i′ ), wherein R h  is selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-10  acyl, C 1-6  alkylsulfonyl, and C 6-10  arylsulfonyl, and each of R i  and R i′ , independently is selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-10  acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R 3  is straight chain or branched C 1-8  alkylidene, straight chain or branched C 1-8  alkylene, C 3-10  cycloalkylidene, C 3-10  cycloalkylene, phenylene, C 6-14  arylalkylidene, C 6-14  arylalkylene, or deleted, and X 3  is H hydroxyl, thiol, carboxyl, amino, halogen, (C 1-6  alkyl)oxycarbonyl, (C 7-14  arylalkyl)oxycarbonyl, or C 6-14  aryl; or R 3  and X 3  taken together are the side chain of any naturally occurring α-amino acid; and  
         L O  is H or an organic moiety having 1 to 25 carbon atoms, 0 to 10 heteroatoms, and 0 to 6 halogen atoms; and  
         a pharmaceutically acceptable carrier.  
       
     
     
         2 . A method of treating cancer, comprising administering to a subject an effective anti-cancer amount of a pharmaceutical composition having the formula:  
       
         
           
           
               
               
           
         
         wherein Z 1  is O, S, SO 2 , NH, or NR a , R a  being C 1-6  alkyl;  
         X 1  is O, S, CH 2 , two singly bonded H, CH(R b ) in the E or Z configuration, or C(R b )(R c ) in the E or Z configuration, each of R b  and R c , independently, being C 1-6  alkyl, C 6-12  aryl, C 3-8  cycloalkyl, C 3-8  heteroaryl, C 3-8  heterocyclic radical, or halogen, provided that when Z 1  is SO 2 , X 1  is two singly bonded H;  
         Z 2  is CHR 1  in the (R) or (S) configuration, R 1  being H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, hydroxyl, halogen, a side chain of a naturally occuring α-amino acid, OR d , SR d , or NR d R e  (each of R d  and R e , independently, being H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, or C 2-5  alkynyl);  
         Z 3  is O, S, NH, or NR j , wherein R j  is C 1-6  alkyl;  
         X 2  is O or S; and  
         A 1  is H, the side chain of any naturally occurring α-amino acid, or is of the following formula,  
           —(CH 2 ) m —Y—(CH 2 ) n —R 3 X 3    
         wherein Y is O, S, C═O, C═S, —(CH═CH)—, vinylidene, —C═NOR h , —C═NNR i R i′ , sulfonyl, methylene, CHX 4  in the (R) or (S) configuration, or deleted, X 4  being halogen, methyl, halomethyl, OR h , SR h , NR i R i′ , —NR i (OR h ), or —NR i (NR i R i′ ), wherein R h  is selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-10  acyl, C 1-6  alkylsulfonyl, and C 6-10  arylsulfonyl; and each of R i  and R i′ , independently is selected from H, C 1-6  alkyl, C 1-6  haloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 1-10  acyl; m is 0, 1, 2, or 3, and n is 0, 1, 2, or 3; and R 3  is straight chain or branched C 1-8  alkylidene, straight chain or branched C 1-8  alkylene, C 3-10  cycloalkylidene, C 3-10  cycloalkylene, phenylene, C 6-14  arylalkylidene, C 6-14  arylalkylene, or deleted, and X 3  is H, hydroxyl, thiol, carboxyl, amino, halogen, (C 1-6  alkyl)oxycarbonyl, (C 7-14  arylalkyl)oxycarbonyl, or C 6-14  aryl; or R 3  and X 3  taken together are the side chain of any naturally occurring α-amino acid; and  
         a pharmaceutically acceptable carrier.  
       
     
     
         3 . The method of  claim 1  or  2 , wherein the cancer is selected from carcinoma, lymphoma, sarcoma, and myeloma.  
     
     
         4 . The method of  claim 1  or  2 , wherein said cancer is selected from adenocarcinoma, acinic cell adenocarcinoma, adrenal cortical carcinomas, alveoli cell carcinoma, anaplastic carcinoma, basaloid carcinoma, basal cell carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, renaladinol carcinoma, embryonal carcinoma, anometroid carcinoma, fibrolamolar liver cell carcinoma, follicular carcinomas, giant cell carcinomas, hepatocellular carcinoma, intraepidermal carcinoma, intraepithelial carcinoma, leptomanigio carcinoma, medullary carcinoma, melanotic carcinoma, menigual carcinoma, mesometonephric carcinoma, oat cell carcinoma, squamal cell carcinoma, sweat gland carcinoma, transitional cell carcinoma, tubular cell carcinoma, amelioblastic sarcoma, angiolithic sarcoma, botryoid sarcoma, endometrial stroma sarcoma, ewing sarcoma, fascicular sarcoma, giant cell sarcoma, granulositic sarcoma, immunoblastic sarcoma, juxaccordial osteogenic sarcoma, Kaposi's sarcoma, leukocytic sarcoma, lymphatic sarcoma, medullary sarcoma, myeloid sarcoma, austiogenci sarcoma, periosteal sarcoma, reticulum cell sarcoma, round cell sarcoma, spindle cell sarcoma, synovial sarcoma, and telangiectatic audiogenic sarcoma, neural blastoma, glioblastoma, astrocytoma, melanoma, leiomyo sarcoma, multiple myeloma, Hemangioma, Hodgkin's disease, Burkitt's lymphoma, and nodular poorly-differentiated lymphocytic lymphoma, nodular mixed lymphocytic lymphoma, nodular histiocytic lymphoma, and diffuse lymphomas.  
     
     
         5 . The method of  claim 1  or  2 , wherein Z 1  is NH or NR a .  
     
     
         6 . The method of  claim 1  or  2 , wherein A 1  is —(CH 2 ) m —Y—(CH 2 ) n —R 3 X 3  and Y is CHX 4  in the (R) or (S) configuration.  
     
     
         7 . The method of  claim 6 , wherein Y is CHX 4  in the (S) configuration and X 3  is H.  
     
     
         8 . The method of  claim 7 , wherein m and n are each 0.  
     
     
         9 . The method of  claim 1  or  2 , wherein Z 2  is CHR 1  in the (R) configuration and R 1  is C 1-6  alkyl.  
     
     
         10 . The method of  claim 2 , wherein X 2  is O and Z 3  is O.  
     
     
         11 . The method of  claim 1 , wherein R 2  is OR f  and R f  is H.