Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof

Abstract

β-Substituted β-amino acids, β-substituted β-amino acid derivatives, and β-substituted β-amino acid analogs and (bio)isosteres and their use as chemotherapeutic agents are disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres are selective LAT1/4F2hc substrates and exhibit rapid uptake and retention in tumors expressing the LAT1/4F2hc transporter. Methods of synthesizing the β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and methods of using the compounds for treating cancer are also disclosed. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs exhibit selective uptake in tumor cells expressing the LAT1/4F2hc transporter and accumulate in cancerous cells when administered to a subject in vivo. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and (bio)isosteres exhibit cytotoxicity toward several tumor types.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 a cell cycle inhibitor comprising a CDK 4/6 inhibitor, a selective inhibitor of T-cell proliferation, a myelosuppressor, a mitotic inhibitor, a checkpoint inhibitor, an immunosuppressor, or a combination of any of the foregoing; and   a compound of Formula (1) or a pharmaceutically acceptable salt thereof:   
       
         
           
           
               
               
           
         
         wherein,
 R 1  comprises a chemotherapeutic moiety; 
 R 4  is selected from the group consisting of hydrogen, —CH 3 , —CH 2 —OH, —O—CH 3  and a second chemotherapeutic moiety; 
 each of R 2 , R 3 , and R 5  is hydrogen; 
 R 6  is selected from the group consisting of —COOH, substituted C 1-4  heteroalkyl, substituted C 1-4  alkyl, and —PH(═O)(—OH), wherein each substituent group is independently selected from C 1-3  alkyl, ═O, and C 1-3  alkoxy; 
 each R 7  is independently selected from the group consisting of hydrogen and hydroxyl; 
 R 8  is selected from hydrogen and —CH 3 ; and 
 L is selected from the group consisting of a bond, —CH 2 —, —CH 2 —O—, —CH 2 —CH 2 —, —CH(—OH)—, —C(═O)—NH—, —C(═O)—N(—CH 3 )—, and —CH 2 —C(═O)—, 
 wherein each of the first chemotherapeutic moiety and the second chemotherapeutic moiety is independently selected from the group consisting of —N(—CH 2 —CH 2 —Cl) 2 , —N(—CD 2 -CD 2 -Cl) 2 , —N(—CH 2 —CH 2 —Br) 2 , —N(—CH 2 —CH 2 —OH) 2 , —CH 2 —N(—CH 2 —CH 2 —Cl) 2 , —CH 2 —C(═O)—N(—CH 2 —CH 2 —Cl) 2 , —O—C(═O)—N(—CH 2 —CH 2 —Cl) 2 , —NH—C(═O)—CH 2 —Br, —CH 2 —O—C(═O)—N(—CH 2 —CH 2 —Cl) 2 , —N(—CH 2 —CH 2 —Cl)(—CH 2 —CH 2 —OH), —N(—O—CH 2 —CH 2 —Cl)(—CH 2 —CH 2 —Cl), —NH—CH 2 —CH 2 —C 1 , —NH—CH 2 —CH 2 —OH, —N + (—O − )(—CH 2 —CH 2 —Cl) 2 , —N(—CH 2 —CH 2 —O—S(═O) 2 —CH 3 ) 2 , —N(—CH 2 —CH 2 —Cl)(—CH 2 —CH 2 —O—S(═O) 2 —CH 3 ), —N(—CH 2 —CH 2 —Br)(—CH 2 —CH 2 —O—S(═O) 2 —CH 3 ), —N(—CH 2 —CH 2 —Cl)(—CH 2 —CH 2 —Br), and 
 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein each of the first chemotherapeutic moiety and the second chemotherapeutic moiety is independently selected from the group consisting of —N(—CH 2 —CH 2 —Cl) 2 , —CH 2 —O—N(—CH 2 —CH 2 —Cl) 2 , —CH 2 —O—C(═O)—N(—CH 2 —CH 2 —Cl) 2 , —O—C(═O)—N(—CH 2 —CH 2 —Cl) 2 , —N(—CH 2 —CH 2 —OH)(—CH 2 —CH 2 —Cl), —NH—CH 2 —CH 2 —C 1 , and —NH—CH 2 —CH 2 —OH. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein each of the first chemotherapeutic moiety and the second chemotherapeutic moiety is —N(—CH 2 —CH 2 —Cl) 2 . 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein R 4  is hydrogen. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein R 4  is the second chemotherapeutic moiety. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein R 6  is carboxylic acid (—COOH). 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein,
 each R 7  is hydrogen; and   R 8  is hydrogen.   
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein,
 R 6  is carboxylic acid (—COOH);   each R 7  is hydrogen; and   R 8  is hydrogen.   
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein L is —CH 2 —. 
     
     
         10 . The pharmaceutical composition of  claim 2 , wherein L is —CH 2 —O—. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (1) is (3S)-3-amino-4-[2-[bis(2-chloroethyl)amino]phenyl]butanoic acid (9) or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (1) is (3S)-3-amino-4-[2-[bis(2-chloroethyl)amino]-5-methyl-phenyl]butanoic acid (50) or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (1) is (3S)-3-amino-4-[2-[bis(2-chloroethyl)amino]-5-methoxy-phenyl]butanoic acid (51) or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (1) is (3S)-3-amino-4-[2-[bis(2-chloroethyl)amino]-5-(hydroxymethyl)phenyl]butanoic acid (52) or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the compound of Formula (1) is (3S)-3-amino-4-[2,5-bis[bis(2-chloroethyl)amino]phenyl]butanoic acid (53) or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the cell cycle inhibitor comprises a CDK 4/6 inhibitor. 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the cell cycle inhibitor comprises a selective inhibitor of T-cell proliferation. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the cell cycle inhibitor comprises a myelosuppressor. 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the cell cycle inhibitor comprises a mitotic inhibitor. 
     
     
         20 . The pharmaceutical composition of  claim 1 , wherein the cell cycle inhibitor comprises a checkpoint inhibitor. 
     
     
         21 . The pharmaceutical composition of  claim 1 , wherein the cell cycle inhibitor comprises an immunosuppressor.