Chiral specific boron-containing compounds and their use in treating cancer or amyloidosis

Abstract

Useful chiral specific boron-containing compounds, such as boronate, boronate esters, boranamines, borane diamines, boranamine thioesters, and boronic mono/di-thioesters, have been prepared. These compounds and compositions containing them are useful as anti-cancer or anti-amyloidosis agents.

What is claimed is: 
     
         1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, and/or hydrate, polymorph crystal or amorphous forms, thereof, wherein:
 Z 3  is a peptide containing 1-20 amide bonds and boron atom attaches to a C atom, not an N atom nor —C═O; 
 Y 3  is C 1  to C 5 , O, S, NH, or NR; 
 R represents an aliphatic or aromatic group with or without heteroatom or functional group, such as COOH, OH, or NH 2 ; 
 each Ra 1  and Ra 2  independently is H, aliphatic, or aromatic substitution group; 
 each Ra 3  and Ra 4  independently is H, aliphatic, or aromatic substitution group; 
 q is 0, 1, or 2; and 
 r is 0, 1, or 2. 
 
     
     
         2 . The compound of  claim 1 , wherein Z 3  is characterized by the bare bones structure or its derivatives of the formula (XI-1): 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein Z 3  is characterized by the bare bones structure or its derivatives of the formula (XI-2): 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein Z 3  is characterized by the bare bones structure or its derivatives of the formula (XI-3): 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein said compound is one of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, and/or hydrate, polymorph crystal or amorphous form thereof, 
       wherein:
 Z 3  is a peptide containing 1-20 amide bonds and boron atom attaches to a C atom, not an N atom nor —C═O; 
 each of Y 1 , Y 2 , and Y 3  independently is O, S, NH, or NR; Y 3  can also be C 1  to C 5 ; 
 R represents an aliphatic or aromatic group with or without heteroatom or functional group, such as COOH, OH, or NH 2 ; 
 each Rb 1  and Rb 2  independently is H, aliphatic, or aromatic substitution group; Rb 1  and Rb 2  can also be a double bond, such as carbonyl group; each Rb 3  and Rb 4  independently is H, aliphatic, or aromatic substitution group; 
 s is 0, 1, or 2; and 
 t is 0, 1, or 2. 
 
     
     
         7 . The compound of  claim 6 , wherein said compound is characterized by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, and/or hydrate, polymorph crystal or amorphous form thereof, 
       wherein:
 Z 3  is a peptide containing 1-20 amide bonds and boron atom attaches to a C atom, not an N atom or —C═O; 
 each Rc 1  and Rc 2  independently is H, aliphatic, or aromatic substitution group; 
 each Rc 3  and Rc 4  independently is H, aliphatic, or aromatic substitution group, —(CH2) p —COOH and —(CH2) p —COOR wherein R is an aliphatic or aromatic group, with or without heteroatom or functional group, such as COOH, OH, or NH 2 ; and 
 u is 0, 1, or 2. 
 
     
     
         8 . The compound of  claim 6 , wherein said compound is characterized by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, and/or hydrate, polymorph crystal or amorphous forms, thereof, 
       wherein:
 Z 3  is a peptide containing 1-20 amide bonds and boron atom attaches to a C atom, not an N atom or —C═O; and 
 each Rd 1  and Rd 2  independently is H, aliphatic, aromatic substitution group, —(CH2) p —COOH and —(CH2) p —COOR wherein R is an aliphatic or aromatic group with or without heteroatom or functional group, such as COOH, OH, or NH 2 . 
 
     
     
         9 . The compound of  claim 6 , wherein said compound is characterized by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, and/or hydrate, polymorph crystal or amorphous form thereof, 
       wherein:
 Z 3  is a peptide containing 1-20 amide bonds and boron atom attaches to a C atom, not an N atom nor —C═O; 
 each Re 1  and Re 2  independently is H, aliphatic, aromatic substitution group, —(CH2) p —COOH and —(CH2) p —COOR wherein R is an aliphatic or aromatic group with or without heteroatom or functional group, such as COOH, OH, or NH 2 ; and 
 each Re 3  and Re 4  independently is H, aliphatic, aromatic substitution group, —(CH2) p —COOH and —(CH2) p —COOR wherein R is an aliphatic or aromatic group. 
 
     
     
         10 . The compound of  claim 6 , wherein said compound is characterized by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, and/or hydrate, polymorph crystal or amorphous form thereof, 
       wherein:
 Z 3  is a peptide containing 1-20 amide bonds and boron atom attaches to a C atom, not an N atom or —C═O; 
 each Rf 1  and Rf 2  independently is H, aliphatic, aromatic substitution group; 
 each Rf 3  and Rf 4  independently is H, aliphatic, aromatic substitution group, —(CH 2 ) p —COOH and —(CH2) p —COOR wherein R is an aliphatic or aromatic group with or without heteroatom or functional group, such as COOH, OH, or NH 2 ; and 
 v is 0, 1, or 2. 
 
     
     
         11 . The compound of  claim 6 , wherein said compound is characterized by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, and/or hydrate, polymorph crystal or amorphous form thereof, 
       wherein:
 Z 3  is a peptide containing 1-20 amide bonds and boron atom attaches to a C atom, not an N atom nor —C═O; 
 R represents an aliphatic or aromatic group with or without heteroatom or functional group, such as COOH, OH, or NH 2 ; 
 each Rg 1  and Rg 2  independently is H, aliphatic, aromatic substitution group; 
 each Rg 3  and Rg 4  independently is H, aliphatic, aromatic substitution group, —(CH2) p —COOH and —(CH2) p —COOR wherein R is an aliphatic or aromatic group with or without heteroatom or functional group, such as COOH, OH, NH 2 ; and 
 w is 0, 1, or 2. 
 
     
     
         12 . The compound of  claim 6 , wherein said compound is one of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A composition for treating cancer, a cancerous condition, or amyloidosis in a human or mammal, comprising as active ingredient a pharmaceutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable acid addition salt thereof, in combination with pharmaceutically acceptable carriers, diluents, or excipients. 
     
     
         14 . The composition of  claim 13  comprising active ingredient in an amount effective to treat multiple myeloma or amyloidosis. 
     
     
         15 . A method of treating cancer, a cancerous condition, or amyloidosis in a human or mammal host in need of such treatment, which comprises perorally, parentally, or rectally administering to said host an effective cancer, cancerous condition, or amyloidosis treatment amount of a compound of  claim 1  or a pharmaceutically acceptable acid addition salt thereof. 
     
     
         16 . A composition for treating cancer, a cancerous condition, or amyloidosis in a human or mammal, comprising as active ingredient a pharmaceutically effective amount of a compound of  claim 6  or a pharmaceutically acceptable acid addition salt thereof, in combination with pharmaceutically acceptable carriers, diluents, or excipients. 
     
     
         17 . The composition of  claim 16  comprising active ingredient in an amount effective to treat multiple myeloma or amyloidosis. 
     
     
         18 . A method of treating cancer, a cancerous condition, or amyloidosis in a human or mammal host in need of such treatment, which comprises perorally, parentally, or rectally administering to said host an effective cancer or cancerous condition treatment amount of a compound of  claim 6  or a pharmaceutically acceptable acid addition salt thereof.