Novel Boronic Chalcone Derivatives and Uses Thereof

Abstract

The present invention relates to novel boronic chalcone derivatives which are useful as antitumor/anticancer agents. The present compounds, which are inexpensive to synthesize, exhibit unexpectedly good inhibitors of the growth of human breast cancer cells. The present invention also relates to the use of the novel boronic chalcone derivatives to treat cancer. The invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing the inhibitors and pharmaceutical compositions in the treatment and prevention of cancer.

1 . A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the Formula (I): 
     
       
         
         
             
             
         
       
     
     where:
 Ar is aryl or heteroaryl, each of which may be unsubstituted or substituted with a substituent selected from the group consisting of F, CI, Br, I, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -OR 1 , Z n -NO 2 , Z n -CN, Z n -CO 2 R 1 , Z n -(C═O)R 1 , Z n -O(C═O)R 1 , Z n —O-alkyl, Z n -OAr, Z n -SH, Z n -SR 1 , Z n -SOR 1 , Z n -SO 2 R 1 , Z n -S—Ar, Z n -SOAr, Z n -SO 2 Ar, Z n —Ar, Z n -heteroaryl, Z n -(C═O)NR 1 R 2 , Z n -NR 1 (C═O)R 1 , Z n -SO 2 NR 1 R 2 , PO 3 H 2 , and SO 3 H 2 ; 
 W is H, Z n -F, Z n -Cl, Z n -Br, Z n -I, Z n -CF 3 , Z n -NO 2 , Z n -OR 1 , Z n -NR 1 R 2 , Z n -COOR 1 , Z n -SR 1 , Z n -(C═O)R 1 , Z n -O(C═O)R 1 , Z n -NR 1 (C═O)R 1 , Z n -(C═O)NR 1 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 X is Z n , Z n -O, Z n -S, Z n -NR 1 , Z n -NR 1 (C═O), Z n -C═O, Z n -OC(═O), or Z n -C(═O)O; 
 R 1  and R 2  are independently H, an amine protecting group, an alcohol protecting group, an acid protecting group, a sulfur protecting group, alkyl, ally), alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted, 
 or R 1  together with R 2  and N forms a saturated or partially unsaturated heterocycle ring having 1 or more heteroatoms in said ring, wherein said heterocycle may be substituted or unsubstituted and wherein said heterocycle may be fused to an aromatic ring; 
 Z is an alkylene having at least 1 carbon, or an alkenylene or alkynylene each having at least 2 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted; and 
 n is zero or any integer. 
 
   
   
       2 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       3 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       4 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       5 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       6 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       7 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       8 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       9 . The compound of  claim 1  having the structure 
     
       
         
         
             
             
         
       
     
   
   
       10 . A compound including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof, said compound having the Formula (III): 
     
       
         
         
             
             
         
       
     
     where
 Ar is aryl or heteroaryl, each of which may be substituted or unsubstituted; 
 R 4  is H, an amine protecting group, Z n -OR 1 , Z n -SR 1 , Z n -NR 1 , Z n -NR 1 (C═O)R 1 , Z n -C═OR 1 , Z n -OC(═O)R 1 , Z n -C(═O)OR 1 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl,-heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 R 1  is H, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted, 
 Z is an alkylene having at least 1 carbon, or an alkenylene or alkynylene each having at least 2 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted; and 
 n is zero or any integer. 
 
   
   
       11 . A method of treating a tumor or cancer in a patient in need thereof comprising administering to said patient an effective amount of a compound having the Formula (III): 
     
       
         
         
             
             
         
       
     
     where
 Ar is aryl or heteroaryl, each of which may be substituted or unsubstituted; 
 R 4  is H, an amine protecting group, Z n -OR 1 , Z n -SR 1 , Z n -NR 1 , Z n -NR 1 (C═O)R 1 , Z n -C═OR 1 , Z n -OC(═O)R 1 , Z n -C(═O)OR 1 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, ally), alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 R 1  is H, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 Z is an alkylene having at least 1 carbon, or an alkenylene or alkynylene each having at least 2 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted; and 
 n is zero or any integer. 
 
   
   
       12 . The method of  claim 11 , wherein said tumor is selected from the group consisting of breast, cervical, stomach, colon, bladder, rectal, liver, pancreatic, lung, cervix uteri, corpus uteri, ovary, prostate, testis, renal, brain/cns, head, neck, throat, anal and oral cancers, eye or ocular cancer, skin melanoma, Ewing's Sarcoma, Kaposi's Sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, mouth/pharynx, esophageal, larynx, kidney and lymphoma, acute lymphocytic leukemia, and acute myelogenous leukemia. 
   
   
       13 . A method of inhibiting MDM2 expression in a mammal, comprising administering an amount of a compound effective to inhibit said expression, said compound having the Formula (I): 
     
       
         
         
             
             
         
       
     
     where
 Ar is aryl or heteroaryl, each of which may be substituted or unsubstituted; 
 W is H, Z n -F, Z n -CI, Z n -Br, Z n -I, Z n -CF 3 , Z n -NO 2 , Z n -OR 1 , Z n -NR 1 R 2 , Z n -COOR 1 , Z n -SR 1 , Z n -(C═O)R 1 , Z n -O(C═O)R 1 , Z n -NR 1 (C═O)R 1 , Z n -(C═O)NR 1 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 X is Z n , Z n -O, Z n -S, Z n -NR 1 , Z n -NR 1 (C═O), Z n -C═O, Z n -OC(═O), or Z n -C(═O)O; 
 R 1  and R 2  are independently H, an amine protecting group, an alcohol protecting group, an acid protecting group, a sulfur protecting group, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted, 
 or R 1  together with R 2  and N forms a saturated or partially unsaturated heterocycle ring having 1 or more heteroatoms in said ring, wherein said heterocycle may be substituted or unsubstituted and wherein said heterocycle may be fused to an aromatic ring; 
 Z is an alkylene having at least 1 carbon, or an alkenylene or alkynylene each having at least 2 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted; and 
 n is zero or any integer. 
 
   
   
       14 . A method of inhibiting MDM2 expression in a mammal, comprising administering an amount of a compound effective to inhibit said expression, said compound having the Formula (II): 
     
       
         
         
             
             
         
       
     
     where
 Ar is aryl or heteroaryl, each of which may be substituted or unsubstituted; 
 W is H, Z n -F, Z n -CI, Z n -Br, Z n -I, Z n -CF 3 , Z n -NO 2 , Z n -OR 1 , Z n -NR 1 R 2 , Z n -COOR 1 , Z n -SR 1 . Z n -(C═O)R 1 , Z n -O(C═O)R 1 , Z n -NR 1 (C═O)R 1 , Z n -(C═O)NR 1 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 X is Z n , Z n -O, Z n -S, Z n -NR 1 , Z n -NR 1 (C═O), Z n -C═O, Z n -OC(═O), or Z n -C(═O)O; 
 R 1  and R 2  are independently H, an-amine protecting group, an alcohol protecting group, an acid protecting group, a sulfur protecting group, alkyl, ally), alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl. allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted, 
 or R 1  together with R 2  and N forms a saturated or partially unsaturated heterocycle ring having 1 or more heteroatoms in said ring, wherein said heterocycle may be substituted or unsubstituted and wherein said heterocycle may be fused to an aromatic ring; 
 R 3  is an electron-withdrawing moiety; 
 Z is an alkylene having at least 1 carbon, or an alkenylene, or alkynylene each having at least 2 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted; and 
 n=zero or any integer. 
 
   
   
       15 . A method of inhibiting MDM2 expression in a mammal, comprising administering an amount of a compound effective to inhibit said expression, said compound having the Formula (III): 
     
       
         
         
             
             
         
       
     
     where
 Ar is aryl or heteroaryl, each of which may be substituted or unsubstituted; 
 R 4  is H, an amine protecting group, Z n -OR 1 , Z n -SR 1 , Z n -NR 1 , Z n -NR 1 (C═O)R 1 , Z n -C═OR 1 , Z n -OC(═O)R 1 , Z n -C(═O)OR 1 , alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, or Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 R 1  is H, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl, wherein said alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Z n -cycloalkyl, Z n -heterocycloalkyl, Z n -Ar or Z n -heteroaryl may be substituted or unsubstituted; 
 Z is an alkylene having at least 1 carbon, or an alkenylene or alkynylene each having at least 2 carbons, wherein said alkylene, alkenylene, or alkynylene may be substituted or unsubstituted; and 
 n is zero or any integer.