Pharmaceutical Composition for Treating Cancer Comprising Trypsinogen and/or Chymotrypsinogen and an Active Agent Selected from a Selenium Compound, a Vanilloid Compound and a Cytoplasmic Glycolysis Reduction Agent

Abstract

The present invention generally relates to pharmaceutical compositions containing a protease proenzyme and use thereof for treating cancer. The pharmaceutical compositions are directed to compositions comprising a protease proenzyme and an active agent, the composition being capable of providing a multi-functional approach for treating cancer. The pharmaceutical compositions are also directed to compositions comprising a first and a second protease proenzyme capable of activation at or near a surface of a tumour cell to enhance cell-to-cell adhesion of tumour cells, effect proteolysis of tumour cells, or induce tumour cell apoptosis, differentiation or immunorecognition, wherein the first protease proenzyme is chymotrypsinogen and the second protease proenzyme is trypsinogen. The pharmaceutical compositions are also directed to compositions comprising a first and second active agent each capable of inducing intracellular activity in tumour cells.

1 . A pharmaceutical composition comprising a therapeutically effective combination of chymotrypsinogen and trypsinogen and a further active agent selected from at least one of a selenium compound, a vanilloid compound and a cytoplasmic glycolysis reduction agent, and a glycoside hydrolase. 
     
     
         2 . (canceled) 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the therapeutically effective combination of chymotrypsinogen:trypsinogen comprises a weight ratio in the range of between 4:1 to 8:1. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the weight ratio of chymotrypsinogen:trypsinogen is in the range of between 5:1 to 7:1. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the weight ratio of chymotrypsinogen:trypsinogen is 6:1. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the selenium compound is a compound of Formula I or Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 3  are each independently selected from H, OH, —C(O)H, —C(O)OH, —C(O)—OR 5 , C 1-4 alkyl and C 2-6 alkenyl, wherein C 1-4 alkyl and C 2-6 alkenyl are optionally substituted with 0-3 substituents independently selected from halogen, OH, —NH 2 , —C(O)OH, —C(O)—OR 5 ; 
 R 2  and R 4  are each independently selected from H, OH, —C(O)H, —C(O)OH, —C(O)—OR 5 , C 1-12 alkyl and C 2-12 alkenyl, wherein C 1-12 alkyl and C 2-12 alkenyl are optionally interrupted with one or more groups selected from —NH—, —N(C 1-4 alkyl)-, —NH(CO)—, —C(O)—, —C(O)O—, —O— and —C(NH 2 )H—C(O)O—, and optionally substituted with 0-3 substituents independently selected from halogen, —NH 2 , —OH, —C 1-4 alkyl, —C(O)OH, —C(O)H, —C(O)—OR 5 , —N(C 1-4 alkyl)H, —N(C 1-4 alkyl) 2 , —C(H 2 )H—C(O)OH, cycloalkyl, cycloalkenyl and aryl; and 
 wherein R5 is selected from alkyl, alkenyl, cycloalkyl and cycloalkenyl. 
 
       
     
     
         7 - 8 . (canceled) 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the selenium compound is methylselenocysteine or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the vanilloid compound is a compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2  are each independently selected from H, OH, OCH 3 , C(O)H, OC 2-6 alkyl, OC 2-6 alkenyl, SH, SC 1-6 alkyl, NH 2 , and NHC 1-6 alkyl and N(C 1-6 alkyl) 2 ; 
 R 3  and R4 are each independently selected from H, C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl, wherein the C 1-20 alkyl, C 2-20 alkenyl and C 2-20 alkynyl, are optionally interrupted with one or more groups selected from —NR 6 —, —NH(CO)—, —C(O)—, —C(O)O—, —O—, —C(NR 6 R 6 )H—C(O)O—, —C(S)—, —C(S)NR 6 — and —NR 6 —C(S)—NR 6 , and optionally substituted with 0-3 substituents independently selected from halogen, —NH 2 , —OH, —C 1-4 alkyl, —C(O)OH, —C(O)OR 5 , —C(O)H, —N(C 1-4 alkyl)H, —N(C 1-4 alkyl) 2 , —C(H 2 )H—C(O)OH, —C(S)—, optionally substituted cycloalkyl, optionally substituted cycloalkenyl and optionally substituted aryl; and 
 
         wherein R 5  is selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl; R 6  is selected from H, C 1-6 alkyl; and R 3  and R 4  may be joined to form an optionally substituted unsaturated or saturated ring having from 3 to 8 carbon atoms in the ring including from 0 to 3 heteroatoms selected from O, S and N. 
       
     
     
         11 - 12 . (canceled) 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the vanilloid compound is selected from capsiate, namely 4-hydroxy-3-methoxybenzyl (E)-8-methyl-6-nonenoate. 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein the glycoside hydrolase is a-amylase. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the cytoplasmic glycolysis reduction agent is 2-deoxy-D-glucose. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein the active agent is one or more of methylselenocysteine, capsiate, a-amylase, and 2-deoxy-D-glucose. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the active agent consists of methylselenocysteine, capsiate, a-amylase and 2-deoxy-D-glucose. 
     
     
         18 - 31 . (canceled) 
     
     
         32 . A method of treating cancer comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition according to  claim 1 . 
     
     
         33 - 37 . (canceled) 
     
     
         38 . A method of treating cancer comprising administering to a subject, a pharmaceutical composition comprising a therapeutically effective combination of chymotrypsinogen and trypsinogen, wherein the chymotrypsinogen is administered in the range of 0.2 mg/kg to 5 mg/kg and the trypsinogen is administered in the range of 0.01 mg/kg to 0.5 mg/kg 
     
     
         39 . The method of  claim 38  wherein the chymotrypsinogen administered is at least 0.2 mg/kg and the trypsinogen administered is less than 0.5 mg/kg. 
     
     
         40 . The method of  claim 38  wherein the chymotrypsinogen administered is the range of 0.2-5 mg/kg and the trypsinogen administered is in the range of 0.01-0.4 mg/kg. 
     
     
         41 . The method of  claim 38  wherein the chymotrypsinogen administered is the range of 0.5-2.0 mg/kg and the trypsinogen administered is in the range of 0.05-0.2 mg/kg. 
     
     
         42 . The method of  claim 38 , wherein the composition does not comprise amylase.