Compounds for the modulation of the glykolysis-enzyme-and/or of the transaminase-complex

Abstract

The invention relates to compounds for the modulation of the glycolysis enzyme complex and of the transaminase complex, pharmaceutical compositions containing such compounds as well as uses of such compounds for preparing pharmaceutical compositions for treating various diseases.

1 . A method for treating cancer comprising administering a pharmaceutical composition comprising a compound that is mixed with one or several physiologically well tolerated auxiliary substances and/or carrier substances and galenically prepared for local, oral, or systemic administration comprising intravenous administration, wherein the compound is according to formula I  
     
       
         
         
             
             
         
       
       wherein R1=-H, —CN, —COO+, —COS+, —COOH, —COSH, —COOR1.1, —COSR1.1, N-phthalimidyl,  
       wherein R1.1=-H, C1-10 alkyl, C1-10 aralkyl or aryl,  
       wherein R2=-H, C1-C4 alkyl, —OR1.1, -Hal (—F —Cl, —Br, -J), —NR2.1R2.2, —Am, —O—Am, —S—Am,  
       wherein R3=-H, C1-C4 alkyl, —OR1.1, -Hal (—F —Cl, —Br, -J), —NR2.1R2.2, —Am, —O—Am, —S—Am,  
       wherein R2.1=-H, C1-10 alkyl, C1-10 aralkyl or aryl,  
       wherein R2.2=-H, C1-10 alkyl, C1-10 aralkyl or aryl,  
       wherein R2.1 and R2.2 may be identical or different,  
       wherein n and m may be identical or different and 0 to 10,  
       wherein o and p may be identical or different and 0 to 3,  
       wherein o>0, if n and m=0,  
       wherein R2 and R3 may be identical or different for Cn and/or Cm,  
       wherein R2 may be identical or different for every Cx=1 . . . n,  
       wherein R3 may be identical or different for every Cy=1 . . . m,  
       wherein —Am is an amino acid radical,  
       wherein q and r=0 or 1 and identical or different,  
       wherein —O r — and/or —O q — may also be replaced by —S r — or —S q —, resp.,  
       wherein —NR2.1R2.2 may be replaced by a linear or branched —C1-C20 alkyl, aralkyl or aryl,  
       wherein a group —CN, —(CO)—CN, —(CO)—O—R1 or —(CO)—R1 or —C—O—R1 may be replaced by —SO 2 —NR2.1R2.2, or a physiologically well tolerated salt of such a compound.  
     
   
   
       2 . The method according to  claim 1 , wherein the cancer comprises tumor cells which overexpress a tumor marker comprising glycolytic enzyme comprising pyruvate kinase M2 as compared to non-cancerous cells.  
   
   
       3 . The method according to  claim 2 , wherein the tumor cells comprise hepatoma cells.  
   
   
       4 . The method according to  claim 1 , wherein the cancer comprises cancer of the liver.  
   
   
       5 . The method according to  claim 1 , wherein R1=-CN.  
   
   
       6 . The method according to  claim 1 , wherein at least one of the R2 is —Am, wherein —Am preferably represents an amino acid radical of an essential amino acid, wherein in particular q=0 and r=1 or q=1 and r=0 or q=1 and r=1, m=1, R3=-H, n=o=p=0, R2.1=R2.2=-H.  
   
   
       7 . The method according to  claim 1 , wherein n=o=p=0, wherein m=0 to 4, wherein R2=R3=-H, or for at least one R2, R2=-Am, wherein R2.1=R2.2=-H, wherein q=0 and r=1.  
   
   
       8 . The method according to  claim 1 , wherein m=p=0, wherein o=1, wherein n=0 to 4, wherein R2=H, or for at least one R2, R2=-Am, wherein R3=-H or -Hal in the case Cx=1, wherein R3=-H for all Cx=n>1, wherein R2.1=R2.2=-H, wherein q=0 and r=1.  
   
   
       9 . The method according to  claim 1 , wherein m=1 to 4, wherein n=o=p=0, wherein R2=H, or for at least one R2, R2=-Am, wherein R3=-H or -Hal in the case Cy=1, wherein R3=-H for all Cy=m>1, wherein R2.1=R2.2=-H, wherein q=0 and r=1.  
   
   
       10 . The method according to  claim 1 , wherein o=p=1, wherein m=0, wherein n=0 to 4, wherein R2=R3=-H, or for at least one R2, R2=-Am, wherein R2.1=R2.2=-H, wherein q=0 and r=1.  
   
   
       11 . The method according to  claim 1 , wherein n=p=0, wherein o=1, wherein m=0 to 4, wherein R2=R3=-H, or for at least one R2, R2=-Am, wherein R2.1=R2.2=-H, wherein q=0 and r=1.  
   
   
       12 . The method according to  claim 1 , wherein m=p=0, wherein o=1, wherein n=1 to 4, wherein R2=R3=-H, or for at least one R2, R2=-Am, wherein R2.1=R2.2=-H, wherein q=0 and r=1.  
   
   
       13 . A method of treating cancer comprising tumor cells which overexpress a tumor market comprising pyruvate kinase M2 compared to non-cancerous cells, comprising administering a pharmaceutical composition comprising a compound according to formula I  
     
       
         
         
             
             
         
       
       wherein R1=-H, —CN, —COO+, —COS+, —COOH, —COSH, —COOR1.1, —COSR1.1, N-phthalimidyl,  
       wherein R1.1=-H, C1-10 alkyl, C1-10 aralkyl or aryl,  
       wherein R2=-H, C1-C4 alkyl, —OR1.1, -Hal (—F —Cl, —Br, -J), —NR2.1R2.2, —Am, —O—Am, —S—Am,  
       wherein R3=-H, C1-C4 alkyl, —OR1.1, -Hal (—F —Cl, —Br, -J), —NR2.1R2.2, —Am, —O—Am, —S—Am,  
       wherein R2.1=-H, C1-10 alkyl, C1-10 aralkyl or aryl,  
       wherein R2.2=-H, C1-10 alkyl, C1-10 aralkyl or aryl,  
       wherein R2.1 and R2.2 may be identical or different,  
       wherein n and m may be identical or different and 0 to 10,  
       wherein o and p may be identical or different and 0 to 3,  
       wherein o>0, if n and m=0,  
       wherein R2 and R3 may be identical or different for Cn and/or Cm,  
       wherein R2 may be identical or different for every Cx=1 . . . n,  
       wherein R3 may be identical or different for every Cy=1 . . . m,  
       wherein —Am is an amino acid radical,  
       wherein q and r=0 or 1 and identical or different,  
       wherein —O r — and/or —O q — may also be replaced by —S r — or —S q —, resp.,  
       wherein —NR2.1R2.2 may be replaced by a linear or branched —C1-C20 alkyl, aralkyl or aryl,  
       wherein a group —CN, —(CO)—CN, —(CO)—O—R1 or —(CO)—R1 or —C—O—R1 may be replaced by —SO 2 —NR2.1R2.2, or a physiologically well tolerated salt of such a compound.  
     
   
   
       14 . The method according to  claim 2 , wherein the compound inhibits glycolysis of the tumor cells.  
   
   
       15 . The method according to  claim 2 , wherein the compound inhibits the activity of the pyruvate kinase M2 of the tumor cells.  
   
   
       16 . The method according to  claim 1 , wherein the cancer comprises solid tumors.  
   
   
       17 . A method for in vitro detection of heart insufficient or chronic cardiac failure comprising comparing a level of pyruvate kinase type M2 in a blood plasma sample of a patient with a predetermined standard level, wherein the level of pyruvate kinase type M2 in the blood plasma sample is measured by an immunological assay using monoclonal antibodies targeted to detect pyruvate kinase type M2.  
   
   
       18 . A method for treating one or several diseases from the group comprising cancer, chronic inflammations, asthma, arthritis, osteoarthritis, chronic polyarthritis, rheumatic arthritis, inflammatory bowl disease, degenerative joint diseases, rheumatic diseases with cartilage disorders, sepsis, autoimmune diseases, type I diabetes, Hashimoto thyreoiditis, autoimmune thrombocytopenia, multiple sclerosis, myasthenia gravis, chronically inflammatory intestinal diseases, Crohn's disease, uveitis, psoriasis, collagenoses, Goodpasture syndrome, diseases with disturbed leukocyte adhesion, cachexia, diseases by increased TNF-alpha concentration, diabetes, adiposity, bacterial infections including those by antibiotic resistant bacteria comprising administering a pharmaceutical composition prepared comprising the compound according to  claim 1.