Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents

Abstract

The present invention provides new uses of DPIV-inhibitors of the present invention, and their corresponding pharmaceutically acceptable acid addition salt forms, for treating conditions mediated by DPIV or DPIV-like enzymes, such as cancer and tumors. In a more preferred embodiment, the compounds of the present invention are useful for the treatment of metastasis and tumor colonization.

We claim:  
     
         1 . A method for reducing cancer or a related disorder comprising the step of administering a therapeutically effective amount of at least one inhibitor of dipeptidyl peptidase IV (DPIV) or DPIV-like enzyme activity, wherein said inhibitor is selected from the group consisting of dipeptide compounds, peptide compounds comprising tri-, tetra- and pentapeptides, peptidylketones, aminoketone derivatives and side chain modified DP IV inhibitors.  
     
     
         2 . The method according to  claim 1 , wherein the related disorder is metastasis.  
     
     
         3 . The method according to  claim 1 , wherein the related disorder is tumor colonization.  
     
     
         4 . The method according to  claim 1 , wherein the dideptidyl peptidase IV-like enzyme is selected from the group consisting of fibroblast activation protein α, dipeptidyl peptidase IV β, dipeptidyl aminopeptidase-like protein, N-acetylated α-linked acidic dipeptidase, quiescent cell proline dipeptidase, dipeptidyl peptidase II, attractin and dipeptidyl peptidase IV related protein (DPP 8), dipeptidyl peptidase 9 (DPP9) or KIAA1492.  
     
     
         5 . The method according to  claim 1 , wherein the structure of the dideptidyl peptidase IV-like enzyme is undiscovered.  
     
     
         6 . The method according to  claim 1 , wherein the inhibitor is a dipeptide compound formed from an amino acid and a thiazolidine or pyrrolidine group, and salts thereof.  
     
     
         7 . The method according to  claim 6  wherein the dipeptide compound is selected from the group consisting of L-threo-isoleucyl pyrrolidine, L-allo-isoleucyl thiazolidine, 1-allo-isoleucyl pyrrolydine, L-glutaminyl thiazolidine, L-glutaminyl pyrrolidine, L-glutamic acid thiazolidine, L-glutamic acid pyrrolidine and salts thereof.  
     
     
         8 . The method according to  claim 1  wherein the inhibitor is a peptide compound useful for competetive modulation of dipeptidyl peptidase IV catalysis represented by the general formula  
       
         
           
           
               
               
           
         
       
       wherein 
 A, B, C, D and E are any amino acid residues including proteinogenic amino acids, non-proteinogenic amino acids, L-amino acids and D-amino acids and wherein E and/or D may be absent or B and/or A may be absent provided that: 
 A is any amino acid residue except D-amino acid residues;  
 B is any proteinogenic amino acid residue, but  
 If B is an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid, then C is any amino acid residue including D-amino acids, except Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid and E may be unused to generate tetrapeptides of the formula A-B-C-D, or D and E may be unused to generate tripeptides of the formula A-B-C provided, but  
 If B is not an amino acid selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid, then C is any α-amino acid except D-amino acids; D is Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid; E is any amino acid residue including D-amino acids, except Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid, but  
 If D is Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid, then C is any α-amino acid except D-amino acids and Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid, and A may be unused to generate tetrapeptides of the formula B-C-D-E, or A and B may be unused to generate tripeptides of the formula C-D-E provided however,  
 If D is not selected from Pro, Ala, Ser, Gly, Hyp, acetidine-(2)-carboxylic acid or pipecolic acid, then E is any amino acid residue including D-amino acids.  
 
 
     
     
         9 . The method according to  claim 1 , wherein the inhibitor is peptidylketone represented by the general formula  
       
         
           
           
               
               
           
         
       
       including all stereoisomers and pharmaceutical acceptable salts thereof, wherein 
 A is selected from:  
                     
  and  
 X 1  is H or a acyl or oxycarbonyl group including all amino acids and peptide residues;  
 X 2  is H, —(CH) n —NH—C 5 H 3 N—Y with n=2-4 or C 5 H 3 N—Y (a divalent pyridyl residue) and Y is selected from H, Br, Cl, I, NO 2  or CN;  
 X 3  is H or selected from an alkyl, alkoxy, halogen, nitro, cyano or carboxy substituted phenyl or pyridyl residue;  
 X 4  is H or selected from an alkyl, alkoxy, halogen, nitro, cyano or carboxy substituted phenyl or pyridyl residue;  
 X 5  is H or an alkyl, alkoxy or phenyl residue; and  
 X 6  is H or a alkyl residue; provided that  
 for n=1, X  
 is selected from: H, OR 2 , SR 2 , NR 2  R 3 , N + R 2  R 3 R 4 , wherein: 
 R 2  stands for acyl residues, which are substituted with alkyl, cycloalkyl, aryl or heteroaryl residues, or for all amino acids and peptidic residues, or alkyl residues, which are substituted with alkyl, cycloalkyl, aryl and heteroaryl residues;  
 R 3  stands for alkyl and acyl functions, wherein R 2  and R 3  may be embedded in ring structures of saturated and unsaturated carbocyclic or heterocyclic structures;  
 R 4  stands for alkyl residues, wherein R 2  and R 4  or R 3  and R 4  may be embedded in ring structures of saturated and unsaturated carbocyclic or heterocyclic structures; and  
 for n=0, X  
 
 is selected from:  
                     
  wherein 
 B stands for: O, S, NR 5 , wherein R 5  is H, a alkyl or acyl, C, D, E, F, G, H are independently selected from alkyl and substituted alkyl residues, oxyalkyl, thioalkyl, aminoalkyl, carbonylalkyl, acyl, carbamoyl, aryl and heteroaryl residues; and  
 Z is selected from H, or a branched or single chain alkyl residue from C 1 -C 9  or a branched or single chain alkenyl residue from C 2 -C 9 , a cycloalkyl residue from C 3 -C 8 , a cycloalkenyl residue from C 5 -C 7 , a aryl- or heteroaryl residue, or a side chain selected from all side chains of all natural amino acids or derivatives thereof.  
 
 
     
     
         10 . The method according to  claim 1  wherein the inhibitor is a aminoketone derivative represented by the general formulas 5, 6, 7, 8, 9, 10 and 11, including all stereoisomers and pharmaceutical acceptable salts thereof,  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is H, a branched or linear C 1 -C 9  alkyl residue, a branched or linear C 2 -C 9  alkenyl residue, a C 3 -C 8  cycloalkyl-, C 5 -C 7  cycloalkenyl-, aryl- or heteroaryl residue or a side chain of a natural amino acid or a derivative thereof;  
 R 3  and R 4  are selected from H, hydroxy, alkyl, alkoxy, aryloxy, nitro, cyano or halogen,  
 A is H or an isoster of an carbonic acid, like a functional group selected from CN, SO 3 H, CONHOH, PO 3 R 5 R 6 , tetrazole, amide, ester, anhydride, thiazole and imidazole;  
 B is selected from:  
                     
  wherein: 
 R 5  is H, —(CH) n —NH—C 5 H 3 N—Y with n=2-4 and C 5 H 3 N—Y (a divalent pyridyl residue) with Y=H, Br, Cl, I, NO 2  CN;  
 R 10  is H, a acyl, oxycarbonyl or a amino acid residue;  
 W is H or a phenyl or pyridyl residue, substituted with alkyl, alkoxy, halogen, nitro, cyano or carboxy residue;  
 W 1  is H, a alkyl, alkoxy or phenyl residue;  
 Z is H or a phenyl or pyridyl residue, substituted with alkyl, alkoxy, halogen, nitro, cyano or carboxy residue;  
 Z 1  is H or a alkyl residue;  
 D is a cyclic C 4 -C 7  alkyl, C 4 -C 7  alkenyl residue or a alkyl substituted derivative thereof or a cyclic 4-7-membered heteroalkyl or 4-7-membered heteroalkenyl residue;  
 X 2  is O, NR 6 , N + (R 7 ) 2 , or S;  
 X 3  to X 12  are selected from CH 2 , CR 8 R 9 , NR 6 , N + (R 7 ) 2 , O, S, SO and SO 2 , including all saturated and unsaturated structures;  
 R 6 , R 7 , R 8 , R 9  are selected from H, a branched or linear C 1 -C 9  alkyl residue, a branched or lienar C 2 -C 9  alkenyl residue, a C 3 -C 8  cycloalkyl residue, a C 5 -C 7  cycloalkenyl residue, an aryl or heteroaryl residue;  
 with the following provisos:  
 
 Formula 6: X 6  is CH if A is not H;  
 Formula 7: X 10  is C if A is not H;  
 Formula 8: X 7  is CH if A is not H; and  
 Formula 9: X 12  is C if A is not H.  
 
     
     
         11 . The method according to  claim 1 , wherein the inhibitor is a side chain modified inhibitor of DPIV or DPIV-like enzyme activity represented by the general formula,  
       
         
           
           
               
               
           
         
       
       including all stereoisomers and pharmaceutical acceptable salts thereof, wherein 
 A is an amino acid having at least one functional group in the side chain;  
 B is a chemical compound covalently bound to at least one functional group of the side chain of A, namely 
 oligopeptides having a chain length of up to 20 amino acids, except for homopolymers of glycine consisting of up to 6 glycine monomers; or  
 polyethylene glycols having molar masses of up to 20,000 g/mol; or  
 optionally substituted organic amines, amides, alcohols, acids or aromatic compounds having from 8 to 50 C atoms; and  
 
 C is a thiazolidine, pyrrolidine, cyanopyrrolidine, hydroxyproline, dehydroproline or piperidine group amide-bonded to A.  
 
     
     
         12 . The method according to  claim 11 , wherein A is an amino acid, preferably an α-amino acid, especially a natural α-amino acid having at least one functional group in the side chain selected from the group consisting of threonine, tyrosine, serine, arginine, lysine, aspartic acid, glutamic acid or cysteine.  
     
     
         13 . The method according to  claim 8  wherein said inhibitor is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a said inhibitor or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         14 . A pharmaceutical composition comprising: an inhibitor of DPIV or DPIV-like enzyme activity or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for inhibiting dipeptidyl peptidase IV or dipeptidyl peptidase IV-like enzyme activity for the prevention or treatment of diseases or conditions related to dipeptidyl peptidase IV or dipeptidyl peptidase IV-like enzymes.  
     
     
         15 . The pharmaceutical composition according to  claim 14  for the manufacture of a medicament for the treatment of cancer and related disorders.  
     
     
         16 . The pharmaceutical composition according to  claim 14  for the manufacture of a medicament for the treatment of metastasis.  
     
     
         17 . The pharmaceutical composition according to  claim 14  for the manufacture of a medicament for the treatment of tumor colonization.  
     
     
         18 . The method according to  claim 9  wherein said inhibitor is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a said inhibitor or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         19 . The method according to  claim 10  wherein said inhibitor is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a said inhibitor or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         20 . The method according to  claim 11  wherein said inhibitor is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of a said inhibitor or a pharmaceutically acceptable acid addition salt thereof.