Beta-hairpin peptidomimetics as selective elastase inhibitors

Abstract

These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

1 . A backbone cyclized peptidic compound, built up from 13 amino acid residues, of the general formula
   cyclo(-Xaa 1 -Xaa 2 -Thr 3 -Xaa 4 -Ser 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Xaa 11 -Xaa 12 -Xaa 13 -)   (I),
   and pharmaceutically acceptable salts thereof,   wherein   Xaa 1  is OctGly; Arg; hArg; Cha; Glu(Phenethyl); or Dab(Butanoyl);   Xaa 2  is Glu; Val; Leu; Nle; Phe; hPhe; DiHPhe; Tyr; hTyr; or Trp;   Xaa 4  is Ala; AllylGly; Abu; or Val;   Xaa 6  is Ile; or OctGly;   Xaa 7  is Pro;   Xaa 8  is Pro;   Xaa 9  is Gln; or Tyr;   Xaa 10  is Lys; or Asn;   Xaa 11  is hLeu; Ser; hSer; hSer(Me); Thr; alloThr; Asn; Gln; hGln; Dap; Tyr; or His;   Xaa 12  is  D Pro; and   Xaa 13  is Pro; Tic; Glu; Asp; Ala; Val; or Lys;   with the proviso that
 if Xaa 1  is OctGly, then 
 Xaa 2  is Glu; or Nle; 
 Xaa 4  is Ala; or Abu; 
 Xaa 6  is Ile; or OctGly; 
 Xaa 10  is Lys; 
 Xaa 11  is Ser; Thr; Asn; or Gln; 
 Xaa 13  is Pro; Tic; Ala; Val; or Lys; 
 and/or if Xaa 6  is OctGly, then 
 Xaa 1  is OctGly; Arg; or Cha; 
 Xaa 2  is Glu; or Nle; 
 Xaa 4  is Ala; or Abu; 
 Xaa 10  is Lys; 
 Xaa 11  is Ser; Thr; Asn; Gln; 
 Xaa 13  is Pro; Tic; Ala; Val; or Lys; 
   and with the further proviso that
 if Xaa 11  is Tyr; or His, then 
 Xaa 1  is Arg; hArg; or Glu(Phenethyl). 
   
     
     
         2 . A compound according to  claim 1  of the formula I wherein
 Xaa 1  is OctGly; Arg; hArg; or Glu(Phenethyl); 
 Xaa 2  is Glu; Nle; hTyr; or Val; 
 Xaa 4  is Ala; or AllylGly; 
 Xaa 6  is Ile; 
 Xaa 7  is Pro; 
 Xaa 8  is Pro; 
 Xaa 9  is Gln; or Tyr; 
 Xaa 10  is Lys; 
 Xaa 11  is hLeu; Ser; Thr; Asn; Tyr; hGln; or His; 
 Xaa 12  is  D Pro; and 
 Xaa 13  is Pro; 
 with the proviso that
 if Xaa 1  is OctGly, then 
 Xaa 2  is Glu; or Nle; 
 Xaa 4  is Ala; 
 Xaa 6  is Ile; 
 Xaa 10  is Lys; 
 Xaa 11  is Ser; Thr; or Asn 
 Xaa 13  is Pro; 
 
 and with the further proviso that
 if Xaa 11  is Tyr; or His, then 
 Xaa 1  is Arg; hArg or Glu(Phenethyl). 
 
 
     
     
         3 . A compound according to  claim 1  of the formula I wherein
 Xaa 1  is OctGly; Arg; or Glu(Phenethyl); 
 Xaa 2  is Glu; Nle; hTyr; or Val; 
 Xaa 4  is Ala; 
 Xaa 6  is Ile; 
 Xaa 7  is Pro; 
 Xaa 8  is Pro; 
 Xaa 9  is Gln; or Tyr; 
 Xaa 10  is Lys; 
 Xaa 11  is Ser; Thr; Asn; Tyr; or His; 
 Xaa 12  is  D Pro; and 
 Xaa 13  is Pro; 
 with the proviso that
 if Xaa 1  is OctGly, then 
 Xaa 2  is Glu; or Nle; 
 
 and with the further proviso that
 if Xaa 11  is Tyr; or His, then 
 Xaa 1  is Arg. 
 
 
     
     
         4 . A compound according to  claim 1  of the formula I wherein
 Xaa 1  is Arg; or hArg; 
 Xaa 2  is Glu; Val; or hTyr; 
 Xaa 4  is Ala; or AllylGly; 
 Xaa 6  is Ile; 
 Xaa 7  is Pro; 
 Xaa 8  is Pro; 
 Xaa 9  is Gln; or Tyr; 
 Xaa 10  is Lys; 
 Xaa 11  is hLeu; Ser; Thr; or hGln; 
 Xaa 12  is  D Pro; and 
 Xaa 13  is Pro. 
 
     
     
         5 . A compound according to  claim 1  which is selected from
 Cyclo(-OctGly-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Asn- D Pro-Pro-); 
 Cyclo(-OctGly-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Tyr-Lys-Thr- D Pro-Pro-); 
 Cyclo(-OctGly-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Ser- D Pro-Pro-); 
 Cyclo(-OctGly-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Thr- D Pro-Pro-); 
 Cyclo(-Arg-hTyr-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr- D Pro-Pro-); 
 Cyclo(-Arg-Nle-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr- D Pro-Pro-); 
 Cyclo(-Arg-Glu-Thr-AllylGly-Ser-Ile-Pro-Pro-Gln-Lys-Thr- D Pro-Pro-); 
 Cyclo(-Arg-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Tyr-Lys-Ser- D Pro-Pro-); 
 Cyclo(-hArg-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Thr- D Pro-Pro-); 
 Cyclo(-Arg-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-hLeu- D Pro-Pro-); 
 Cyclo(-Arg-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Thr- D Pro-Pro-); 
 Cyclo(-Arg-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Tyr-Lys-hGln- D Pro-Pro-); 
 Cyclo(-Arg-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Tyr-Lys-Thr- D Pro-Pro-); 
 Cyclo(-Arg-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Tyr-Lys-His- D Pro-Pro-); 
 Cyclo(-Glu(Phenethyl)-Glu-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr- D Pro-Pro-); 
 Cyclo(-Arg-Val-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Thr- D Pro-Pro-); 
 Cyclo(-Arg-hTyr-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Thr- D Pro-Pro-); 
 Cyclo(-Arg-Val-Thr-Ala-Ser-Ile-Pro-Pro-Gln-Lys-Tyr- D Pro-Pro-). 
 
     
     
         6 . A compound according to  claim 1  of the formula I, in free form or in pharmaceutically acceptable salt form, for use as a medicament. 
     
     
         7 . A compound according to  claim 1  of the formula I, in free form or in pharmaceutically acceptable salt form, having inhibitory activity against elastase for the treatment or prevention of lung cancer; breast cancer; psoriasis; alpha 1 antitrypsin deficiency; pulmonary emphysema; cystic fibrosis; chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; bronchiectasis; pulmonary hypertension; arterial pulmonary hypertension; cardiac hypertrophy; myocarditis; acute myocardial infarction; rheumatoid arthritis; osteoarthritis; atherosclerosis; multiple sclerosis; pancreatitis; allergic rhinitis; systemic inflammatory respiratory syndrome; inflammatory dermatoses; inflammatory bowel disease; or Crohn's disease. 
     
     
         8 . A pharmaceutical composition comprising a compound or a mixture of compounds according to  claim 1  of the formula I, in free form or in pharmaceutically acceptable salt form, and a pharmaceutically inert carrier, particularly in a form suitable for inhalation, for oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration especially in the form of a tablet, dragee, capsule, solution, liquid, gel, plaster, cream, ointment, syrup, slurry, suspension, powder or suppository. 
     
     
         9 . A method of selectively inhibiting protease activity, in particular against human neutrophil elastase, and/or inducing anticancer activity and/or anti inflammatory activity and/or anti infective activity and/or anticardiovascular activity and/or antiimmunological activity and/or antineurodegenerative activity, said method comprising:
 administering a therapeutically effective amount of a compound according to  claim 1 , in free form or in pharmaceutically acceptable salt form.   
     
     
         10 . A method for inhibiting elastase activity for the treatment or prevention of infections or diseases related to such infections; or, such as lung cancer, or breast cancer, mediated or resulting from; or immunological diseases, such as psoriasis, mediated or resulting from; or pulmonary diseases, such as alpha 1 antitrypsin deficiency, pulmonary emphysema, cystic fibrosis, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, bronchiectasis, pulmonary hypertension, or arterial pulmonary hypertension, mediated or resulting from; or cardiovascular diseases, such as cardiac hypertrophy, myocarditis, or acute myocardial infarction, mediated or resulting from; or neurodegenerative diseases mediated or resulting from; or inflammation or diseases related to inflammation, such as rheumatoid arthritis, osteoarthritis, atherosclerosis, multiple sclerosis, pancreatitis, allergic rhinitis, systemic inflammatory respiratory syndrome, inflammatory dermatoses, inflammatory bowel disease, or Crohn's disease, mediated or resulting from elastase activity; or where immunological reaction is mediated or resulting from elastase activity, said method comprising:
 administering a therapeutically acceptable amount of a compound according to  claim 1 , in free form or in pharmaceutically acceptable salt form, or a pharmaceutical composition containing the compound in free form or in pharmaceutically acceptable form, and a pharmaceutically inert carrier, particularly in a form suitable for inhalation, for oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration especially in the form of a tablet, dragee, capsule, solution, liquid, gel, plaster, cream, ointment, syrup, slurry, suspension, powder or suppository.   
     
     
         11 . (canceled) 
     
     
         12 . A method of treating an infection or a disease or disorder associated with such an infection resulting from; or cancer mediated or resulting from; or immunological diseases mediated or resulting from; or pulmonary diseases mediated or resulting from; or cardiovascular diseases mediated or resulting from; or neurodegenerative diseases mediated or resulting from; or inflammation mediated or resulting from elastase activity; or where immunological reaction is mediated or resulting from elastase activity, comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a compound or pharmaceutical composition according to  claim 1 . 
     
     
         13 . A process for the manufacture of a compound as defined in  claim 1  of the formula I comprising the steps of
 (a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the desired end-product corresponds to Xaa n , wherein n is 13, 8, 7, 6, 5 or 4, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; 
 (b) removing the N-protecting group from the product thus obtained; 
 (c) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which in the desired end-product corresponds to Xaa n−1 , any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected; 
 (d) removing the N-protecting group from the product obtained in step (c); 
 (e) effecting steps substantially corresponding to steps (c) and (d) using appropriately N-protected derivatives of amino acids which in the desired end-product are in positions n−2 to 1, any functional group(s) which may be present in said N-protected amino acid derivatives being likewise appropriately protected; 
 (f) if n is not 13, further effecting steps substantially corresponding to steps (c) and (d) using appropriately N-protected derivatives of amino acids which in the desired end-product are in positions 13 to n+1, any functional group(s) which may be present in said N-protected amino acid derivatives being likewise appropriately protected; 
 (g) detaching the product thus obtained from the solid support; 
 (h) cyclizing the product cleaved from the solid support; 
 (i) removing any protecting groups present on functional groups of any members of the chain of amino acid residues; and 
 (j) if desired, converting the product thus obtained into a pharmaceutically acceptable salt or converting a pharmaceutically acceptable, or unacceptable, salt thus obtained into the corresponding free compound or into a different, pharmaceutically acceptable, salt.