Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity

Patent metadata

Field	Value
Publication number	US-10562933-B2
Application number	US-201816130520-A
Country	US
Kind code	B2
Filing date	Sep 13, 2018
Priority date	Feb 17, 2005
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

Abstract

Template-fixed β-hairpin peptidomimetics of the general formulae

wherein Z is a chain of 11 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or Pro(4NHCOPhe), or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to inhibit proteases, in particular serine proteases, especially Cathepsin G or Elastase or Tryptase. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

First claim

The invention claimed is:

1. A compound of the general formula (I)

wherein

is a dipeptide made up of two different amino acid building blocks, the dipeptide being D Pro- L Pro(5RPhe), D Ala- L Pro, D Ile- L Pro, D Pro- L Leu, D Pro- L Glu, D Ala- L Asp, D Asn- L Pro, D Thr- L Pro, D Asp- L Pro, D Phe- L Pro, D Arg- L Pro, D Ser- L Pro, D Val- L Pro, D Pic- L Pro, D Pro- L Asp, D Pro- L Phe, D Pro- L Gln, D Pro- L Ser, D Pro- L Val, D Thr- L Thr, D Lys- L Glu, D Phe- L Thr, D Pro- L Ile, or D Gln- L Gln, and
Z is an undecapeptide chain made up of eleven amino acid residues, in which
P1 is selected from Phe, Nle, OctG, or hPhe;
P2 is Cys;
P3 is Thr;
P4 is selected from Lys or Ala;
P5 is Ser;
P6 is selected from Asp, Ile, OctG, or Cha;
P7 is Pro;
P8 is selected from Pro or Pro(4NHCOPhe);
P9 is selected from Ile or Gln;
P10 is Cys; and
P11 is selected from Ser, Tyr, Gln, Cha, or 2Cl-Phe;

two residues of Cys, which are present as the P2 and P10 residues, being linked by a disulfide bridge formed by replacement of the two —SH groups by one —S—S— group,
in free form or in a pharmaceutically acceptable salt form.

2. The compound according to claim 1 , in which in the said undecapeptide chain
P1 is Phe;
P2 is Cys;
P3 is Thr;
P4 is Lys;
P5 is Ser;
P6 is Asp;
P7 is Pro;
P8 is Pro;
P9 is Ile;
P10 is Cys; and
P11 is Ser.

3. The compound according to claim 1 , in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Ile;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

4. The compound according to claim 1 , in which the template is D Pro- L Pro(5RPhe), D Ala- L Pro, D Ile- L Pro, D Pro- L Leu, D Pro- L Glu, D Ala- L Asp, D Asn- L Pro, or D Thr- L Pro, and in which in the said undecapeptide chain
P1 is Phe;
P2 is Cys;
P3 is Thr;
P4 is Lys;
P5 is Ser;
P6 is Asp;
P7 is Pro;
P8 is Pro;
P9 is Ile;
P10 is Cys; and
P11 is Ser.

5. The compound according to claim 1 , in which the template is D Asp- L Pro, D Phe- L Pro, D Arg- L Pro, D Ser- L Pro, D val- L Pro, D Pic- L Pro, D Pro- L Asp, D Pro- L Phe, D Pro- L Phe, D Pro- L ser, D Pro- L Val, D Thr- L Thr, D Lys- L Glu, D Phe- L Thr, D Ala- L Pro, or D Pro- L Ile, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Ile;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

6. The compound according to claim 1 , in which the template is D Lys- L Glu, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is OctG;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

7. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Cha;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Gln.

8. The compound according to claim 1 , in which the template is D Lys- L Glu, and
in which in the said undecapeptide chain
P1 is OctG;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Ile
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

9. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is OctG;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

10. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Cha;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

11. The compound according to claim 1 , in which the template is D Gln- L Gln, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Cha;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Cha.

12. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Cha;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Cha.

13. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is hPhe;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Ile;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

14. The compound according to claim 1 , in which the template is D Lys- L Glu, and
in which in the said undecapeptide chain
P1 is hPhe;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Ile;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

15. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Cha;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is 2Cl-Phe.

16. The compound according to claim 1 , in which the template is D Gln- L Gln, and
in which in the said undecapeptide chain
P1 is Nle;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Cha;
P7 is Pro;
P8 is Pro(4NHCOPhe);
P9 is Gln;
P10 is Cys; and
P11 is Gln.

17. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is OctG;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is Ile;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Tyr.

18. The compound according to claim 1 , in which the template is D Pro- L Gln, and
in which in the said undecapeptide chain
P1 is OctG;
P2 is Cys;
P3 is Thr;
P4 is Ala;
P5 is Ser;
P6 is OctG;
P7 is Pro;
P8 is Pro;
P9 is Gln;
P10 is Cys; and
P11 is Gln.

19. An enantiomer of the compound of formula I as defined in claim 1 .

20. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20 in a form suitable for oral, buccal, rectal, vaginal, topical, transdermal, transmucosal, pulmonary, injection, inhalation, or implantation administration.

22. The pharmaceutical composition according to claim 20 in form of a tablet, a dragee, a capsule, a lozenge, a pill, a powder, a liquid, a solution, a syrup, an elixir, a slurry, a suspension, an emulsion, a gel, a cream, an ointment, a plaster, a spray, a nebulizer, an inhaler, an insufflator, a suppository, a sustained-release system, a long acting formulation, a depot preparation, or a liposome.

23. A method for treating a disease by inhibiting a protease enzyme in a subject in need thereof, the method comprising administering an effective amount of the compound of claim 1 to said subject.

24. The method according to claim 23 , wherein said inhibition treats an infection in a healthy subjec

Assignees

• Polyphor Ltd
• Univ Zuerich

Inventors

• Demarco Steven J
• Moehle Kerstin
• Henze Heiko
• Sellier Odile
• Jung Francoise
• Gombert Frank
• Obrecht Daniel
• Ludin Christian

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title