# US 9,518,092 B2 · Template-fixed beta-hairpin peptidomimetics with CXCR4 antagonizing activity

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,518,092 B2
- Document ID: US9518092B2
- Status: Granted
- Kind: B2
- Application number: 14/495,737
- Filed: 2014-09-24
- Published: 2015-03-26
- Granted: 2016-12-13
- Earliest claimed: 2003-05-02
- Assignees: Polyphor AG; UniversitäT ZüRich
- Applicants: Polyphor Ltd.; Universität Zürich
- Inventors: Jürg Zumbrunn; Steven J. Demarco; Sergio Lociuro; Jan Wim Vrijbloed; Frank Gombert; Reshmi Mukherjee; Kerstin Moehle; Daniel Obrecht; John Anthony Robinson; Heiko Henze; Barbara Romagnoli; Christian Ludin
- Web page: https://patentgrep.com/patent/US9518092B2

## CPC

- C07K 7/64: Cyclic peptides containing only normal peptide links
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 1/047: {Simultaneous synthesis of different peptide species; Peptide libraries}
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 12, 14 or 18 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Gly, NMeGly, Pro or Pip, 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 CXCR4 antagonizing properties These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

## Claims

### Claim 1

A compound of the general formula
is a dipeptide residue made up of two different amino acid building blocks, the dipeptide being DPro-LPro; and
Z is a chain made up of 12 α-amino acid residues, in which
the P1 residue is the residue of Tyr;
the P2 residue is the residue of Arg or Gly;
the P3 residue is the residue of Cit;
the P4 residue is the residue of Val, Phe, Cys, Gly, Ile, Thr or Gln;
the P5 residue is the residue of Arg;
the P6 residue is the residue of DArg or Arg;
the P7 residue is the residue of Arg;
the P8 residue is the residue of 2-Nal or Trp;
the P9 residue is the residue of Phe, Val, Cys, Gly, Ile, Thr or Gln;
the P10 residue is the residue of Tyr;
the P11 residue is the residue of Cit or Gly;
the P12 residue is the residue of Lys;
when P4 and P9 are both cysteine, a disulfide bridge is present between the two side chains thereof; or an enantiomer of said compound,
or a pharmaceutically acceptable salt of said compound.

### Claim 2 (depends on 1)

A An enantiomer of a compound of claim 1.

### Claim 3 (depends on 1)

A compound according to claim 1 having CXCR4 antagonizing activity, which also has anticancer activity and/or anti-inflammatory activity, wherein the cancer is selected from the group consisting of breast cancer, brain cancer, prostate cancer, lung cancer, kidney cancer, neuroblastoma, non-hodgkin's lymphoma, ovarian cancer, multiple myeloma, chronic lymphocytic leukemia, pancreatic cancer, melanoma, and whereas the inflammatory activity is selected from the group consisting of asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias, delayed-type hypersensitivity, interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing sponylitis, systemic sclerosis, Sjogren's syndrome, systemic anaphylaxis or hypersensitivity responses, drug allergies, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes, glomerulonephritis, autoimmune thyroiditis, graft rejection including allograft rejection or graft-versus-host disease, inflammatory bowel diseases and inflammatory dermatoses.

### Claim 4 (depends on 1)

A pharmaceutical composition containing a compound according to claim 1 and a pharmaceutically inert carrier.

### Claim 5 (depends on 4)

A composition according to claim 4 in a form suitable for oral, topical, transdermal, injection, buccal, transmucosal, pulmonary or inhalation administration.

### Claim 6 (depends on 4)

A composition according to claim 4 in form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuliser or suppositories.

### Claim 7 (depends on 1)

A method of antagonizing CXCR4 in a patient in need thereof, comprising administering to the patient an effective amount of a compound according to claim 1.

### Claim 8 (depends on 7)

The method according to claim 7 wherein said antagonism of CXCR4 is intended to be for slowing viral progression in infected patients.

### Claim 9 (depends on 1)

A process for the manufacture of a compound according to claim 1 which process comprises
(a) coupling an appropriately functionalized solid support with an appropriately N-protected derivative of that amino acid which in the end-product is in position 8, 9 or 10, 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 is one position nearer the N-terminal amino acid residue, 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 thus obtained;
(e) repeating steps (c) and (d) until the N-terminal amino acid residue has been introduced;
(f) coupling the product thus obtained with a compound of the general formula
is as defined in claim 1 and X is an N-protecting group
(g) removing the N-protecting group from the product obtained in step (f);
(h) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which is in position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(i) removing the N-protecting group from the product thus obtained;
(j) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(k) removing the N-protecting group from the product thus obtained;
(l) repeating steps (j) and (k) until all amino acid residues have been introduced;
(m) optionally, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated;
(n) optionally, forming one, two or three interstrand linkage(s) between side-chains of appropriate amino acid residues at opposite positions of the chain of 12 α-amino acid residues;
(o) detaching the product thus obtained from the solid support;
(p) cyclizing the product cleaved from the solid support;
(q) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, optionally, any protecting group(s) which may in addition be present in the molecule; and
(r) optionally 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 of formula I or into a different, pharmaceutically acceptable, salt.

### Claim 10 (depends on 1)

A process for the manufacture of a compound according to claim 1 which process comprises
(a′) coupling an appropriately functionalized solid support with a compound of the general formula
is as defined above and X is an N-protecting group
(b′) removing the N-protecting group from the product obtained in step (a′);
(c′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid is in position 12, 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 thus obtained;
(e′) coupling the product thus obtained with an appropriately N-protected derivative of that amino acid which is one position farther away from position 12, any functional group which may be present in said N-protected amino acid derivative being likewise appropriately protected;
(f′) removing the N-protecting group from the product thus obtained;
(g′) repeating steps (e′) and (f′) until all amino acid residues have been introduced;
(h′) optionally, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated;
(i′) optionally, forming one, two or three interstrand linkage(s) between side-chains of appropriate amino acid residues at opposite positions of the chain of 12 α-amino acid residues;
(j′) detaching the product thus obtained from the solid support;
(k′) cyclizing the product cleaved from the solid support;
(l′) removing any protecting groups present on functional groups of any members of the chain of amino acid residues and, optionally, any protecting group(s) which may in addition be present in the molecule; and
(m′) optionally, 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 of formula I or into a different, pharmaceutically acceptable, salt.

### Claim 11 (depends on 9)

The process according to claim 9 wherein the process is modified for the manufacture of enantiomers of the compounds in which enantiomers of all chiral starting materials are used.

### Claim 12 (depends on 10)

A The process according to claim 10 wherein the process is modified for the manufacture of enantiomers of the compounds in which enantiomers of all chiral starting materials are used.