Template-fixed peptidomimetics with CXCR7 modulating activity

• US 8,629,112 B2
• Filed: 02/05/2010
• Issued: 01/14/2014
• Est. Priority Date: 02/05/2010
• Status: Active Grant

• Current Assignee: Polyphor AG
• Original Assignee: Polyphor AG
• Inventors: Gombert, Frank Otto, Lederer, Alexander, Obrecht, Daniel, Romagnoli, Barbara, Bisang, Christian, Ludin, Christian
• Primary Examiner(s): Skowronek, Karlheinz R
• Assistant Examiner(s): MADER, CATHERINE J
• Application Number:
  US13/577,153
• Publication Number:
  US 20130023483A1
• Time in Patent Office: 1,439 Days
• Field of Search: None
• US Class Current: 514/21.1
• CPC Class Codes: 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
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 7/64 Cyclic peptides containing only normal peptide links

Abstract

Specific template-fixed β-hairpin peptidomimetics of the general formula (I) wherein the single elements T or P are α-amino acid residues connected from the carbonyl (C═O) point of attachment to the nitrogen (N) of the next element in clockwise direction and wherein said elements, depending on their positions in the chain, are defined in the description and the claims have the property to act on the receptor CXCR7. Thus, these β-hairpin peptidomimetics can be useful in the treatment or prevention of diseases or conditions in the area of dermatological disorders, metabolic diseases, inflammatory diseases, fibrotic diseases, infectious diseases, neurological diseases, cardiovascular diseases, respiratory diseases, gastro-intestinal tract disorders, urological diseases, ophthalmic diseases, stomatological diseases, haematological diseases and cancer; or the mobilization of stem cells.

Claims

1. A compound of the general formula (I)

2. The compound of claim 1, wherein

T¹ is ^DPro;

^DPip;

or ^DTic;

T² is Tic;

Tiq;

Oic;

Azt;

Pro;

or (4S)-Hyp(Bn);

P¹ is Trp;

Phe;

1Nal;

2Nal;

Tyr;

His;

His(Me);

Ala;

Ile;

Abu;

or Arg;

P² is ^DPhe;

^DTrp;

^D1Nal;

^DHis;

^DIle;

^DThr;

^DArg;

or ^DOrn;

P³ is Trp;

Phe;

2Nal;

Tyr;

His;

Ile;

or Arg;

P⁴ is Arg;

Lys;

His;

Orn;

Dab;

Trp;

Be;

or Tyr;

and pharmaceutically acceptable salts thereof.

3. The compound of claim 1 selected from

cyclo(-Ala-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Phe-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-His-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-His(Me)-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Tyr-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Arg-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-1Nal-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-2Nal-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DTrp-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DIle-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DHis-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DArg-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DOrn-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Phe-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Tyr-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-2Nal-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Ile-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Arg-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Lys-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Orn-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Dab-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-His-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Tyr-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Arg-^DPro-Tiq-);

cyclo(-Trp-^DPhe-Trp-Arg-^DPro-Oic-);

cyclo(-1Nal-^DArg-Trp-Arg-^DPro-Tic-);

cyclo(-1Nal-^DHis-Ile-Arg-^DPro-Tic-);

cyclo(-Abu-^DArg-Arg-Trp-^DPro-Tic-);

cyclo(-His-^DTrp-His-Arg-^DPro-Tic-);

cyclo(-Ile-^DHis-Trp-Arg-^DPro-Tic-);

cyclo(-Ile-^DArg-Ile-Arg-^DPro-Tic-);

cyclo(-Ile-^DTrp-His-Arg-^DPro-Tic-);

cyclo(-Arg-^DTrp-His-Arg-^DPro-Tic-);

cyclo(-Arg-^DHis-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DArg-His-Arg-^DPro-Tic-);

cyclo(-Trp-^DArg-His-Trp-^DPro-Tic-);

cyclo(-His-^D1Nal-His-Trp-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Arg-^DTic-Pro-);

cyclo(-Trp-^DPhe-Trp-Arg-^DPip-Pro-);

cyclo(-1Nal-^DHis-Ile-Arg-^DPro-Azt-);

cyclo(-1Nal-^DArg-Ile-Arg-^DPro-Azt-);

cyclo(-1Nal-^DArg-Trp-Arg-^DPro-Azt-);

cyclo(-1Nal-^DHis-Tyr-Arg-^DPro-Azt-);

cyclo(-Trp-^DArg-Trp-Ile-^DPro-Azt-);

cyclo(-Trp-^DHis-Ile-Arg-^DPro-Azt-);

cyclo(-Trp-^DHis-Trp-Arg-^DPro-Azt-);

cyclo(-Trp-^DThr-Tyr-Arg-^DPro-Azt-);

cyclo(-Trp-^DArg-Ile-Arg-^DPro-Azt-);

cyclo(-Trp-^DArg-Trp-Arg-^DPro-Azt-);

and pharmaceutically acceptable salts thereof.

4. The compound of claim 3 selected from

cyclo(-Tyr-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Arg-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-2Nal-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Arg-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Orn-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Dab-^DPro-Tic-);

cyclo(-Trp-^DPhe-Trp-Arg-^DPro-Tiq-);

cyclo(-Trp-^DPhe-Trp-Arg-^DPro-Oic-);

cyclo(-Ile-^DArg-Ile-Arg-^DPro-Tic-);

and pharmaceutically acceptable salts thereof.

5. The compound of claim 1 wherein said compound is therapeutically active against diseases or conditions mediated by or sustained through the activity of CXCR7.

6. The compound of claim 1 having modulating activity against the CXCR7 receptor.

7. A method of recruiting β

-arrestin to CXCR7 comprising binding the compound according to claim 1 to the CXCR7 receptor.

8. A pharmaceutical composition containing one or more compounds of claim 1 and a pharmaceutically inert carrier.

9. The composition of claim 8 in a dosage form selected from the group consisting of:

oral, topical, transdermal, injection, buccal, transmucosal, rectal, pulmonary or inhalation administration, especially in the form of tablets, dragees, capsules, solutions, liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions, spray, nebuliser and suppositories.

10. A method of treating a subject in need thereof, which comprises:

administering to the subject one or more of the compounds of claim 1, wherein the subject may be suffering from any one or more of the following diseases;

dermatological disorders, metabolic diseases, inflammatory diseases, fibrotic diseases, infectious diseases, neurological diseases, cardiovascular diseases, respiratory diseases, gastro-intestinal tract disorders, urological diseases, ophthalmic diseases, stomatological diseases, haematological diseases, and defects in the mobilisation of stem cells.

11. A method of treating a subject in need thereof, which comprises:

administering to the subject one or more of the compounds of claim 1, wherein the subject may be suffering from an one or more of the diseases selected from the group consisting of;

HIV infections, Epstein-Barr Virus infection, conjunctivitis, scleritis, uveitis, dry eye syndrome, Sjö

gren'"'"'s syndrome, glaucoma, age-related macular degeneration, rhinosinusitis, Whim syndrome, lupus erythematosus, pulmonary hypertension, pulmonary hypoxia, chronic obstructive pulmonary disease, asthma, osteoarthritis, rheumatoid arthritis, synovitis, psoriasis, multiple sclerosis, diabetes mellitus, Crohns disease, mixed connective tissue disease, chronic lymphocytic thyroiditis, Graves'"'"' disease, graft-versus-host disease, atherosclerosis, myocarditis, heart failure;

angiogenesis, sarcoma;

lipoma;

carcinoma;

solid tumors;

lymphoma;

multiple myeloma and leukemia;

for stem cell mobilisation of peripheral blood stem cells and/or mesenchymal stem cells.

12. A process for the preparation of a compound of claim 1, comprising:

(a) coupling a solid support to an N-protected derivative of an amino acid which in the desired end-product is in position T¹ or T² or P¹ to P⁴ of general formula (I), wherein said N-protected amino acid derivative further comprises protection of a functional group, if present;

(b) removing the N-protecting group from the product obtained in step (a);

(c) coupling the product of step (b) with an N-protected derivative of the amino acid in the position of the next element, (T or P), following general formula (I) counterclockwise in —

COOH to —

NH₂ orientation, wherein said N-protected amino acid derivative further comprises protection of a functional group, if present;

(d) removing the N-protecting group from the product obtained in step (c);

(e) repeating steps (c) and (d) until all amino acid residues have been introduced;

(f) if desired, selectively deprotecting one or several protected functional group(s) present in the molecule and appropriately substituting the reactive group(s) thus liberated;

(g) detaching the product from the solid support;

(h) cyclizing the product of step (g);

(i) removing any protecting groups present on the amino acid residues;

(j) optionally, implementing additional chemical transformations of one or more reactive group(s) present in the molecule; and

(k) optionally, converting the product into a pharmaceutically acceptable salt.

13. The method of claim 11, wherein the sarcoma is selected from one or more sarcomas of the group consisting of:

osteosarcoma, rhabdomyosarcoma, Kaposi'"'"'s sarcoma, and synovial sarcoma.

14. The method of claim 11, wherein the lipoma is selected from one or more lipomas of the group consisting of:

angiolipoma;

glioblastoma multiforme, astrocytomas, metastasis, and neuroblastoma.

15. The method of claim 11, wherein the carcinoma is one or more carcinomas selected from the group consisting of:

adenocarcinoma;

malignant epithelial and mucoepidermoid neoplasms, thyroid neoplasm, gonadal neoplasms, prostate cancer, breast cancer, melanoma, lung carcinoma, pancreatic carcinoma and colorectal cancer.

16. The method of claim 11, wherein the lymphoma is one or more lymphomas selected from the group consisting of:

Birkitt'"'"'s lymphoma, Hodgkin'"'"'s lymphoma, and non-Hodgkin'"'"'s lymphoma.