SYNTHETIC PEPTIDE AMIDES AND DIMERIC FORMS THEREOF

• US 20110118186A1
• Filed: 05/05/2010
• Published: 05/19/2011
• Est. Priority Date: 11/10/2006
• Status: Active Grant

• Current Assignee: Cara Therapeutics, Inc.
• Original Assignee: Cara Therapeutics, Inc.
• Inventors: Alexander, Roberta Vezza, Spencer, Robert H., Schteingart, Claudio D., Jiang, Guangcheng, Chalmers, Derek T., Sueiras-Diaz, Javier, Luo, Zhiyong, Menzaghi, Frederique
• Granted Patent: US 8,486,894 B2
• Time in Patent Office: Days
• US Class Current: 514/13.5
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 5/1016 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 7/02 Linear peptides containing at least one abnormal peptide link

Abstract

The invention relates to synthetic peptide amides that are ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P₄₅₀ CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure:

wherein Xaa is a D-amino acid and G is selected from the following three groups:

The compounds are useful in the prophylaxis and treatment of pain, pruritis and inflammation associated with a variety of diseases and conditions.

Claims

1. A synthetic peptide amide having the formula:

5. The synthetic peptide amide of claim 1, wherein G is

6. The synthetic peptide amide of claim 5, wherein p, q, r, s and t are each 1.

7. The synthetic peptide amide of claim 5, wherein Xaa₁ is selected from the group consisting of (A) D-Phe, (α

-Me)D-Phe, D-Tyr, D-Tic, (tert-butyl)D-Gly, and β

-(E)D-Ala, wherein A is selected from the group consisting of —

H, —

F, —

Cl, —

NO₂, and —

CH₃, and (E) is selected from the group consisting of tert-butyl, cyclopentyl and thienyl;

Xaa₂ is selected from the group consisting of (A)(A′

)D-Phe, D-1Nal, D-2Nal, D-Tyr, and D-Trp, wherein (A′

) is H or Cl;

Xaa₃ is selected from the group consisting of D-Nle, D-Phe, (cyclopentyl)D-Ala, D-Leu, (α

-Me)D-Leu, D-Hle, D—

Val, and D-Met; and

Xaa₄ is selected from the group consisting of D-Arg, (ethyl)₂D-Arg, D-Nar, D-Har, (ethyl)₂D-Har, c-(isopropyl)D-Lys, D-Lys, D-Amf, amidino-D-Amf, β

-amidino-D-Dap, D-Dbu, D-Orn, α

-(methyl)D-Orn and δ

-(isopropyl)D-Orn.

8. The synthetic peptide amide of claim 7, wherein Xaa₁ is D-Phe, Xaa₂ is D-Phe, Xaa₃ is D-Leu and Xaa₄ is selected from the group consisting of D-Nar, D-Orn, (isopropyl)D-Orn.

9. The synthetic peptide amide of claim 5, wherein

L is a linker selected from the group consisting of ε

-D-Lys, ε

-Lys, δ

-D-Orn, δ

-Orn, 4-amino-4-carboxylic piperidine and bis(D-Lys-Gly)Lactam.

10. The peptide amide of claim 5, having a structure selected from the group consisting of:

11. The synthetic peptide amide of claim 1, wherein G is

12. The synthetic peptide amide of claim 11, wherein J is a 5-membered heterocyclic ring moiety.

13. The synthetic peptide amide of claim 12, wherein J comprises 2 heteroatoms which two heteroatoms are both N.

14. The synthetic peptide amide of claim 11, wherein R₃ and R₄ are each —

H.

15. The synthetic peptide amide of claim 1, wherein G is

51. A pharmaceutical composition comprising the synthetic peptide amide according to claim 1, and a pharmaceutically acceptable excipient or carrier.

52. A method of prophylaxis or treatment of a kappa opioid receptor-associated disease or condition in a mammal, the method comprising administering to the mammal a composition comprising an effective amount of a synthetic peptide amide according to claim 1.

53. The method according to claim 52, wherein the kappa opioid receptor-associated disease or condition is selected from the group consisting of pain, inflammation, pancreatitis, pruritis, ileus, tussis or glaucoma.

54. The method according to claim 52, wherein the kappa opioid receptor-associated disease or condition is a disease or condition associated with hyponatremia or hypokalemia.

55. The method according to claim 54, wherein the disease or condition associated with hyponatremia or hypokalemia is congestive heart failure, liver cirrhosis, nephrotic syndrome, hypertension, or edema.

2-4. -4. (canceled)

16-50. -50. (canceled)