Formyl-methionyl chemotatic peptide antibiotic conjugates useful in treating infections

• US 4,427,660 A
• Filed: 03/03/1982
• Issued: 01/24/1984
• Est. Priority Date: 03/03/1982
• Status: Expired due to Term

• Current Assignee: Research Corporation Technologies
• Original Assignee: Research Corporation
• Inventors: Schiffman, Elliott, Altman, Leonard C.
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/354,357
• Time in Patent Office: 692 Days
• Field of Search: 424/177, 260/112.5 R
• US Class Current: 514/2.3
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/635 having a heterocyclic ring, e.g. sulfadiazine
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/081 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/1013 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
• CPC Class Codes: Y10S 930/19 Antibiotic
• CPC Class Codes: Y10S 930/28 Bound to a nonpeptide drug, nonpeptide label, nonpeptide carrier, or a nonpeptide resin
• CPC Class Codes: Y10S 930/29 Polyamino acid or polypeptide with an uninterrupted series of peptide repeating units

Abstract

A group of synthetic N-formyl methionine tri and tetra peptides in covalent combination with antibiotics are useful in treating infections. These peptideantibiotic conjugates exhibit a high degree of chemotactic activity for polymorphonuclear leukocytes and monocytes while simultaneously inhibiting the growth of microorganisms. The use of chemotactic peptide-silver sulfadiazine conjugates is particularly effective for treating burns.

Claims

1. An N-formyl peptide-antibiotic complex selected from the group consisting of f-Met-Leu-Phe-R, f-Met-Met-Phe-R, f-Met-Met-Met-R, f-Nle-Leu-Phe-R, f-Met-Leu-Phe-Lys-R, and their pharmaceutically acceptable non-toxic acid addition salts, wherein R is an agent selected from the group consisting of sulfonamide antimicrobial agents, silver containing antimicrobial agents, and antifungal agents.

2. The N-formyl peptide-antibiotic complex of claim 1, wherein R is silver sulfadiazine, which is f-Met-Leu-Phe-silver sulfadiazine.

3. The N-formyl peptide-antibiotic complex of claim 1, wherein R is silver sulfadiazine, which is f-Met-Met-Phe-silver sulfadiazine.

4. The N-formyl peptide-antibiotic complex of claim 1, wherein R is silver sulfadiazine, which is f-Met-Met-Met-Met-silver sulfadiazine.

5. The N-formyl peptide-antibiotic complex of claim 1, wherein R is silver sulfadiazine, which is f-Nle-Leu-Phe-silver sulfadiazine.

6. The N-formyl peptide-antibiotic complex of claim 1, wherein R is silver sulfadiazine, which is f-Met-Leu-Phe-Lys-silver sulfadiazine.

7. The N-formyl peptides of claim 1 wherein said antifungal agent is miconazole.

8. The N-formyl peptides of claim 1 wherein said antifungal agent is clotrimazole.

9. The N-formyl peptides of claim 1 wherein said antifungal agent is nystatin.

10. The N-formyl peptides of claim 1 wherein said antifungal agent is amphotericin B.

11. A method of treating septic trauma comprising the application of a pharmacologically effective amount of the compounds of claim 1.

13. A method of treating a burn victim comprising the application of a pharmacologically effective amount of the compounds of claim 1.

14. A method of treating fungal infections comprising the application of a pharmacologically effective amount of the compounds of claim 1.

12. A method of treating burns comprising the application of a pharmacologically effective amount of formyl-methionyl-leucyl-phenylalanine-silver sulfadiazine.

15. A method of treating as in claim 12 wherein the pharmacologically effective amount of chemotactic-antibiotic complex is supplied topically to create a concentration gradient wherein the concentration is higher at the trauma site and progressively lower in the surrounding tissue.