Compounds, compositions and methods for controlling biofilms and bacterial infections

• US 7,612,045 B2
• Filed: 09/14/2005
• Issued: 11/03/2009
• Est. Priority Date: 09/14/2004
• Status: Expired due to Fees

• Current Assignee: Sequoia Sciences, Inc.
• Original Assignee: Sequoia Sciences, Inc.
• Inventors: Eldridge, Gary R.
• Primary Examiner(s): Henley, III; Raymond J
• Application Number:
  US11/662,806
• Publication Number:
  US 20080145322A1
• Time in Patent Office: 1,511 Days
• Field of Search: 514/31, 514/34, 514/37, 514/39, 514/41, 514/152, 514/154, 514/561, 424/49
• US Class Current: 514/31
• 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 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 8/63 Steroids; Derivatives thereof
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: C07J 63/008 Expansion of ring D by one atom, e.g. D homo steroids

Abstract

The present invention provides compounds and compositions useful for controlling bacterial biofilms as well as for controlling and/or preventing bacterial infections. The compounds of the invention are pentacyclic acid triterpenes. Methods for controlling biofilms and for controlling and/or preventing bacterial infections are also disclosed.

Claims

1. A compound corresponding to the following chemical structure:

2. The compound of claim 1, wherein said compound contains a C-28 carboxyl group and wherein said prodrug of said compound is selected from the group consisting of esters, amides, and hydrazides of said C-28 carboxyl group.

3. The compound of claim 1 wherein the compound is not a salt, hydrate, solvate, prodrug or N-oxide of the chemical structure.

4. A method for treating, controlling, reducing or inhibiting a bacterial infection in a subject in need thereof by administering to the subject an effective amount of a composition comprising a compound having the following chemical structure:

5. The method of claim 4, wherein R¹ is in the β

stereochemical configuration and R² is in the α

stereochemical configuration.

6. The method of claim 4, wherein R¹ is in the α

stereochemical configuration and R² is in the β

stereochemical configuration.

7. The method of claim 4, wherein the composition is administered to the subject orally, topically, rectally, percutaneously, by parenteral injection, intranasally or by inhalation.

8. The method of claim 7, wherein the infection is a chronic bacterial infection.

9. The method of claim 8, wherein the chronic bacterial infection is selected from the group consisting of urinary tract infection, gastritis, lung infection, ear infection, cystitis, pyelonephritis, arterial damage, leprosy, tuberculosis, benign prostatic hyperplasia, prostatitis, osteomyelitis, bloodstream infection, cirrhosis, skin infection, acne, rosacea, open wound infection, atopic dermatitis, chronic wound infection, and sinus infection.

10. The method of claim 9, wherein the chronic bacterial infection causes an autoimmune disease.

11. The method of claim 4, wherein the subject is a mammal and the carrier is a pharmaceutically acceptable carrier.

12. The method of claim 11, wherein the mammal is a human.

13. The method of claim 4, wherein the composition further comprises an antimicrobial agent.

14. The method of claim 13, wherein the antimicrobial agent is an antibiotic.

15. The method of claim 14, wherein the antibiotic is selected from the group consisting of tobramycin, clindamycin, ciprofloxacin, tetracyclines, rifampin, triclosan, oxfloxacin, macrolides, penicillins, cephalosporins, amoxicillin/clavulanate, quinupristin/dalfopristin, amoxicillin/sulbactum, metronidazole, fluoroquinolones, quinolones, ketolides, or aminoglycosides.

16. A compound corresponding to the following chemical structure:

17. A compound corresponding to the following chemical structure:

18. A compound corresponding to the following chemical structure:

19. A composition comprising a compound corresponding to the following structure:

20. The composition of claim 19, wherein the composition is a racemic mixture of the compound and its isomer wherein R¹ is in the α

stereochemical configuration and R² is in the β

stereochemical configuration.

21. The composition of claim 19, wherein the pharmaceutically acceptable carrier permits administration of the pharmaceutical composition orally, topically, rectally, percutaneously, by parenteral injection, intranasally or by inhalation.

22. The composition of claim 21, wherein the composition is a topical preparation.

23. The composition of claim 21, wherein the topical preparation is a gel, cream, emollient, or soap.

24. The composition of claim 19, wherein the composition is a dentifrice.

25. The composition of claim 24, wherein the dentifrice is selected from the group consisting of toothpaste, toothpowder, liquid dentifrice, mouth detergent, mouthwash, troches, chewing gum, dental or gingival massage cream, dental strip, dental gel, and gargle tablet.

26. The composition of claim 25, wherein the dentifrice is a tooth paste and further comprises a tooth or gum adherence promoting substance selected from the group consisting of copolymers of methyl vinyl ether and maleic anhydride, copolymers of vinyl pyrrolidone and vinyl acetate, and cyclodextrins.

27. The composition of claim 25, further comprising an antimicrobial agent selected from the group consisting of triclosan, metronidazole, tetracyclines, quinolones, plant essential oils, camphor, thymol, carvacrol, menthol, eucalyptol, and methyl salicylate.

28. The composition of claim 19 wherein the composition is a pharmaceutical composition.

29. The composition of claim 28, wherein R¹ is in the α

stereochemical configuration and R² is in the β

stereochemical configuration.

30. The composition of claim 28, wherein the pharmaceutically acceptable carrier permits administration of the pharmaceutical composition orally, topically, rectally, percutaneously, by parenteral injection, intranasally or by inhalation.

31. The composition of claim 28, further comprising an antimicrobial agent selected from the group consisting of triclosan, metronidazole, tetracyclines, quinolones, plant essential oils, camphor, thymol, carvacrol, menthol, eucalyptol, and methyl salicylate.

32. The composition of claim 28, further comprising an antimicrobial agent an antibiotic.

33. The composition of claim 32, wherein the antibiotic is selected from the group consisting of tobramycin, clindamycin, ciprofloxacin, tetracyclines, rifampin, triclosan, oxfloxacin, macrolides, penicillins, cephalosporins, amoxicillin/clavulanate, quinupristin/dalfopristin, amoxicillin/sulbactum, metronidazole, fluoroquinolones, quinolones, ketolides, or aminoglycosides.

34. The composition of claim 19 wherein the compound is not a salt, hydrate, solvate, prodrug or N-oxide of the chemical structure.

36. The composition of claim 21, wherein the antimicrobial agent is an antibiotic.

37. The composition of claim 22, wherein the antibiotic is selected from the group consisting of tobramycin, clindamycin, ciprofloxacin, tetracyclines, rifampin, triclosan, oxfloxacin, macrolides, penicillins, cephalosporins, amoxicillin/clavulanate, quinupristin/dalfopristin, amoxicillin/sulbactum, metronidazole, fluoroquinolones, quinolones, ketolides, or aminoglycosides.

38. The composition of claim 37, wherein the composition comprises about 0.1% to about 20.0% of the compound.

39. The composition of claim 38, wherein the composition comprises about 0.1% to about 5.0% of the compound.

40. The composition of claim 39, wherein the composition comprises about 2% of the compound.

46. The method of claim 33, wherein the prevention, inhibition or reduction of biofilm formation is effected in a vessel hull, car, airplane, industrial equipment, device, membrane, filter, microtiter plate, continuous flow chamber, or piece of machinery.

35. A composition comprising an antimicrobial agent and a compound corresponding to the following chemical structure:

41. A method for inhibiting or reducing a biofilm comprising contacting the biofilm or a cell capable of biofilm formation with an effective amount of a composition comprising a compound corresponding to the following chemical structure:

42. The method of claim 41, wherein the biofilm or biofilm formation is prevented, inhibited or reduced in vivo and the acceptable carrier is a pharmaceutically acceptable carrier.

43. The method of claim 41, wherein the biofilm or biofilm formation is inhibited or prevented on a substrate.

44. The method of claim 43, wherein the substrate is a biological structure selected from the group consisting of a regenerating protein of a mammalian cellular membranes, dental enamel, gum, tongue, and biological polymer.

45. The method of claim 43, wherein the substrate is a medical device selected from the group consisting of a central venous catheter, urinary catheter, endotracheal tube, mechanical heart valve, pacemaker, vascular graft, stent, and prosthetic joint.

47. The method of claim 41, wherein the biofilm or cell capable of biofilm formation is associated with a respiratory infection and wherein the biofilm or a cell capable of biofilm formation is contacted by administering the composition by an inhaler or nebulizer.

48. The method of claim 47, wherein the respiratory infection occurs in a patient with cystic fibrosis.

49. The method of claim 41, wherein the composition further comprises an antimicrobial agent.

50. The method of claim 49, wherein the antimicrobial agent is an antibiotic.

51. The method of claim 50, wherein the antibiotic is selected from the group consisting of tobramycin, clindamycin, ciprofloxacin, tetracyclines, rifampin, triclosan, oxfloxacin, macrolides, penicillins, cephalosporins, amoxicillin/clavulanate, quinupristin/dalfopristin, amoxicillin/sulbactum, metronidazole, fluoroquinolones, quinolones, ketolides, or aminoglycosides.

52. The method of claim 41 wherein the compound is not a salt, hydrate, solvate, prodrug or N-oxide of the chemical structure.

53. A compound corresponding to the following chemical structure:

54. The compound of claim 53, wherein the compound is part of a racemic mixture.

55. A compound corresponding to the following chemical structure:

56. A compound corresponding to the following chemical structure:

57. A compound corresponding to the following chemical structure: