Photodynamic porphyrin antimicrobial agents

• US 20030050296A1
• Filed: 09/26/2001
• Published: 03/13/2003
• Est. Priority Date: 09/27/2000
• Status: Active Grant

• Current Assignee: Frontier Scientific
• Original Assignee: Frontier Scientific
• Inventors: Jori, Giulio, Bommer, Jerry C.
• Granted Patent: US 6,573,258 B2
• Time in Patent Office: Days
• US Class Current: 514/185
• CPC Class Codes: A61K 31/409 having four such rings, e.g. porphine derivatives, bilirubin, biliverdine hemin, hematin A61K31/555
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 41/0071 PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A series of novel positively-charged porphyrins is disclosed which exhibit a markedly increased efficiency in photosensitizing both Gram-positive and Gram-negative bacteria to the action of visible light, causing death to such bacteria when present at much lower concentrations and much shorter irradiation times than those porphyrins taught in the prior art. These porphyrins are characterized by the presence of up to four positive charges in the peripheral substituents and at least one hydrophobic tail comprising between 6 and 22 carbons inclusive, originating at one or more of the charged sites.

Claims

1. A photodynamic antimicrobial agent comprising:

a porphyrin having four quaternized nitrogens, wherein the porphyrin further comprises a hydrocarbon tail beginning at one of the quaternized nitrogens.

2. The photodynamic antimicrobial agent of claim 1, wherein the porphyrin is a reduced porphyrin.

3. The photodynamic antimicrobial agent of claim 2, wherein the reduced porphyrin is selected from the group consisting of chlorin and bacteriochlorin.

4. The photodynamic antimicrobial agent of claim 1, wherein the porphyrin is a metal chelated porphyrin.

5. The photodynamic antimicrobial agent of claim 4, wherein the metal chelated porphyrin is a metal chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Tl, Si, Ge, Sn, Pd, and Pt.

6. The photodynamic antimicrobial agent of claim 2, wherein the porphyrin is a metal chelated porphyrin.

7. The photodynamic antimicrobial agent of claim 6, wherein the metal chelated porphyrin is a metal chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Tl, Si, Ge, Sn, Pd, and Pt.

8. The photodynamic antimicrobial agent of claim 1, wherein the hydrocarbon tail is selected from the group consisting of straight chain alkyls, straight chain alkenes, branched alkyl chains, branched alkenyl chains, aromatics, mixed alkyl-aromatic species, and mixed alkenyl-aromatic species.

9. The photodynamic antimicrobial agent of claim 8, wherein the hydrocarbon tail contains between 6 and 22 carbon atoms.

10. The photodynamic antimicrobial agent of claim 9, wherein the hydrocarbon tail contains between 6 and 18 carbon atoms.

11. The photodynamic antimicrobial agent of claim 10, wherein the hydrocarbon tail comprises a benzyl group.

12. The photodynamic antimicrobial agent of claim 10, wherein the hydrocarbon tail comprises a six-carbon atom chain.

13. The photodynamic antimicrobial agent of claim 10, wherein the hydrocarbon tail comprises a ten-carbon atom chain.

14. The photodynamic antimicrobial agent of claim 10, wherein the hydrocarbon tail comprises a fourteen-carbon atom chain.

15. The photodynamic antimicrobial agent of claim 10, wherein the hydrocarbon tail comprises an eighteen-carbon atom chain.

16. A photodynamic antimicrobial agent comprising a meso-tetra-(N-methyl-pyridyl) porphyrin having four quaternized nitrogens, and wherein one N-methyl group has been replaced by a hydrocarbon tail.

17. The photodynamic antimicrobial agent of claim 16, wherein the hydrocarbon tail contains between 6 and 22 carbon atoms.

18. The photodynamic antimicrobial agent of claim 16, wherein the hydrocarbon tail contains greater than 6 and fewer than 18 carbon atoms.

19. The photodynamic antimicrobial agent of claim 16, wherein the porphyrin is a reduced porphyrin.

20. The photodynamic antimicrobial agent of claim 19, wherein the reduced porphyrin is selected from the group consisting of chlorin and bacteriochlorin.

21. The photodynamic antimicrobial agent of claim 16, wherein the porphyrin is a metal chelated porphyrin.

22. The photodynamic antimicrobial agent of claim 21, wherein the metal chelated porphyrin is a chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Tl, Si, Ge, Sn, Pd, and Pt.

23. The photodynamic antimicrobial agent of claim 19, wherein the porphyrin is a metal chelated porphyrin.

24. The photodynamic antimicrobial agent of claim 23, wherein the metal chelated porphyrin is a metal chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Tl, Si, Ge, Sn, Pd, and Pt.

25. The photodynamic antimicrobial agent of claim 16, wherein the hydrocarbon tail is selected from the group consisting of straight chain alkyls, straight chain alkenes, branched alkyl chains, branched alkenyl chains, aromatics, mixed alkyl-aromatic species, and mixed alkenyl-aromatic species.

26. The photodynamic antimicrobial agent of claim 25, wherein the hydrocarbon tail comprises a benzyl group.

27. The photodynamic antimicrobial agent of claim 25, wherein the hydrocarbon tail comprises a six-carbon atom chain.

28. The photodynamic antimicrobial agent of claim 25, wherein the hydrocarbon tail comprises a ten-carbon atom chain.

29. The photodynamic antimicrobial agent of claim 25, wherein the hydrocarbon tail comprises a fourteen-carbon atom chain.

30. The photodynamic antimicrobial agent of claim 25, wherein the hydrocarbon tail comprises an eighteen-carbon atom chain.

31. A method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail comprising the steps of:

quaternizing a first nitrogen of a porphyrin by reacting it with a sub-stoichiometric quantity of a halide salt of the desired hydrophobic hydrocarbon tail to form a mono-quaternized porphyrin; and

quaternizing the remaining nitrogens of the porphyrin using a methylating agent to form a porphyrin with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic tail.

32. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic tail of claim 31, further comprising the step of separating the mono-quaternized porphyrin from any remaining porphyrin or halide salts.

33. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 32, wherein the step of separating the mono-quaternized porphyrin from any remaining porphyrin or halide salts is accomplished utilizing solubility differences.

34. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic tail of claim 32, further comprising the step of separating the resulting porphyrin with four symmetrically distributed positive charges and a single hydrophobic hydrocarbon tail from any remaining porphyrins, other byproducts, and halide salts.

35. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 34, wherein the step of separating the resulting porphyrin with four symmetrically distributed positive charges and a single hydrophobic hydrocarbon tail from any remaining porphyrins, other byproducts, and halide salts is accomplished using chromatography.

36. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 34, wherein the halide salt is selected from the group consisting of a straight chain alkyl, straight chain alkene, branched alkyl, branched alkenyl, aromatic, mixed alkyl-aromatic, or mixed alkenyl-aromatic halide salt.

37. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 34, wherein the methylating agent is selected from the group consisting of methyl-p-toluene sulformate, methyl iodide, dimethyl sulfate, and methyl fluorosulfonate.

38. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 34, wherein the porphyrin is a reduced porphyrin.

39. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 38, wherein the reduced porphyrin is selected from the group consisting of chlorin and bacteriochlorin.

40. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 34, wherein the porphyrin is a metal chelated porphyrin.

41. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 40, wherein the metal chelated porphyrin is a metal chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Tl, Si, Ge, Sn, Pd, and Pt.

42. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 38, wherein the porphyr in is a metal chelated porphyrin.

43. The method of synthesizing porphyrins with four symmetrically distributed positive charges on four quaternized nitrogens and a single hydrophobic hydrocarbon tail of claim 42, wherein the metal chelated porphyrin is a metal chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Tl, Si, Ge, Sn, Pd, and Pt.

44. A method of killing Gram-positive or Gram-negative bacteria comprising the steps of:

exposing Gram-positive or Gram-negative bacteria to a photodynamic antimicrobial agent comprising a porphyrin with four symmetrically-distributed positive charges and a hydrocarbon tail; and

irradiating the bacteria and antimicrobial agent.

45. The method of claim 44, wherein the porphyrin is a reduced porphyrin.

46. The method of claim 45, wherein the reduced porphyrin is selected from the group consisting of chlorin and bacteriochlorin.

47. The method of claim 44, wherein the porphyrin is a metal chelated porphyrin.

48. The method of claim 47, wherein the metal chelated porphyrin is a chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Ti, Si, Ge, Sn, Pd, and Pt.

49. The method of claim 45, wherein the porphyrin is a metal chelated porphyrin.

50. The method of claim 49, wherein the metal chelated porphyrin is a metal chelate of a metal selected from the group consisting of Mg, Sc, Zn, Al, In, Tl, Si, Ge, Sn, Pd, and Pt.

51. The method of claim 44, wherein the hydrocarbon tail is selected from the group consisting of straight chain alkyls, straight chain alkenes, branched alkyl chains, branched alkenyl chains, aromatics, mixed alkyl-aromatic species, and mixed alkenyl-aromatic species.

52. The method of claim 51, wherein the hydrocarbon tail contains between 6 and 22 carbon atoms.

53. The method of claim 52, wherein the hydrocarbon tail contains greater than 6 and fewer than 18 carbon atoms.

54. The method of claim 53, wherein the hydrocarbon tail comprises a benzyl group.

55. The method of claim 53, wherein the hydrocarbon tail comprises a six-carbon atom chain.

56. The method of claim 53, wherein the hydrocarbon tail comprises a ten-carbon atom chain.

57. The method of claim 53, wherein the hydrocarbon tail comprises a fourteen-carbon atom chain.

58. The method of claim 53, wherein the hydrocarbon tail comprises an eighteen-carbon atom chain.

59. The method of claim 44, wherein the porphyrin is present in a concentration of from about 10 μ

M to about 0.1 μ

M.

60. The method of claim 44, wherein the porphyrin is present in a concentration of from about 5 μ

M to about 0.5 μ

M.

61. The method of claim 44, wherein the porphyrin is present in a concentration of 1 μ

M.