Porphyrins with virucidal activity

• US 20050090428A1
• Filed: 01/08/2003
• Published: 04/28/2005
• Est. Priority Date: 01/08/2002
• Status: Abandoned Application

• Current Assignee: Emory University, Georgia State University Research Foundation, Inc.
• Original Assignee: Emory University, Georgia State University Research Foundation, Inc.
• Inventors: Compans, Richard W., Dixon, Dabbey W., Sears, Amy E., Marzilli, Luigi G.
• Application Number:
  US10/500,884
• Publication Number:
  US 20050090428A1
• Time in Patent Office: Days
• US Class Current: 424/85.4
• CPC Class Codes: A61K 31/409 having four such rings, e.g. porphine derivatives, bilirubin, biliverdine hemin, hematin A61K31/555
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61P 31/18 for HIV

Abstract

Compositions and methods of using thereof for the prevention of sexually transmitted diseases resulting from infection with one or more of viral pathogens have been developed. The compositions contain one or more porphyrins, tetrapyrrole macrocycle compounds with bridges of one carbon joining the pyrroles. In a preferred embodiment, the compositions are administered in a formulation suitable for administration to a mucosal surface.

Claims

1. A method for preventing a viral infection in a human comprising administering to a mucosal surface of a composition comprising a synthetic porphyrin or a pharmaceutically acceptable salt thereof to a human, wherein the porphyrin has the following structure:

2. The method of claim 1 wherein the viral infection is caused by a virus selected from the group consisting of HIV viruses, HSV viruses, hepatitis B and C viruses, or papilloma viruses

3. The method of claim 1 wherein the viral infection is caused by a virus selected from the group consisting of HIV viruses.

4. The method of claim 1 wherein the viral infection is caused by a virus selected from the group consisting of HSV viruses.

5. The method of claim 1 wherein the viral infection is caused by a virus selected from the group consisting hepatitis B and C viruses, or papilloma viruses.

6. The method of claim 1 wherein the infection is caused by a virus selected from the group consisting of HIV and HSV viruses,

wherein R¹, R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, and R¹² are hydrogen, and R², R⁵, R⁸, and R¹¹ are alkyl, heteroalkyl, aryl, or heteroaryl groups, and

wherein the porphyrin as a whole bears one or more sulfonic acid or derivatized sulfonic acid groups.

7. The method of claim 6 wherein the porphyrin is a Cu or Fe chelate of the structure of Formula 1.

8. The method of claim 1 where the infection is caused by a virus selected from the group consisting of HSV viruses,

wherein R², R⁵, R⁸, and R¹¹ are hydrogens and R¹, R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, and R¹² are hydrogen, alkyl, heteroalkyl, or substituted alkyl groups, and

wherein the molecule as a whole bears two or more carboxylic acid groups.

9. The method of claim 8 wherein the porphyrin is a Cu or Fe chelate of the structure of Formula 1.

10. The method of claim 1 wherein the viral infection is caused by a virus selected from the group consisting of HIV viruses, and

wherein the compound is selected from the group consisting of TNapPS, TPP(2,6-F2)S,Cu;

TAnthPS, TMPS,Co, DPEG,Fe, DPEG,Zn;

TPPC,Fe;

TPPC;

TPP(2,6-C12)S,Fe and TPP(2,6C12)S;

TPP2FS;

TPP4ClS;

TPP(2,6-C12);

TPP(2,6-F2)S,Cu;

TPP(2F,FCF3)S; and

mixtures thereof.

11. The method of claim 1 where the viral infection is caused by a virus selected from the group consisting of HSV viruses, and

wherein the compound is selected from the group consisting of DPIX,Fe;

HPIX,Fe;

HPIX,Zn;

PPIX,In;

MPIX,Co;

PPIX,Co;

PPIX,Fe;

PPIX,In;

DPIX 2,4-bis ethylene glycol,Cu;

tetrakis(2,6-difluorosulfonatonatophenyl)porphyrin;

tetrakis(2,6-difluorosulfonatonatophenyl)porphyrin,Cu;

tetrakis(2,6-dichlorosulfonatonatophenyl)porphyrin;

tetrakis(2-chlorosulfonatophenyl)porphyrin;

tetrakis(3-chlorosulfonatophenyl)porphyrin;

tetrakis(2-fluorosulfonatonatophenyl)porphyrin;

tetrakis(2-fluorosulfonatonatophenyl)porphyrin,Cu;

TMesPS,Co;

TMesPS,Fe;

TPPC4;

TPPS3;

TPPS3,Ag;

TPPS3,Cu;

TPPS3,Fe;

TPPS3,Zn;

TPPS4,Ag;

TPPS4,Cu;

TPPS4,Fe;

TPPS4,Zn; and

the sulfonated derivatives of tetrakis(1-naphthyl)porphyrin and tetrakis(2-naphthyl)porphyrin, the Zn, Fe, and Cu chelates thereof, and mixtures thereof.

12. The method of claim 1 wherein the compound is protected against rapid elimination from the body.

13. The method of claim 1 further comprising providing the compound in a pharmaceutically acceptable carrier selected from the group consisting of ointments, creams, gels, lotions, troches, suppositories, vaginal rings, liposomes, nanoparticulates, microspheres, and controlled release formulations.

14. The method of claim 1 further comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of antibiotics, virucidals, antifungals, and immunostimulants.

15. The method of claim 1 further comprising administering a therapeutically effective amount of at least one microbicide selected from the group consisting of carraguard, antibodies, defensins, cyclodextrins, polyethylene hexamethylene biguanide, and other compounds which are active in preventing viral infection.

16. The method of claim 14 wherein the virucidal is selected from the group consisting of HPA-23, interferons, ribavirin, phosphonoformate, ansamycin, suramin, imuthiol, penicillamine, carbovir, 3′

-azido-3′

-deoxythymidine (AZT), 2′

,3′

-dideoxycytidine (DDC), 2′

,3′

-dideoxyinosine (DDI), 2′

,3′

-dideoxyadenosine (DDA), 3′

-azido-2′

,3′

-dideoxyuridine (CS-87), 2′

,3′

-dideoxy-2′

,3′

-didehydrocytidine (D4C), 3′

-deoxy-2′

,3′

-didehydrothymidine (D4T) and 3′

-azido-5-ethyl-2′

,3′

-dideoxyuridine (CS-85).

17. The method of claim 1 wherein the composition is administered topically or to the mucosa.

18. The method of claim 17 wherein the composition is administered to the female genital tract.

19. The method of claim 17 wherein the composition is administered rectally.

20. The method of claim 1 wherein the M is selected from the group consisting of gallium (Ga), aluminum (Al), cadmium (Cd), ruthenium (Ru), rhodium (Rh), platinum (Pt), osmium (Os), iridium (Ir), iron (Fe), cobalt (Co), zinc (Zn), molybdenum (Mo), titanium (Ti), manganese (Mn), chromium (Cr), nickel (Ni), magnesium (Mg), copper (Cu), indium (In), vanadium (V), silver (Ag), gold (Au), and tin (Sn).

21. The method of claim 20 wherein M is Cu.

22. The method of claim 20 wherein M is Fe.

23. A composition for mucosal administration for preventing a viral infection comprising a synthetic porphyrin or pharmaceutically active salt thereof having the following structure:

24. The composition of claim 23 wherein the pharmaceutically acceptable carrier is selected from the group consisting of ointments, creams, gels, lotions, troches, suppositories, vaginal rings, liposomes, nanoparticulates, microspheres, and controlled release formulations.

25. The composition of claim 23 further comprising a therapeutically effective amount of at least one compound selected from the group consisting of antibiotics, virucidals, antifungals, and immunostimulants.

26. The composition of claim 23 comprising a therapeutically effective amount of at least one microbicide selected from the group consisting of carraguard, antibodies, defensins, cyclodextrins, and polyethylene hexamethylene biguanide.

27. The composition of claim 25 wherein the virucidal is selected from the group consisting of HPA-23, interferons, ribavirin, phosphonoformate, ansamycin, suramin, imuthiol, penicillamine, carbovir, 3′

-azido-3′

-deoxythymidine (AZT), 2′

,3′

-dideoxycytidine (DDC), 2′

,3′

-dideoxyinosine (DDI), 2′

,3′

-dideoxyadenosine (DDA), 3′

-azido-2′

,3′

-dideoxyuridine (CS-87), 2′

,3′

-dideoxy-2′

,3′

-didehydrocytidine (D4C), 3′

-deoxy-2′

,3′

-didehydrothymidine (D4T) and 3′

-azido-5-ethyl-2′

,3′

-dideoxyuridine (CS-85).

28. The composition of claim 23 in a formulation for topical administration.

29. The composition of claim 23 in a formulation for administration via the female genital tract.

30. The composition of claim 23 wherein the porphyrin composition is effective for treating a sexually transmitted disease.

31. The composition of claim 23 in a formulation for administration via the rectum.

32. The composition of claim 23 wherein M is selected from the group consisting of gallium (Ga), aluminum (Al), cadmium (Cd), ruthenium (Ru), rhodium (Rh), platinum (Pt), osmium (Os), iridium (Ir), iron (Fe), cobalt (Co), zinc (Zn), molybdenum (Mo), titanium (Ti), manganese (Mn), chromium (Cr), nickel (Ni), magnesium (Mg), copper (Cu), indium (In), vanadium (V), silver (Ag), gold (Au), and tin (Sn).

33. The composition of claim 32 wherein M is selected from the group consisting of Cu and Fe.

34. The composition of claim 23 selected from the group consisting of TNapPS, TPP(2,6-F2)S,Cu;

TAnthPS, TMPS,Co, DPEG,Fe, DPEG,Zn;

TPPC,Fe;

TPPC;

TPP(2,6-C12)S,Fe and TPP(2,6-C12)S;

TPP2FS;

S;

TPP(2,6-C12);

TPP4ClS;

TPP(2,6-F2)S,Cu;

TPP(2F,FCF3)S; and

mixtures thereof.

35. The composition of claim 23 wherein the composition is effective to inhibit infection or replication of a virus selected from the group consisting of HIV viruses and HSV viruses.

36. The composition of claim 23 wherein the composition is effective to inhibit infection or replication of a virus selected from the group consisting hepatitis B and C viruses, and papilloma viruses.

37. The composition of claim 35

wherein R¹, R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, and R¹² are hydrogen, and R², R⁵, R⁸, and R¹¹ are alkyl, heteroalkyl, aryl, or heteroaryl groups, and

wherein the porphyrin as a whole bears one or more sulfonic acid or derivatized sulfonic acid groups.

38. The composition of claim 37 wherein the porphyrin is a Cu or Fe chelate of the structure of Formula 1.

39. The composition of claim 23 where the composition is effective to inhibit infection or replication of a HSV virus,

wherein R², R⁵, R⁸, and R¹¹ are hydrogens and R¹, R³, R⁴, R⁶, R⁷, R⁹, R¹⁰, and R¹² are hydrogen, alkyl, heteroalkyl, or substituted alkyl groups, and

wherein the molecule as a whole bears two or more carboxylic acid groups.

40. The composition of claim 39 wherein the porphyrin is a Cu or Fe chelate of the structure of Formula I.

41. The composition of claim 23 wherein the composition is effective to inhibit infection or replication of a HIV virus,

wherein the compound is selected from the group consisting of TNapPS, TPP(2,6-F2)S,Cu;

TAnthPS, TMPS,Co, DPEG,Fe, DPEG,Zn;

TPPC,Fe;

TPPC;

TPP(2,6-C12)S,Fe and TPP(2,6-C12)S;

TPP2FS;

TPP4ClS;

TPP(2,6-C12);

TPP(2,6-F2)S,Cu;

TPP(2F,FCF3)S; and

mixtures thereof.

42. The composition of claim 39 wherein the compound is selected from the group consisting of DPIX,Fe;

HPIX,Fe;

HPIX,Zn;

PPIX,In;

MPIX,Co;

PPIX,Co;

PPIX,Fe;

PPIX,In;

DPIX 2,4-bis ethylene glycol,Cu;

tetrakis(2,6-difluorosulfonatonatophenyl)porphyrin;

tetrakis(2,6-difluorosulfonatonatophenyl)porphyrin,Cu;

tetrakis(2,6-dichlorosulfonatonatophenyl)porphyrin;

tetrakis(2-chlorosulfonatophenyl)porphyrin;

tetrakis(3-chlorosulfonatophenyl)porphyrin;

tetrakis(2-fluorosulfonatonatophenyl)porphyrin;

tetrakis(2-fluorosulfonatonatophenyl)porphyrin,Cu;

TMesPS,Co;

TMesPS,Fe;

TPPC4;

TPPS3;

TPPS3,Ag;

TPPS3,Cu;

TPPS3,Fe;

TPPS3,Zn;

TPPS4,Ag;

TPPS4,Cu;

TPPS4,Fe;

TPPS4,Zn; and

the sulfonated derivatives of tetrakis(1-naphthyl)porphyrin and tetrakis(2-naphthyl)porphyrin, the Zn, Fe, and Cu chelates thereof, and mixtures thereof.

43. The composition of claim 23 wherein the porphyrin or a metal chelate of the porphyrin is covalently linked to one or more sugars or sugar derivatives.

44. The composition of claim 23 wherein the porphyrin or a metal chelate of the porphyrin is covalently linked to one or more amino acids or peptides.