Anti Mineralocorticoid Therapy of Infection

• US 20090053294A1
• Filed: 10/31/2006
• Published: 02/26/2009
• Est. Priority Date: 10/28/2005
• Status: Abandoned Application

• Current Assignee: Patrick T. Prendergast
• Original Assignee: Patrick T. Prendergast
• Inventors: Prendergast, Patrick T.
• Application Number:
  US12/084,312
• Publication Number:
  US 20090053294A1
• Time in Patent Office: Days
• US Class Current: 424/450
• 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 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/567 substituted in position 17 alpha, e.g. mestranol, norethandrolone
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/6913 the liposome being modified on its surface by an antibody
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/02 Suppositories; Bougies; Bases therefor; Ovulesapparatus for making A61J3/08; devices for introducing into the body A61M31/00
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• 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

Antimineralocorticoid compounds are disclosed for use in the prophylaxis and therapy of viral infections, especially the retroviral infection by HIV. These compounds can be administered alone or in combination with conventional anti-viral agents or anti-sense mineralocorticoid Steroid ReceptorNA or DNA mutants of heat shock proteins.

Claims

1. A pharmaceutical composition comprising at least one antimineralocorticoid compound or molecule.

2. The pharmaceutical composition claimed in claim 1, wherein the antimineralocorticoid compound is selected from the group consisting of spironolactone, spirorenone, 1,2-dihydro-spirorenone, 1,2α

-methylene-spirorenone, eplerenone, drospirenone, potassium canrenoate, canrenoate, canrenone and pharmaceutically acceptable salts thereof, and their metabolites thereof.

3. The pharmaceutical composition as claimed in claim 2, wherein the antimineralocorticoid compound is spironolactone.

4. The pharmaceutical composition as claimed in claim 1 wherein the antimineralocorticoid compound is an anti-idiotypic monoclonal antibody which has binding specificity to a binding epitope present on aldosterone.

5. The pharmaceutical composition as claimed in claim 2 wherein the antimineralocorticoid compound is drospirenone.

6. The pharmaceutical composition as claimed in claim 1 wherein the antimineralocorticoid compound is selected from the group consisting of progesterone, gestodene, dimethisterone, drospirenone, ethinyloestradiol, ethisterone, 11β

-hydroxyprogesterone, 17α

-hydroxyprogesterone, 16α

-methyl progesterone, hydroxyprogesterone caproate, medroxyprogesterone acetate, proligestone and pharmaceutically acceptable salts thereof, and metabolites, thereof.

7. The pharmaceutical composition as claimed in claim 1 wherein, the antimineralocorticoid compound is a 7α

-acetylthio-4-pregnene-3,20-dione represented by formula B

8. The pharmaceutical composition as claimed in claim 7 wherein, R₁ is hydroxyl or OR₂, and R₂ is derived from a carboxylic acid from 3 to 12 carbon atoms.

9. The pharmaceutical composition as claimed in claim 7 wherein R₁ is selected from the group consisting of hydroxy, monocarboxylic and a straight or branched-chain alkanooyloxy group having up to 12 carbon atoms.

10. The pharmaceutical composition formulation as claimed in claim 7 wherein R₁ is selected from the group consisting of hydrogen, hydroxy, acetoxy, propionyloxy, n-butyryloxy, trimethylacetoxy, n-valeroyloxy and n-heptanoyloxy.

11. The pharmaceutical composition as claimed in claim 7 wherein the antimineralocorticoid compound is selected from the group consisting of:

7α

-acetylthio-4-pregnene-3,20-dione;

7α

-acetylthio-21-hydroxy-4-pregnene-3,20-dione;

7α

-acetylthio-21-acetoxy-4-pregnene-3,20-dione;

7α

-acetylthio-21-propionyloxy-4-pregnene-3,20-dione;

7α

-acetylthio-21-n-butyryloxy-4-pregnene-3,20-dione;

7α

-acetylthio-21-trimethylacetoxy-4-pregnene-3,20-dione;

7α

-acetylthio-21-n-valeroyloxy-4-pregnene-3,20-dione;

7α

-acetylthio-21-heptanoyloxy-4-pregnene-3,20-dione;

7α

-acetylthio-3-oxo-4,15-androstadiene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one;

3-oxo-7α

-propionylthio-4,15-androstadiene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one;

6β

,7β

-Methylene-3-oxo-4,15-androstadiene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one;

15α

, 16α

-Methylene-3-oxo-7α

-propionylthio-4-androstene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one;

6β

,7β

,15α

, 16α

-Dimethylene-3-oxo-4-androstene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one;

7α

-Acetylthio-15α

,16α

-methylene-3-oxo-4-androstene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one;

7α

-Acetylthio-15β

, 16β

-methylene-3-oxo-4-androstene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one;

15β

, 16β

-Methylene-3-oxo-7β

-propionylthio-4-androstene-[17(β

-1′

)-spiro-5′

]perhydrofuran-2′

-one; and

6β

,7β

,15β

,16β

-Dimethylene-3-oxo-4-androstene-[17(β

-1′

)- spiro-5′

]perhydrofuran-2′

-one.

12. The pharmaceutical composition claimed in claim 1 wherein the antimineralocorticoid compound is a 9,11-epoxy steroid compound.

13. The pharmaceutical composition claimed in claim 1, wherein the antimineralocorticoid compound is halogenated.

14. The pharmaceutical composition as claimed in claim 13, wherein the halogen is selected from the group consisting of chlorine, bromine, fluorine and iodine.

15. The pharmaceutical composition claimed in claim 1, wherein the composition further includes at least one other anti-viral agent.

16. The pharmaceutical composition as claimed in claim 15, wherein the anti-viral agents are selected from the group consisting of nucleoside analogues;

non-nucleoside reverse transcriptase inhibitors;

protease inhibitors;

ALX40-4C;

hydroxyurea;

lobucavir;

pentafuside;

T-1249;

PRO 542;

FP-21399;

AMD 3100;

HE-2000 and peptide T.

17. The pharmaceutical composition as claimed in claim 15, wherein the antiviral agents are selected from the group consisting of Abacavir;

Acemannan;

Acyclovir;

Acyclovir Sodium;

Adefovir;

Alovudine;

Alvircept Sudotox;

Amantadine Hydrochloride;

Aranotin;

Arildone;

Atevirdine Mesylate;

Avridine;

Cidofovir;

Cipamfylline;

Coviracil;

Cytarabine Hydrochloride;

Delavirdine Mesylate;

Desciclovir;

Didanosine;

Disoxaril;

Edoxudine;

Emivirine;

Emtricitabine;

Enviradene;

Enviroxime;

Epivir;

Famciclovir;

Famotine Hydrochloride;

Fiacitabine;

Fialuridine;

Fosarilate;

Foscamet Sodium;

Fosfonet Sodium;

Ganciclovir;

Ganciclovir Sodium;

Idoxuridine;

Indinavir;

Kethoxal;

Lamivudine;

Lobucavir;

Lodenosine;

Lopinavir, Memotine Hydrochloride;

Methisazone;

Nelfinavir;

Nevirapine;

Penciclovir;

Pirodavir;

Ribavirin;

Rimantadine Hydrochloride;

Saquinavir Mesylate;

Ritonavir;

Somantadine Hydrochloride;

Sorivudine;

Statolon;

Stavudine;

Tenofovir;

Tilorone Hydrochloride;

Trifluridine;

Valacyclovir Hydrochloride;

Vidarabine;

Vidarabine Phosphate;

Vidarabine Sodium Phosphate;

Tipranavir, Viroxime;

Zalcitabine;

Zidovudine and Zinviroxime.

18. The pharmaceutical composition as claimed in claim 1, wherein the composition further comprises a protease inhibitor.

19. The pharmaceutical composition as claimed in claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.

24. The pharmaceutical composition as claimed in claim 1 wherein the composition has an enteric coating made of a polymer.

25. The pharmaceutical composition as claimed in claim 24 wherein the enteric coating consists essentially of a polymer or copolymer selected from the group consisting of poly(lactic-glycolic acid) polyester, cellulose acetate phthalate, hydroxypropyl-methyl cellulose phthalate poly(butyl methacrylate), (2-dimethyl aminoethyl) methacrylate and methyl methacrylate.

27. The pharmaceutical composition as claimed in claim 1, wherein the composition is formulated into liposomes or carbohydrate or cyclodextrin vehicles.

28. The pharmceutical composition as claimed in claim 27, wherein the liposomes or carbohydrate vehicles are targeted to HIV infected cells by conjoining antibodies with a binding specificity for viral-specific binding epitopes to their surface.

29. The pharmaceutical composition as claimed in claim 28, wherein the viral antibodies are directed to at least one of the HIV coat protein gp160, gp120 and gp41.

31. The pharmaceutical composition as claimed in claim 1, wherein the composition is a unit dose that comprises 5-500 mg of the antimineralocorticoid compound, alone or in combination with other antivirals.

33. The pharmaceutical composition as claimed in claim 1, wherein said antimineralocorticoid compound is a pro-drug entity.

87. The pharmaceutical composition as claimed in claim 16, wherein:

the nucleoside analogues are selected from the group consisting of AZT, ddC, ddl, d4T, 3TC, BW 1592, PMEA/bis-POM PMEA, dOTC, and DAPD;

the non-nucleoside reverse transcriptase inhibitors are selected from the group consisting of delavirdine, DMP 266, HBY097, loviride, nevirapine, emivirine, AG1549, PNU142721, Calanolide A, and DPC961; and

the protease inhibitors are selected from the group consisting of ABT-378, ritonavir, nelfinavir, BW 141, KNI-272, indinavir, saquinavir, L-756,423, DMP-450 and BMS-232630.

20-23. -23. (canceled)

26. (canceled)

30. (canceled)

32. (canceled)

34-65. -65. (canceled)

66. A method of preparing a vaccine comprising a virus, the method comprising the step of mutating or deleting from the viral genome nucleotides which encode for hydrophobic amino acid residues which cause binding of the virus to an aldosterone binding site on a mineralocorticoid steroid receptor, wherein the deletion or mutation prevents expression of the hydrophobic amino acid residues by the virus.

67. A method for the treatment and/or prophylaxis of a viral infection in a subject, the method comprising the step of:

administering a therapeutically effective amount of a pharmaceutical composition comprising at least one antimineralocorticoid compound to a the subject.

68. The method as claimed in claim 67, wherein the viral infection is infection by a retrovirus.

69. The method as claimed in claim 68, wherein the retrovirus is selected from the group consisting of HIV, Herpes virus and cytomegalovirus.

73. The method as claimed in claim 67 wherein the antimineralocorticoid compound is selected from the group consisting of spironolactone, spirorenone, 1,2-dihydro-spirorenone, 1,2α

-methylene-spirorenone, eplerenone, drospirenone, potassium canrenoate, canrenoate and canrenone, and pharmaceutically acceptable salts and metabolites thereof.

74. The method as claimed in claim 67 wherein the antimineralocorticoid compound is spironolactone or a pro-drug, derivative or analogue thereof and the viral infection is HIV.

75. The method as claimed in claim 67 wherein the antimineralocorticoid compound is an anti-idiotypic monoclonal antibody which has binding specificity to a binding epitope present on aldosterone.

76. The method as claimed in claim 67, wherein the antimineralocorticoid compound is selected from the group consisting of progesterone, gestodene, dimethisterone, ethinyloestradiol, ethisterone, 11β

-hydroxyprogesterone, 17α

-hydroxyprogesterone, 16α

-methyl progesterone, hydroxyprogesterone caproate, medroxyprogesterone acetate and proligestone, and pharmaceutically acceptable salts and metabolites thereof.

77. The method as claimed in claim 67, wherein, the antimineralocorticoid compound is a 7α

-acetylthio-4-pregnene-3,20-dione represented by Formula B;

78. The method as claimed in claim 67, wherein the composition further comprises at least one further anti-viral agent.

79. The method as claimed in claim 67, wherein the composition further comprises a protease inhibitor.

80. The method as claimed in claim 67, wherein the viral infection is infection by a virus selected from the group consisting of a retrovirus, a togavirus, a flavivirus, a rubivirus, a pestivirus, a lipid envelope virus, a picornavirus, a rhinovirus, a coronavirus, a respiratory syncytial virus, a poliovirus, a parainfluenza virus, influenza virus, hantavirus, HIV, HTLV-1, HTLV-3, Kaposi'"'"'s sarcoma-associated herpes virus, HHV-6, HHV-8, the viruses of the genus Molluscipoxvirus, HAV, HBV, HCV, Epstein Barr virus, Herpes virus and cytomegalovirus.

81. The method as claimed in claim 67, wherein said subject is a neonate and the pharmaceutical composition is administered prior to delivery of said neonate and/or during delivery of said neonate.

82. The method as claimed in claim 67, wherein the composition is administered enterally, parenterally, topically, orally, rectally, nasally or vaginally.

83. The method as claimed in claim 67, wherein the composition is administered intermittently.

70. (canceled)

71. (canceled)

72. (canceled)

84. A method for the treatment and/or prophylaxis of an AIDS related syndrome in a subject, the method comprising the step of:

administering a therapeutically effective amount of a pharmaceutical composition comprising at least one antimineralocorticoid compound to the subject.

85. The method of claim 84 wherein the AIDS related syndrome is selected from the group consisting of cachexia, wasting syndrome, lipodystrophy, and combinations thereof.

86. A vaccine for immune clearance and immune memory cell development, the vaccine comprising a viral genome wherein the nucleotides which encode for the hydrophobic amino acid residues, which cause binding of the virus to an aldosterone binding site on a mineralocorticoid steroid receptor, have been deleted or mutated such that expression of the hydrophobic amino acid residues is prevented.