WO1995028940A1 - Technique d'inhibition du virus de l'immunodeficience humaine - Google Patents

Technique d'inhibition du virus de l'immunodeficience humaine Download PDF

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Publication number
WO1995028940A1
WO1995028940A1 PCT/US1994/004436 US9404436W WO9528940A1 WO 1995028940 A1 WO1995028940 A1 WO 1995028940A1 US 9404436 W US9404436 W US 9404436W WO 9528940 A1 WO9528940 A1 WO 9528940A1
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WO
WIPO (PCT)
Prior art keywords
formulation
active agent
deaza
neplanocin
hiv
Prior art date
Application number
PCT/US1994/004436
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English (en)
Inventor
Peter K. Chiang
Douglas L. Mayers
Donald S. Burke
Original Assignee
Department Of The Army
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Department Of The Army filed Critical Department Of The Army
Priority to PCT/US1994/004436 priority Critical patent/WO1995028940A1/fr
Publication of WO1995028940A1 publication Critical patent/WO1995028940A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Definitions

  • This invention relates to use of neplanocin-A, 4'thio- adenosine, 5-aza-cytidine, 3-deaza-aristeromycin and 3-deaza- neplanocin for inhibition of human immunodeficiency virus (HIV), especially when the virus is resistent toward 3'-azido- 3'-deoxythymidne (AZT) .
  • HIV human immunodeficiency virus
  • AZT 3'-azido- 3'-deoxythymidne
  • AZT AZT-resistant erythroid hypoplasia and megaloblastic changes in the bone marrow.
  • the drug itself is expensive and the cost of laboratory monitoring of patients results in still further expense.
  • Additional effects of AZT include severe headache, nausea, insomnia and myalgias. It is essential that new agents be found that will effectively inhibit AZT-resistant strains and are devoid of toxic reactions.
  • antiviral agent against other viruses.
  • antiviral agents which are effective against other viral infections have proven to be ineffective against HIV, and AZT is not effective against such viruses as herpes simplex or varicella.
  • Dideoxyinosine (ddl) and dideoxycytidine (ddC) have also been shown to be useful in the treatment of AIDS.
  • Di- deoxyinosine has presently been approved for clinical use.
  • the primary toxic effects are primarily peripheral neuropathy and pancreatitis. When given in conjunction with AZT some of the more serious effects of both drugs can be minimized.
  • the drug ddC has shown excellent antiviral activity and is presently undergoing clinical trials.
  • pancreatic effects appear to be less serious than effects seen using ddl.
  • Neplanocins have been known previously to have antitumor activity. Some of the neplanocins, including A and C, have also been known to have growth inhibitory activity on some kinds of plant pathogenic fungi. Neplanocin-A has also been reported to have antimalarial activity. (Whaun, et al.. Journal of Pharmacology and Experimental Therapeutics. Vol. 236, No. 1, pp 277-282 (1986)) There is no suggestion that neplanocin-A would inhibit HIV.
  • Adenosine analogues as substrates and as inhiitors of S- adenosylhomocysteine hydrolase, including carbocyclic adeno ⁇ sine, are taught by Guranowski, et al. (Biochemistry. Vol. 20, No. 1, pp 110-155 (1981)). There is no teaching regarding neplanocin-A therein. Antiviral properties of neplanocin-A and its analogs are described by DeClerq, et al. (Antimicrobial Agents and Chemotherapy. Vol. 33 No. 3, pp 1291-1297 (1989)). De Clerq comes to the conclusion that neplanocin-A is not effective against HIV at non-toxic levels.
  • 3-Deaza-aristeromycin (also known as carbocyclic 3-deaza- adenosine) is disclosed in U.S. Patent 4,386,093 to Chiang, et al which is incorporated herein by reference, has been shown to be effective for inhibiting herpes simplex virus. There is no suggestion therein that 3-deaza-aristeromycin would be effective against HIV.
  • the 3-deaza-aristeromycin is relatively non-cytotoxic at antiviral concentrations and is not subject to deamination or phosphorylation.
  • At a K, of 3 X 10 ' °M it acts as a competitive inhibitor of S-adenosylhomocysteine hydrolase.
  • Wyde, et al. Antiviral Research.
  • neplanocin-A, 4'thioadenosine, 5-aza-cytidine 3-deaza-aristeromycin and 3-deazaneplanocin are very effective HIV inhibiting agents. Even more surprising is the discovery that these compounds are particularly effective against HIV that have been shown to be AZT resistant.
  • the use of the particular species for purposes of inhibiting the activity of the AIDS virus is particularly important in the fight against AIDS in persons who have been treated with AZT and either no longer respond to treatment or are suffering from unacceptable side effects.
  • amino and hydroxy groups may be carboxylated to provide esters and amides, the unsubstituted compounds are believed to be most useful for providing immediate beneficial results against the HIV virus.
  • compositions have been studied in accord with the methods described below.
  • HIV-1 isolates All clinical HIV-1 isolates were obtained by co-cultivation of phytohemagglutinin (PHA)-stimulated donor peripheral blood mononuclear cells (PBMC) with fresh patient PBMC obtained by ficoll-Hypaque separation of heparinized blood. Isolates were expanded on fresh donor PBMC to obtain a virus stock which was frozen in aliquots at -180 ⁇ C.
  • PHA phytohemagglutinin
  • PBMC peripheral blood mononuclear cells
  • Viral Stock Titration ACTG/DOD Consensus HIV-l Drug Suscepti ⁇ bility Assay: The tissue culture infectious dose 50% (TCID 50 ) was determined by endpoint dilution using sextuplicate serial 4-fold dilutions ranging from 1:16 to 1:64,000 in a 96-well microtiter plate. Each well contained 2 X 10 5 PHA-stimulated donor PBMC in a total volume of 200 ⁇ l of supplemented RPMI- 1640. Plates were incubated at 37 °C in humidified air with 5% C0 2 . On the fourth day, the cells were resuspended, split 1:3, and fresh medium was added.
  • TCID 50 was defined as the amount of virus stock at which 50% of the inoculated wells were positive and was based on the number of positive wells at each viral dilution using the Spearman-Karber method.
  • ACTG/DOD HIV-1 Drug Susceptibility Assay PHA-stimulated donor PBMC were incubated with cell-free virus stock at 200 TCID 50 per 2 X 10 5 cells for one hour at 37°C. The cells were washed with RPMI-1640 and centrifuged at 300 g for 10 minutes.
  • the supernatant was removed and the cells were resuspended in 8.0 ml of fresh medium.
  • a 96-well microtiter plate was set up with 2 X 10 5 cells/well added to drug containing media with final concentrations of 0.001, 0.01, 0.1, 1.0, and 5.0 ⁇ M zidovudine (AZT) .
  • the concentration of 3-deazanucleosides used in this study were 0.001, 0.01, 0.1 and 1.0 ⁇ M.
  • Co-cultures were incubated at 37 ⁇ C in humidified air with 5% C0 2 .
  • PBMC peripheral blood mononuclear cells
  • HIV ISOLATE AZT DZNep DZAri DZA pre-AZT (A012) 0.0163 0.0095 (95) 0.1597 (6) 0.1909 (5) post-AZT(A012) 2.0729 0.0012 (750) 0.3970 (2) 0.1038 (7) re-AZT (A018) 0.0252 0.0153 (59) 0.1867 (5) 0.2187 (3) post-AZT(AOl ⁇ ) 2.2881 0.0051 (177) 0.0838 (11) 0.6254 (1)
  • DZNep 3-deazaneplanocin
  • DZAri 3-deaza-aristeromycin
  • DZA 3-deaza-adenosine
  • compositions for therapeutic use were unexpectedly susceptible to inhibition by active agents of the invention. The reason for this is not known. However, it is clear that these agents are particularly effective for inhibit ⁇ ing HIV activity of organisms already exposed to AZT.
  • compositions of the invention may be administered by mouth or parenterally. However, when the condition being treated is chronic in nature, it is economically advantageous to adminis- ter the drug either in tablet or capsule form or through the mucous membrane.
  • Compositions for administration to the mucous membranes may advantageously be delivered as a mist to the membranes of the respiratory tract or may be administered buccally or sublingually.
  • the active agents may be adminis- tered as cyclodextrin inclusion complexes prepared in accord with the teaching of U.S. Patent 4,727,064, which is incorpo ⁇ rated herein by reference.
  • Compositions may also be adminis ⁇ tered rectally as supposititories.
  • the active agents may be formulated in liposomes, microcrystals or mcirodroplets.
  • parenteral administration the usual carriers, including saline, may be used.
  • Other microbials may be administered in conjunction with neplanocin-A.
  • homocysteine or homocysteine thiolactone may be administered to enhance anti- HIV activity.
  • Compositions of the invention may be administered parenterally by, for example, intramuscular, subcutaneous, or intravenous routes. Dosage of from 0.01 to 4 mg/Kg/day should be administered. Higher dosages may be required early in the treatment program to raise blood levels to effective levels. Dosage of .02 to .5 mg/Kg/day would be more usual.
  • the following examples are provided as examples only and are not intended as limitations.
  • the resulting formulation may be placed in a capsule or formed into a tablet for oral administration.
  • the resulting formulation can be placed in a capsule for oral administration or be formed into a tablet.
  • compositions containing the active agents may be administered intravenously in the usual carriers such as normal physiological saline, lactated Ringer's solution, or 5% dextrose in water.
  • compositions may also be administered intraocullarly. Many AIDS patients suffer from cytomegalovirus as a secondary infection.
  • the compositions of the invention may be particu ⁇ larly useful for administration to these patients. Dosages may be determined by the method described which gave rise to the data in Table I and II. It is possible thereby to evaluate the susceptability of the HIV strains that infect patients and to deliver a sufficient dosage to reach the required concentra ⁇ tion for inhibition HIV.
  • the suggested initial dosage is that amount required to deliver a blood concentration of 2X to 3X the IC 50 determined as described above.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des formulations pharmaceutiques à base de néplanocine-A, 3-déazanéplanocine 3-déaza-adénosine, 4'thioadénosine et 5-azacytidine, comprenant homocystéine ou lactone d'homocystéine comme constituants additionnels, ainsi que des procédés de traitement du VIH au moyen de ces formulations. L'invention se rapporte en outre aux mêmes cinq agents antiviraux, formant des complexes avec cyclodextrine, et aptes à être utilisés dans le traitement du VIH chez un hôte humain.
PCT/US1994/004436 1994-04-22 1994-04-22 Technique d'inhibition du virus de l'immunodeficience humaine WO1995028940A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/US1994/004436 WO1995028940A1 (fr) 1994-04-22 1994-04-22 Technique d'inhibition du virus de l'immunodeficience humaine

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PCT/US1994/004436 WO1995028940A1 (fr) 1994-04-22 1994-04-22 Technique d'inhibition du virus de l'immunodeficience humaine

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005115450A1 (fr) * 2004-05-26 2005-12-08 Biovaxim Limited Compositions comprenant des agents demethylisants renforçant l'immunotherapie dans le traitement d'infections chroniques et de maladies neoplasiques, et procede de traitement associe
WO2006063111A2 (fr) * 2004-12-10 2006-06-15 Supergen, Inc. Formulations pharmaceutiques d'analogues de cytidine et derives
US7642247B2 (en) * 2002-09-24 2010-01-05 Koronis Pharmaceuticals, Incorporated 1,3,5-triazines for treatment of viral diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5651414A (en) * 1979-10-02 1981-05-09 Toyo Jozo Co Ltd Antibiotic substance neplanocin preparation
GB2200651A (en) * 1987-02-07 1988-08-10 Al Sumidaie Ayad Mohamed Khala A method of obtaining a retrovirus-containing fraction from retrovirus-containing cells
US5039689A (en) * 1988-11-09 1991-08-13 Burroughs Wellcome Co. Antiparasitic 3(4-amino benzotriazo-1-yl-)1,2-cyclopentanediols

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5651414A (en) * 1979-10-02 1981-05-09 Toyo Jozo Co Ltd Antibiotic substance neplanocin preparation
GB2200651A (en) * 1987-02-07 1988-08-10 Al Sumidaie Ayad Mohamed Khala A method of obtaining a retrovirus-containing fraction from retrovirus-containing cells
US5039689A (en) * 1988-11-09 1991-08-13 Burroughs Wellcome Co. Antiparasitic 3(4-amino benzotriazo-1-yl-)1,2-cyclopentanediols

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol. 33, No. 8, issued August 1989, DeCLERCQ et al., "Broad-Spectrum Antiviral Activities of Neplanocin A, 3-Deazaneplanocin A and Their 5'-Nor Derivatives", pages 1291-1297. *
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol. 34, No. 2, issued February 1990, BOUCHARD et al., "5 -Azacytidine and 5- Azadeoxycytidine Inhibit Human Immunodeficiency Virus Type 1 Replication in Vitro", pages 206-209. *
BIOCHEMICAL PHARMACOLOGY, Vol. 38, No. 11, issued 01 June 1989, DeCLERCQ et al., "Homocysteine Potentiates the Antiviral and Cytostatic Activity of Those Nucleoside Analogues that Are Targeted as S-Adenosylhomocysteine Hydrolase" pp. 1771-1776. *
FASEB J., Vol. 3, No. 4, issued 19 March 1989, WALKER et al., "5-Azacytidine and 5-Azadeoxycytidine Inhibit HIV Replication In Vitro", page A1117, Abstr. No. 5176. *
J. MED. CHEM., Vol. 35, No. 3, issued 1992, SECRIST III et al., "Synthesis and Anti-HIV Activity of 4'-Thio-2',3'-Dideoxynucleosides", pages 533-538. *
J. MED. CHEM., Vol. 36, No. 15, issued 1992, SECRIST III et al., "Synthesis of 5'- Substituted Analogues of 3- Deazaadenosine as Potential Antivirals", pages 2102-2106. *
MUTATION RESEARCH, Vol. 208, issued 1988, RASCATI, "Effects of Cytidine Analogs On Methylation of DNA and Retrovirus Induction", pages 21-25. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7642247B2 (en) * 2002-09-24 2010-01-05 Koronis Pharmaceuticals, Incorporated 1,3,5-triazines for treatment of viral diseases
US7772197B2 (en) 2002-09-24 2010-08-10 1,3,5-Triazines for Treatment of Viral Diseases 1,3,5-triazines for treatment of viral diseases
WO2005115450A1 (fr) * 2004-05-26 2005-12-08 Biovaxim Limited Compositions comprenant des agents demethylisants renforçant l'immunotherapie dans le traitement d'infections chroniques et de maladies neoplasiques, et procede de traitement associe
WO2006063111A2 (fr) * 2004-12-10 2006-06-15 Supergen, Inc. Formulations pharmaceutiques d'analogues de cytidine et derives
WO2006063111A3 (fr) * 2004-12-10 2009-04-09 Supergen Inc Formulations pharmaceutiques d'analogues de cytidine et derives

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