ZA200305423B - DAPD combination therapy with IMDPH inhibitors such as ribavirin or mycophenolic acid. - Google Patents
DAPD combination therapy with IMDPH inhibitors such as ribavirin or mycophenolic acid. Download PDFInfo
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- ZA200305423B ZA200305423B ZA200305423A ZA200305423A ZA200305423B ZA 200305423 B ZA200305423 B ZA 200305423B ZA 200305423 A ZA200305423 A ZA 200305423A ZA 200305423 A ZA200305423 A ZA 200305423A ZA 200305423 B ZA200305423 B ZA 200305423B
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- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 title claims description 22
- 229960000329 ribavirin Drugs 0.000 title claims description 22
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- 229960000951 mycophenolic acid Drugs 0.000 title claims description 21
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DAPD COMBINATION THERAPY WITH INOSINE MONOPHOSPHATE
DEHYDROGENASE INHIBITOR
The present invention relates to pharmaceutical compositions and methods for the treatment or prophylaxis of human immunodeficiency virus (HIV) infection in a host comprising administering such compositions. This application claims priority to U.S. provisional application 60/256,068 filed on December 15, 2000 and to U.S. provisional application 60/272,605 filed on March 1, 2001.
AIDS, Acquired Immune Deficiency Syndrome, is a catastrophic disease that has reached global proportions. From July 1998 through June 1999 a total of 47,083 AIDS cases were reported in the US alone. With more than 2.2 million deaths in 1998,
HIV/AIDS has now become the fourth leading cause of mortality and its impact is going to increase. The death toll due to AIDS has reached a record 2.6 million per year, while new HIV infections continued to spread at a growing rate, according to a recent : UNAIDS report.
AIDS was first brought to the attention of the Center for Disease Control and
Prevention (CDC) in 1981 when seemingly healthy homosexual men came down with
Karposi's Sarcoma (KS) and Pneumocystis Carinii Pneumonia (PCP), two opportunistic diseases that were only known to inflict immuno-deficient patients. A couple of years . later, the causitive agent of AIDS, a lymphoadenopathy associated retrovirus, the human immunodefieciency virus (HIV) was isolated by the Pasteur Institute in Paris, and later . confirmed by an independent source in the National Cancer Institute of the United States.
In 1986, at the second International Conference on AIDS in Paris, preliminary reports on the use of a drug against AIDS were presented. This drug, 3’-azido-3’-deoxy-
thymidine (AZT, Zidovudine, Retrovir), was approved by the Food And Drug
Administration (FDA) and it became the first drug to be used in the fight against AIDS.
Since the advent of AZT, several nucleoside analogs have been shown to have potent antiviral activity against the human immunodeficiency virus type I (HIV-I). In . particular, a number of 2°,3’-dideoxy-2’,3’-didehydro-nucleosides have been shown to have potent anti-HIV-1 activity. 2°,3’-Dideoxy-2’,3’-didehydro-thymidine (“D4T”; also . referred to as 1-(2,3-dideoxy-B-D-glycero-pent-2-eno-furanosyl)thymine)) is currently sold for the treatment of HIV under the name Stavudine by Bristol Myers Squibb.
It has been recognized that drug-resistant variants of HIV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication, and most typically in the case of HIV, reverse transcriptase, protease or DNA polymerase.
Recently, it has been demonstrated that the efficacy of a drug against HIV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous pressures on the virus. One cannot predict, however, what mutations will be induced in the HIV-1 genome by a given drug, whether the mutation is permanent or transient, or how an infected cell with a mutated HIV-1 sequence will respond to therapy with other agents in combination or alternation. This is exacerbated by the fact that there is a paucity of data on the kinetics of drug resistance in long-term cell cultures treated with modern antiretroviral agents.
HIV-1 variants resistant to 3’-azido-3’-deoxythymidine (AZT), 2’,3’- dideoxyinosine (DDI) or 2’,3’-dideoxycytidine (DDC) have been isolated from patients receiving long term monotherapy with these drugs (Larder BA, Darby G, Richman DD.
Science 1989;243:1731-4; St Clair MH, Martin JL, Tudor WG, et al. Science 1991;253:1557-9; St Clair MH, Martin JL, Tudor WG, et al. Science 1991;253:1557-9; and Fitzgibbon JE, Howell RM, Haberzettl CA, Sperber SJ, Gocke DJ, Dubin DT. ,
Antimicrob Agents Chemother 1992;36:153-7). Mounting clinical evidence indicates that AZT resistance is a predictor of poor clinical outcome in both children and adults
(Mayers DL. Lecture at the Thirty-second Interscience Conference on Antimicrobial
Agents and Chemotherapy. (Anaheim, CA. 1992); Tudor-Williams G, St Clair MH,
McKinney RE, et al. Lancet 1992;339:15-9; Ogino MT, Dankner WM, Spector SA. J : Pediatr 1993;123:1-8; Crumpacker CS, D’Aquila RT, Johnson VA, et al. Third
Workshop on Viral Resistance. (Gaithersburg, MD. 1993); and Mayers D, and the RV43 ‘ Study Group. Third Workshop on Viral Resistance. (Gaithersburg, MD. 1993)).
The rapid development of HIV-1 resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) has also been reported both in cell culture and in human clinical trials (Nunberg JH, Schleif WA, Boots EJ, et al. J Virol 1991;65(9):4887-92; Richman D, Shih CK, Lowy 1, et al. Proc Natl Acad Sci (USA) 199188 :11241-5; Mellors JW, Dutschman GE, Im GJ, Tramontano E, Winkler SR,
Cheng YC. Mol Pharm 1992;41:446-51; Richman DD and the ACTG 164/168 Study
Team. Second International HIV-1 Drug Resistance Workshop. (Noordwijk, the
Netherlands. 1993); and Saag MS, Emini EA, Laskin OL, ef al. N Engl J Med 1993:329:1065-1072). In the case of the NNRTI L’697,661, drug-resistant HIV-1 emerged within 2-6 weeks of initiating therapy in association with the return of viremia to pretreatment levels (Saag MS, Emini EA, Laskin OL, et al. N Engl J Med 1993;329:1065-1072). Breakthrough viremia associated with the appearance of drug- resistant strains has also been noted with other classes of HIV-1 inhibitors, including protease inhibitors (Jacobsen H, Craig CJ, Duncan IB, Haenggi M, Yasargil K, Mous J.
Third Workshop on Viral Resistance. (Gaithersburg, MD. 1993)). This experience has led to the realization that the potential for HIV-1 drug resistance must be assessed early on in the preclinical evaluation of all new therapies for HIV-1. 1,3-Dioxolanyl Nucleosides
The success of various synthetic nucleosides in inhibiting the replication of HIV in vivo or in vitro has led a number of researchers to design and test nucleosides that . substitute a heteroatom for the carbon atom at the 3'-position of the nucleoside.
Norbeck, et al, disclosed that (+/-)-1-[(2-B, 4-B)-2-(hydroxymethyl)-4- dioxolanyljthymine (referred to as (+/-)-dioxolane-T) exhibits a modest activity against
HIV (ECso of 20 pM in ATHS cells), and is not toxic to uninfected control cells at a concentration of 200 pM. Tetrahedron Letters 30 (46), 6246, (1989).
On April 11, 1988, Bernard Belleau, Dilip Dixit, and Nghe Nguyen-Ba at
BioChem Pharma filed patent application U.S.S.N. 07/179,615 which disclosed a generic group of racemic 2-substituted-4-substituted-1,3-dioxolane nucleosides for the treatment of HIV. The ‘615 patent application matured into European Patent Publication
No. 0 337 713; U.S. Patent No. 5,041,449; and U.S. Patent No. 5,270,315 assigned to
BioChem Pharma, Inc.
On December 5, 1990, Chung K. Chu and Raymond F. Schinazi filed U.S.S.N. 07/622,762, which disclosed an asymmetric process for the preparation of enantiomerically enriched B-D-1,3-dioxolane nucleosides via stereospecific synthesis, and certain nucleosides prepared thereby, including (-)-(2R,4R)-9-[(2-hydroxymethyl)- 1,3-dioloan-4-yl]guanine (DXG), and its use to treat HIV. This patent application issued as U.S. Patent No. 5,179,104.
Q
NH
1 =
N Po, a 0
DXG
On May 21, 1991, Tarek Mansour, et al, at BioChem Pharma filed U.S.S.N. 07/703,379 directed to a method to obtain the enantiomers of 1,3-dioxolane nucleosides using a stereoselective synthesis that includes condensing a 1,3-dioxolane intermediate covalently bound to a chiral auxiliary with a silyl Lewis acid. The corresponding application was filed in Europe as EP 0 515 156.
On August 25, 1992, Chung K. Chu and Raymond F. Schinazi filed U.S.S.N. 07/935,515, disclosing certain enantiomerically enriched B-D-dioxolanyl purine compounds for the treatment of humans infected with HIV of the formula:
R . 0 a N < | PY . N NH, “NY 0) wherein R is OH, Cl, NH; or H, or a pharmaceutically acceptable salt or derivative of the compounds optionally in a pharmaceutically acceptable carrier or diluent. The compound wherein R is chloro is referred to as (-)-(2R,4R)-2-amino-6-chloro-9-[(2- hydroxymethyl)-1,3-dioxolan-4-yljpurine. The compound wherein R is hydroxy is (-)- (2R,4R)-9-[(2-hydroxy-methyl)-1,3-dioxolan-4-yl]guanine. The compound whereinR is amino is (-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]adenine. ~The compound wherein R is hydrogen is (-)-(2R,4R)-2-amino-9-{(2-hydroxymethyl)-1,3- dioxolan-4ylJpurine. This application issued as U.S. Patent Nos. 5,925,643 and 5,767,122.
In 1992, Kim et al., published an article teaching how to obtain (-)-L-B- dioxolane-C and (+)-L-p-dioxolane-T from 1,6-anhydro-L-B-glucopyranose. Kim et al.,
Potent anti-HIV and anti-HBV Activities of (-)-L-B-Dioxolane-C and (+)-L-f-Dioxolane-
T and Their Asymmetric Syntheses, Tetrahedron Letters Vol 32(46), pp 5899-6902.
On October 28, 1992, Raymond Schinazi filed U.S.S.N. 07/967,460 directed to the use of the compounds disclosed in U.S.S.N. 07/935,515 for the treatment of hepatitis
B. This application has issued as U.S. Patent Nos. 5,444,063; 5,684,010; 5,834,474; and 5,830,898.
In 1993, Siddiqui, et al., at BioChem and Glaxo published that cis-2,6- diaminopurine dioxolane can be deaminated selectively using adenosine deaminase.
Siddiqui, et al., Antiviral Optically Pure dioxolane Purine Nucleoside Analogues, . Bioorganic & Medicinal Chemistry Letters, Vol. 3 (8), pp 1543-1546 ( 1993). (-)-(2R,4R)-2-amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]adenine (DAPD) is ) a selective inhibitor of HIV-1 replication in vitro as a reverse transcriptase inhibitor (RTI). DAPD is thought to be deaminated in vivo by adenosine deaminase, a ubiquitous enzyme, to yield (-)-B-D-dioxolane guanine (DXG), which is subsequently converted to the corresponding 5'-triphosphate (DXG-TP). Biochemical analysis has demonstrated that DXG-TP is a potent inhibitor of the HIV reverse transcriptase (HIV-RT) with a Ki 0f 0.019 uM.
NH,
N ‘ 4
GALA
N° NH, ie 0
DAPD
Triangle Pharmaceuticals, Inc. (Durham, N.C.) is currently developing this compound for the treatment of HIV and HBV under license agreement from Emory
University in collaboration with Abbott Laboratories, Inc.
Ribavirin - 10 Ribavirin (1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a synthetic, non- interferon-inducing, broad spectrum antiviral nucleoside analog sold under the trade name Virazole (The Merck Index, 11th edition, Editor: Budavari, S., Merck & Co., Inc,
Rahway, NJ, p1304, 1989). U.S. Patent No. 3,798,209 and RE29,835 disclose and claim ribavirin. In the United States, ribavirin was first approved as an aerosol form for the treatment of a certain type of respiratory virus infection in children. Ribavirin is structurally similar to guanosine, and has in vitro activity against several DNA and RNA viruses including Flaviviridae (Gary L. Davis Gastroenterology 118:5104-S114, 2000). }
Ribavirin reduces serum amino transferase levels to normal in 40% of patients, but it does not lower serum levels of HCV-RNA (Gary L. Davis Gastroenterology 118:5104- ,
S114, 2000). Thus, ribavirin alone is not effective in reducing viral RNA levels. It is being studied in combination with DDI as an anti-HIV treatment. More recently, it has been shown to exhibit activity against hepatitis A, B and C. Since the beginning of the
AIDS crisis, people have used ribavirin as an anti-HIV treatment, however, when used as a monotherapy, several controlled studies have shown that ribavirin is not effective : against HIV. It has no effect on T4 cells, T8 cells or p24 antigen. ) 5 The combination of IFN and ribavirin for the treatment of HCV infection has been reported to be effective in the treatment of IFN naive patients (Battaglia, A.M. et al., Ann. Pharmacother. 34:487-494, 2000). Results are promising for this combination treatment both before hepatitis develops or when histological disease is present (Berenguer, M. et al. Antivir. Ther. 3(Suppl. 3):125-136, 1998). Side effects of combination therapy include hemolysis, flulike symptoms, anemia, and fatigue (Gary L.
Davis. Gastroenterology 118:S104-S114, 2000).
[0]
HO. { N
NT
Oo
OH OH
RIBAVIRIN
Mycophenolic Acid
Mycophenolic acid (6-(4-hydroxy-6-methoxy-7-methy}-3-oxo0-5-phthalanyl)-4- methyl-4-hexanoic acid) is known to reduce the rate of de novo synthesis of guanosine monophosphate by inhibition of inosine monophosphate dehydrogenase (“IMPDH”). It also reduces lymphocyte proliferation. oo 7 .
CHj 0 HC 0
CH, ow © :
MYCOPHENOLIC ACID
Scientists have shown that mycophenolic acid has a synergistic effect when combined with Abacavir (Ziagen) in vitro. Mycophenolic acid depletes guanosine, one of the essential DNA building blocks. Abacavir is an analog of guanosine and as such, must compete with the body's natural production of guanosine in order to have a therapeutic effect. By depleting naturally occurring guanosine, mycophenolic acid improves Abacavir's uptake by the cell. Scientists have determined that the combination of mycophenolic acid and Abacavir is highly active against Abacavir-resistant virus.
However, notably the combination of mycophenolic acid and zidovudine or stavudine was antagonistic, likely due to the inhibition of thymidine phosphorylation by mycophenolic acid. 39" Interscience Conference on Antimicrobial Agents and
Chemotherapy,San Francisco, California, September 26-29, 1999. Heredia, A.
Margolis, D.M., Oldach, D., Hazen, R., Redfield, R.R. (1999) Abacavir in combination with the IMPDH inhibitor mycophenolic acid, is active against multi-drug resistant HIV. } J Acquir Immune Defic Syndr.; 22:406-7. Margolis, D.M., Heredia, A., Gaywee, J,
Oldach, D., Drusano, G., Redfield, R.R. (1999) Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase, have profound and synergistic anti-
HIV activity. J Acquir Immune Defic Syndr., 21:362-370.
U.S. Patent No. 4,686,234 describes various derivatives of mycophenolic acid, its synthesis and uses in the treatment of autoimmune disorders, psoriasis, and inflammatory diseases, including, in particular, rheumatoid arthritis, tumors, viruses, and for the treatment of allograft rejection. .
On May 5, 1995, Morris et al., in U.S. Patent No. 5,665,728, disclosed a method of preventing or treating hyperproliferative vascular disease in a mammal by administering an antiproliferative effective amount of rapamycin alone or in combination with mycophenolic acid.
In light of the global threat of the HIV epidemic, it is an object of the present invention to provide new methods and compositions for the treatment of HIV.
It is another object of the present invention to provide methods and compositions to treat drug resistant strains of HIV.
It has been unexpectedly found that a drug resistant strain of HIV exhibits the behavior of drug-naive virus when given the combination of a B-D-1,3-dioxolanyl nucleoside and an IMPDH inhibitor. In one nonlimiting embodiment, the HIV strain is resistant to a p-D-1,3-dioxolanyl nucleoside.
The present invention, therefore, is directed to compositions and methods for the treatment or prophylaxis of HIV, and in particular to a drug-resistant strain of HIV, including but not limited to a DAPD and/or DXG resistant strain of HIV, in an infected host, and in particular a human, comprising administering an effective amount ofa B-D- dioxolanyl purine 1,3-dioxolanyl nucleoside (“B-D-1,3-dioxolanyl nucleosides”) of the formula:
R
AA
: R NY N NH, oO wherein R is H, OH, Cl, NH, or NR'R%; R! and R? are independently hydrogen, alkyl or cycloalkyl, and R® is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety, including a phospholipid,
C20 or an ether-lipid, or its pharmaceutically acceptable salt or prodrug, optionally in a pharmaceutically acceptable carrier or diluent, in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitor.
Co 9
Claims (50)
1. A substance or composition for use in a method for the treatment or prophylaxis of an HIV infection in a host, said substance or composition comprising an effective amount of a 8-D-1,3-dioxolany! purine of the formula:
R . a 3 N = R Ae N NH, 0 or its pharmaceutically acceptable salt or prodrug, wherein Ris H, OH, C1, NH, or NR!R2; R! and R? are independently hydrogen, alkyl or cycloalkyl, and R? is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety, including a phospholipid, or an etherlipidin combination with at least one inosine monophosphate dehydrogenase (IMPDH) inhibitor, optionally in a pharmaceutically acceptable carrier or diluent, and said method comprising administering said substance or composition.
2. A substance or composition for use in a method of treatment or prevention of claim 1, wherein the B8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-2-amino-9-[(2- hydroxymethyl)-1,3-dioxolan-4-yl]-adenine (DAPD).
3. A substance or composition for use in a method of treatment or prevention of claim 1, wherein the B8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-9-[(2-hydroxymethyl)-1,3- dioxolan-4-yl]-guanine (DXG).
4. A substance or composition for use in a method of treatment or prevention of any one of claims 1-3, wherein the IMPDH inhibitor is selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, 5-ethynyl-1-B-D-ribofuranosylimidazole-4-carboxamide (EICAR) 42 AMENDED SHEET
PCT/US01/48817 and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl-carbamic acid tetrahydrofuran-3-yl-ester (VX-497).
5. A substance or composition for use in a method of treatment or prevention of claim 4, wherein the IMPDH inhibitors is mycophenolic acid.
6. A substance or composition for use in a method of treatment or prevention of claim 4, wherein the IMPDH inhibitors is ribavirin.
7. A substance or composition for use in a method of treatment or prevention of claims 1-6, wherein the 8-D-1,3-dioxolanyl purine is enantiomerically enriched.
8. A substance or composition for use in a method of treatment or prevention of claim 1 in a pharmaceutically acceptable carrier suitable for oral delivery.
9. A substance or composition for use in a method of treatment or prevention of claim 1 in a pharmaceutically acceptable carrier suitable for intravenous delivery. ~
10. A substance or composition for use in a method of treatment or prevention of claim 1 in a pharmaceutically acceptable carrier suitable for parenteral delivery.
11. A substance or composition for use in a method of treatment or prevention of claim 1 in a pharmaceutically acceptable carrier suitable for topical delivery.
12. A substance or composition for use in a method of treatment or prevention of claim 1 in a pharmaceutically acceptable carrier suitable for systemic delivery.
13. A method for the prophylaxis of a drug resistant strain of HIV infection in a host, comprising administering an effective amount of a 8-D-1,3-dioxolanyl purine of the formula: R ~ N SN ¢ Tr ROTO N N NH, 0 or its pharmaceutically acceptable salt or prodrug, wherein Ris H, OH, C1, NH, or NR!R?; R! and R? are independently hydrogen, alkyl or 43 AMENDED SHEET
PCT/US01/48817 cycloalkyl, and R?is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitors, optionally in a pharmaceutically acceptable carrier or diluent.
14. The method of claim 13, wherein the 8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-2- amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-adenine (DAPD).
15. The method of claim 13, wherein the 8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-9- [(2-hydroxymethyl)-1,3-dioxolan-4-yl]-guanine (DXG).
16. The method of any one of claims 13-15, wherein the IMPDH inhibitor is selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, 5-ethynyl-1-8-D-ribofuranosylimidazole-4-carboxamide (EICAR) and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]}-benzyl- : carbamic acid tetrahydrofuran-3-yl-ester (VX-497).
17. The method of claim 16, wherein the IMPDH inhibitor is mycophenolic acid.
18. The method of claim 16, wherein the IMPDH inhibitor is ribavirin.
19. The method of claim 16, wherein the HIV infection is resistant to DAPD and/or
DXG.
20. The method of any one of claims 13-19, wherein the host is a human.
21. A method for the prophylaxis of HIV infection in a host, comprising administering an effective amount of a 8-D-1,3-dioxolanyl purine of the formula: r a 30— ¢ | NN. KR NX Ha oO or its pharmaceutically acceptable salt or prodrug, wherein Ris H, OH, C1, NH, or NRIR?; R! and R? are independently hydrogen, alkyl or cycloalkyl, and R3 is H, alkyl, aryl, acyl, phosphate, including monophosphate, 44 AMENDED SHEET
PCT/US01/48817 diphosphate or triphosphate or a stabilized phosphate moiety in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitors, optionally in a pharmaceutically acceptable carrier or diluent.
22. The method of claim 21, wherein the 8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-2- amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yi]-adenine (DAPD).
23. The method of claim 21, wherein the 8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-9- [(2-hydroxymethyl)-1,3-dioxolan-4-yl]-guanine (DXG).
24. The method of any one of claims 21-23, wherein IMPDH inhibitor is selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, S5-ethynyl-1-8-D-ribofuranosylimidazole-4-carboxamide (EICAR) and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl- carbamic acid tetrahydrofuran-3-yl-ester (VX-497).
25. The method of claim 24, wherein the IMPDH inhibitor is mycophenolic acid.
26. The method of claim 24, wherein the IMPDH inhibitor is ribavirin.
27. The method of any one of claims 21-26, wherein the host is a human.
28. Use of an effective amount of a 8-D-1,3-dioxolanyl purine of the formula: R N ST FOTN ° NT NH, Sy or its pharmaceutically acceptable salt or prodrug, wherein Ris H, OH, C1, NH, or NR!R?; R! and R? are independently hydrogen, alkyl or cycloalkyl, R? is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitor, optionally in a pharmaceutically acceptable carrier or diluent, for use in medical therapy. 45 AMENDED SHEET
PCT/US01/48817
29. Use of an effective amount of a 8-D-1,3-dioxolany! purine of the formula: x N AN <1 PN SN N NH, Oo or its pharmaceutically acceptable salt or prodrug, wherein Ris H, OH, C1, NH, or NRIR?; R! and R? are independently hydrogen, alkyl or cycloalkyl, and R3 is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitors, optionally in a pharmaceutically acceptable carrier or diluent, for the treatment or prophylaxis of an HIV infection in a host.
30. Use of an effective amount of a 8-D-1,3-dioxolanyl purine of the formula: R ae PN FOTO N° NH, 0 / or its pharmaceutically acceptable salt or prodrug, wherein Ris H, OH, C1, NH, or NR!R?; R! and R? are independently hydrogen, alkyl or cycloalkyl; R3 is H, alkyl, aryl, acyl, phosphate, including monophosphate, diphosphate or triphosphate or a stabilized phosphate moiety in combination or alternation with an inosine monophosphate dehydrogenase (IMPDH) inhibitors, 46 AMENDED SHEET }
PCT/US01/48817 optionally in a pharmaceutically acceptable carrier or diluent, in the manufacture of a medicament for the treatment or prophylaxis of an HIV infection in a host.
31. The use of claim 29, wherein the B8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-2- amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-adenine (DAPD).
32. The use of claim 29, wherein the B-D-1,3-dioxolanyl purine is (-)-(2R,4R)-9-[(2- hydroxymethyl)-1,3-dioxolan-4-yl]-guanine (DXG).
33. The use of claim 29, wherein at least one of the IMPDH inhibitors selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, 5-ethynyl-1-B-D-ribofuranosylimidazole-4-carboxamide (EICAR) and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl- carbamic acid tetrahydrofuran-3-yl-ester (VX-497).
34. The use of claim 29, wherein the IMPDH inhibitor is mycophenolic acid.
35. The use of claim 29, wherein the IMPDH inhibitor is ribavirin.
36. The use of claim 29, wherein the HIV infection is DAPD-resistant and/or DXG- resistant.
37. The use of any one of claims 29 or 31 to 36, wherein the host is a human.
38. The use of an effective amount of a 8-D-1,3-dioxolanyl purine of the formula as defined in claim 28, or its pharmaceutically acceptable salt or prodrug, in the manufacture of a preparation for treating or preventing a medical disease, condition or disorder.
39. The use of claim 30, wherein the 8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-2- amino-9-[(2-hydroxymethyl)-1,3-dioxolan-4-yl]-adenine (DAPD).
40. The use of claim 30, wherein the 8-D-1,3-dioxolanyl purine is (-)-(2R,4R)-9-[2- hydroxymethyl)-1,3-dioxolan-4-yl]-guanine (DXG).
41. The use of claim 30, wherein at least one of the IMPDH inhibitors selected from the group consisting of ribavirin, mycophenolic acid, benzamide riboside, tiazofurin, selenazofurin, 5-ethynyl-1-B-D-ribofuranosylimidazole-4-carboxamide (EICAR) and (S)-N-3-[3-(3-methoxy-4-oxazol-5-yl-phenyl)-ureido]-benzyl- carbamic acid tetrahydrofuran-3-yl-ester (VX-497).
42. The use of claim 30, wherein the IMPDH inhibitor is mycophenolic acid.
43. The use of claim 30, wherein the IMPDH inhibitor is ribavirin.
44. The use of claim 30, wherein the HIV infection is DAPD-resistant and/or DXG- 47 AMENDED SHEET
PCT/US01/48817 resistant.
45. The use of any one of claims 30 or 39 to 44, wherein the host is a human.
46. A substance or composition for use in a method of treatment or prevention of a medical disease, condition or disorder, said substance or composition comprising a B-D-1,3-dioxolanyl purine of the formula as defined in claim 28 or its pharmaceutically acceptable salt or prodrug, and said method comprising administering an effective amount of said substance or composition.
47. A substance or composition for use in a method of treatment or prevention according to any one of claims 1 to 12 or 46, substantially as herein described and illustrated.
48. A method according to any one of claims 13 to 27, substantially as herein described and illustrated.
49. Use according to any one of claims 28 to 45, substantially as herein described and illustrated.
50. A substance or composition for a new use in a method of treatment or prevention, a new non-therapeutic method of treatment, or a new use of a compound as defined in any one of claims 28 to 35, substantially as herein described. 48 AMENDED SHEET .
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