Prodrug azide compositions and compounds

Details Prodrug azide compositions and compounds Prodrug azide compositions and compounds

1998-03-03

2001-08-07

Geist, Gary (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S051000, C514S117000, C514S198000, C514S200000, C536S004100, C536S026230, C536S026260, C536S026700, C536S027600, C536S027610, C536S027620, C536S027140, C536S027400, C544S080000, C544S264000

Reexamination Certificate

active

06271212

ABSTRACT:

FIELD OF THE INVENTION
This invention is in the field of pharmaceuticals, specifically azide derivatives of pharmaceutically active compounds.
BACKGROUND OF THE INVENTION
In recent years the pharmaceutical industry has developed an effective panoply of therapeutic compounds for the treatment of human disease. Antibacterial compounds such as penicillin, the sulfa drugs, and more recently, aminoglycocide and cephalosporin antibiotics have drastically reduced fatalities from bacterial infection. Viral infections, once thought to be untreatable, can now be controlled with antiviral agents, notably nucleoside analogs such as acyclovir and related compounds. A diagnosis of cancer, at one time a virtual death sentence, is now simply a prelude to often-successful treatment with antineoplastic drugs such as methotrexate. Even epilepsy, whose victims were thought to have been chosen by the gods as special vehicles of divine possession, has yielded to the protection of dopamine. AIDS itself, the newest and most frightening of our diseases, has been at least retarded in its progress by nucleoside replication inhibitors such as AZT (3′-azido-3′-deoxythymidine).
Effective as these pharmaceuticals are, however, once inside the patient's body, many are quickly inactivated by degrading enzymes, particularly deaminases. In some cases, for example when it is necessary for the active drug to cross the blood-brain barrier, undesirably large doses of the drug must be administered in order to ensure enough will remain in circulation long enough to reach the brain in therapeutic quantities. In other cases, drugs must be administered continuously, effectively tying the patient to the iv needle, in order to provide enough active form of the drug in circulation without having to administer toxically high concentrations.
It is thus desirable to provide therapeutic compounds in a form which will persist for a longer time in the patient's body without degrading than drugs currently in use.
A number of efforts have been made to improve these effective pharmaceuticals by increasing their lipophilicity by attaching lipophilic groups such as acetyl or even cholesterol so as to allow faster penetration into intercellular spaces and compartments with lipophilic barriers, such as the blood-brain barrier. However, these measures have not always been as effective as desired.
One class of particularly effective antiviral pharmaceuticals which has been used in the treatment of herpes viruses as well as other viruses, particularly in immunocompromised patients such as those infected with the AIDS virus, are nucleoside analogs. These analogs, after phosphorylation by the enzymes of the cell, disrupt DNA synthesis and are thus useful as anticancer agents as well as inhibitors of virus multiplication. One of the early compounds used for this purpose was 5-iodo-2′-deoxyuridine (IDU). [Darby, G. (1995), “In search of the perfect antiviral,” Antiviral Chem. & Chemother. 1:54-63]. This article discloses that such drugs also tend to be toxic to normal cells due to the fact that they inhibit DNA replication. Acyclovir and valaclovir are mentioned as particularly useful compounds in this regard because they become phosphorylated only within infected cells, and thus inhibit DNA replication only in these cells. These drugs, however, have low oral bioavailability (15-20%), which limits their usefulness. Again, a method for increasing the half-lives of such drugs is needed.
Vidarabine, 9-(&bgr;-D-arabinofuranosyl)adenine (ara-A) was originally discovered as an antitumor agent [Reist, E. J. et al., “Potential anticancer agents. LXXVI. Synthesis of purine nucleosides of &bgr;-D-arabinofuranose,” J. Org. Chem. (1962) 27:3274-3279] and in later studies, it was shown to be active against herpes simplex virus type 1 and 2 [Drach, J. C. and Shipman, C. Jr., “The selective inhibition of viral DNA synthesis by chemotherapeutic agents: an indicator of clinical usefulness?” Ann. NY Acad Sci (1977) 284:396-409; Andrei, G. et al., “Comparative activity of various compounds against clinical strains of herpes simplex virus,” Eur. J. Clin. Microbiol. Infect. Diseases (1992) 11:143-151]. Ara-A is a licensed compound for the treatment of herpes simplex keratitis [Denis, J. et al., “Treatment of superficial herpes simplex hepatitis with Vidarabine (Vira A): A multicenter study of 100 cases,” J. Fr. Ophthalmol. (1990) 13:143-150] and encephalitis [Whitley, R. J., “Herpes simplex virus infections of the central nervous system. Encephalitis and neonatal herpes,” Drugs (1991) 42:406-427; Stula, D. and Lyrer, P., “Severe herpes simplex encephalitis: Course 15 years following decompressive craniotomy,” Schweiz. Med. Wochenschr. (1992) 122:1137-1140; Whitley, R. J., “Neonatal herpes simplex virus infections,” J. Med. Virol. (1993), Suppl. 1, 13-21]. It has also been considered for the treatment of genital and disseminated herpes infections [DRUGDEX (R) Information System, Gelman, C. R. and Rumack, B. H., Eds.; MicroMedex, Inc., Englewood, Colo. 84, Expired May 31, 1995], cytomegalovirus encephalitis [Suzuki, Y. et al., “Cytomegalovirus encephalitis in immunologically normal adults,” Rinsho. Shinkeigaku (1990) 30:168-173], chronic hepatitis B virus (HBV) infection [Chien, R. N. and Liaw, Y. F., “Drug therapy in patients with chronic type B hepatitis,” J. Formos. Med. Assoc. (1995) 94(suppl. 1):s1-s9; Fu, X. X., “Therapeutic effect of combined treatment with ara-A, dauricine and Chinese herbs in chronic hepatitis B infection,” Chung. Hua. Nei. Ko. Tas. Chih. (1991) 30:498-501] and acute non-lymphoid leukemia [Resegotti, L., “Treatment of acute non-lymphoid leukemia (ANLL) in elderly patients. The GIMEMA experience,” Leukemia (1992) 6(suppl. 2):72-75]. Ara-A may also be an alternative therapy for acyclovir-resistant herpes simplex virus, cytomegalovirus and varicella-zoster virus infections [Chatis, P. A. and Crumpacker, C. S., “Resistance of herpes viruses to antiviral drugs,” Antimicrob. Agents Chemother. (1992) 36:1589-1595; Nitta, K. et al., “Sensitivities to other antiviral drugs and thymidine kinase activity of acyclovir-resistant herpes simplex virus type 1,” Nippon. Ganka. Gakkai. Zasshi (1994) 98:513-519]. However, the use of ara-A as a clinically effective agent is limited due to its rapid deamination to ara-H by adenosine deaminase (ADA) in vivo [Cass, E. C., “9-&bgr;-D-Arabinofuranosyladenine (Ara-A),” In
Antibiotics. Mechanism of Action of Anti
-
eukarvotic and Antiviral Compounds
; Hahn, F. E., Ed.; Springer-Verlag: New York (1979) V:87-109; Whitley, R. et al., “Vidarabine: a preliminary review of its pharmacological properties and therapeutic use,” Drugs (1980) 20:267-282] as well as its poor solubility in water.
There were several attempts to prevent the rapid metabolism of ara-A [Plunkett, W. and Cohen, S. S., “Two approaches that increase the activity of analogs of adenine nucleosides in animal cells,” Cancer Res. (1975) 35:1547-1554], including the co-administration of adenosine deaminase inhibitors such as deoxycoformycin [Cass, C. E. and Ah-Yeung, T. H., “Enhancement of 9-&bgr;-D-arabinofuranosyladenine cytotoxicity to mice leukemia L1210 in vitro by 2′-deoxycoformycin,” Cancer Res. (1976) 36:1486-1491; LePage, G. A. et al., “Enhancement of antitumor activity of arabinofuranosyl adenine by 2′-deoxycoformycin,” Cancer Res. (1975) 36(4):1481-1485; Cass, C. E. et al., “Antiproliferative effects of 9-&bgr;-D arabinofuranosyladenine-5′-monophosphate and related compounds in combination with adenosine deaminase inhibitors against a mouse leukemia L1210/C2 cells in culture,” Cancer Res. (1979) 39(5):1563-1569; Plunkett, W. et al., “Modulation of 9-&bgr;-D-arabinofuranosyladenine-5′-triphosphate and deoxyadenosine-triphosphate in leukemic cells by 2′-deoxycoformycin during therapy with 9-&bgr;-D-arabinfuranosyladenine,” Cancer Res. (1982) 42(5):2092-2096; Agar

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