40372-00-7

Novel nucleoside analog compounds are disclosed. The novel compounds or pharmaceutically acceptable esters or salts thereof may be used in pharmaceutical compositions, and such compositions may be used to treat an infection, an infestation, a neoplasm, or an autoimmune disease. The novel compounds may also be used to modulate aspects of the immune system, including modulation of Type 1 and Type 2 activity.

A drug is modified by covalently coupling a blocking group to the drug via a nitrogen atom in the blocking group. The blocking group in the modified drug prevents metabolic conversion and sequestration of the drug in non-target cells, and the blocking group is enzymatically removed in the target cell. Particularly contemplated advantages of presented compounds and methods include reduction of cytotoxicity by inhibition of metabolic conversion to potentially cytotoxic metabolites, reduction of dosages of drugs by reduction of sequestration into non-target cells, and increase of selectivity of a drug.

Ten, hitherto unreported, analogues of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (2a, ribamidine) and methyl carboxamidate 5 have been synthesized.These include the N-cyano (2b), N-alkyl (2c-e), N-amino acid (2f-h), N,N'-disubstituted (6,7a,b), and the N-methylated carboxamide (1f) analogues of ribavirin.In addition, a new facile synthesis of carboxamidine 2a was also developed.All compounds were evaluated for biological activity against the following RNA viruses: Punta Toro (PT) and sandfly fever (SF) viruses (bunyaviruses); Japanese encephalitis (JE), yellow fever (YF), and dengue-4 viruses (flaviviruses); parainfluenza type 3 (PIV3), respiratory syncytial virus (RSV), and measles viruses (paramyxoviruses); influenza A and B viruses (orthomyxoviruses); Venezuelan equine encephalomyelitis virus (VEE, alphavirus); human immunodeficiency virus type-1 (HIV-1, lentivirus); the DNA-containing vaccina (VV) virus (poxvirus); and adeno type-5 (Ad5) viruses.All of the compounds except for 2a and 7a,b exhibited activity against the bunyaviruses such as that observed with 2a; however, higher IC50 values were generally observed.Glycine analogue 2f showed activity in PT-virus-infected mice in therms of increased survivors and descreased markers of viral pathogenicity.Carboxamidine 2a, carboximidate 5, and dimethyl amidine 6 exhibited activity against dengue type-4 virus.Monomethyl amidine 2c demonstrated activity against RSV, PIV3, and, to a lesser extent, influenza A and B.Activity of 2c generally required higher IC50 values than unsubstituted 2a.The latter exhibited hitherto unreported activity against RSV; therapeutic indices for 2a against RSV and PIV3 were >64 and >21.No substantial in vitro activity was observed for any of the compounds tested against Ad5, measles, JE, YF, VEE, or HIV-1.In addition, evidence is presented which argues in favor of a distinct antiviral mechanism of action for carboxamidines, e.g. 6, in contrast to a role as a carboxamide precursor.

A novel class of alkyl-1-(β-D-ribofuranosyl)[1,2,4]triazole-3-carboximidates of the formula: STR1 wherein R1 is methyl or ethyl and R2 is β-D-ribofuranosyl, are useful as anti-leukemic agents.

Methyl 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboximidate (4) and ethyl 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboximidate (6) were synthesized and tested for antitumor and antiviral activity. A new facile synthesis of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine hydrochloride (5), starting with imidate 4, was also developed. The imidates 4 and 6 differed greatly in solubility and dosing requirements. Even so, both compounds exhibited significant activity in vivo against murine leukemia L1210. Nontoxic dosing with 4 also significantly diminished Friend leukemia induced splenomegaly. In contrast, neither imidate was active in vitro.

As antiviral agents and intermediates therefor, 3-substituted 1-(β-D-glycosyl)-1,2,4-triazoles, O-acylated analogs thereof, and 5'- and 3',5'-cyclic phosphates of the triazole nucleosides, "glycosyl" being .[.a pentofuranosyl moiety, preferably one whose 2'-oxygen is trans to the triazole aglycon, e.g., xylofuranosyl,.]. ribofuranosyl, .[.2-0-methylribofuranosyl, etc.,.]. the triazole aglycon being 3-substituted with cyano, methylcarboxylate, carboxamidoxime, carboxamido-, thiocarboxamido, or carboxamidine. Preparation of these nucleosides is by silylation of the substituted triazole followed by glycosylation with the appropriate blocked glycosyl halide. Alternatively, acid-catalyzed fusion of the requisite 1,2,4-triazole with an O-acylated pentofuranose yields the nucleosides.