Enantiomerically Pure Beta-D-(-)-Dioxolane-Nucleosides
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Europäisches Patentamt *EP001600448A2* (19) European Patent Office Office européen des brevets (11) EP 1 600 448 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.7: C07D 405/04, A61K 31/506 30.11.2005 Bulletin 2005/48 (21) Application number: 05075365.6 (22) Date of filing: 05.12.1991 (84) Designated Contracting States: (72) Inventors: AT BE CH DE DK ES FR GB GR IT LI LU MC NL SE • Chu, Chung K. Athens, GA 30605 (US) (30) Priority: 05.12.1990 US 622762 • Schinazi, Raymond F. Decatur, GA 30333 (US) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (74) Representative: Hallybone, Huw George et al 01203571.3 / 1 164 133 Carpmaels and Ransford, 92902800.9 / 0 562 009 43-45 Bloomsbury Square London WC1A 2RA (GB) (71) Applicants: • UNIVERSITY OF GEORGIA RESEARCH Remarks: FOUNDATION, INC. This application was filed on 14 - 02 - 2005 as a Athens, Georgia 30602 (US) divisional application to the application mentioned • EMORY UNIVERSITY under INID code 62. Atlanta, GA 30322 (US) (54) Enantiomerically pure beta-D-(-)-Dioxolane-Nucleosides (57) An asymmetric process for the preparation of enantiomerically pure dioxolane nucleosides is lower enantiomerically pure β-D-(-)-dioxolane-nucleosides. than that of the racemic mixture of the nucleosides, be- The enantiomerically pure dioxolane nucleosides are cause the nonnaturally occurring α-isomer is not includ- active HIV agents, that are significantly more effective ed. The product can be used as a research tool to study than the prior prepared racemic mixtures of the nucleo- the inhibition of HIV in vitro or can be administered in a sides. The anti-viral activity of the compounds is surpris- pharmaceutical composition to inhibit the growth of HIV ing in light of the generally accepted theory that moieties in vivo. in the endo conformation, including these dioxolanes, are not effective antiviral agents. The toxicity of the EP 1 600 448 A2 Printed by Jouve, 75001 PARIS (FR) 1 EP 1 600 448 A2 2 Description and C4'-substituents are on the same side of the carbo- hydrate plane (i.e., the substituents are cis) is referred [0001] The government has rights in this invention by to as a "β-configuration." A carbohydrate configuration virtue of grants from the Public Health Service of the Na- in which the C1' and C4'-substituents are on the oppo- tional Institute of Allergy and Infectious Diseases and 5 site side of the carbohydrate plane (i.e., the substituents the Department of Veteran's Affairs that partially funded are trans) is referred to as, an "α-configuration". Refer- research leading to this invention. ring to compound 1 of Figure 2, a nucleoside is desig- nated a D-nucleoside if the non-hydrogen substituent at- Background of the Invention tached to the C4'-atom is above the plane of the carbo- 10 hydrate ring. The nucleoside is designated an L-nucle- [0002] This invention is in the area of organic synthe- oside if the non-hydrogen substituent attached to the sis of nucleosides, and in particular relates to a process C4'-atom is below the plane of the carbohydrate ring. for the preparation of enantiomerically pure β-D-(-)-di- [0007] The non-naturally occurring α-isomers of nucl- oxolane nucleosides. eosides (in which the C1' or C4' substituents are on op- [0003] A number of 2',3'-dideoxynucleosides have 15 posite sides of the carbohydrate plane) are rarely bio- been found to be potent antiviral agents against human logically active, and are typically toxic. immunodeficiency virus (HIV), the causative agent of [0008] An analysis of the solid-state conformations of acquired immunodeficiency syndrome (AIDS). The lead six active and two inactive anti-HIV nucleoside agents compound, AZT (Mitsuya, H.; Broder, S. Proc. Natl. was recently performed to attempt to correlate the pres- Acad. Sci. U.S.A., 1986 83, 1911) has been approved 20 ence or absence of certain stereochemical features with by the U.S. Food and Drug Administration for patients high HIV activity. Van Roey, P.,et al., J. Am. Chem. Soc., with AIDS and AIDS-related complex. Several other 2', 1988, 110, 2277; and Van Roey, P., et al., Proc. Natl. 3'-dideoxynucleosides are undergoing various stages of Acad. Sci. U.S.A., 1989, 86, 3929. The x-ray structures clinical trials, including 3'-azido-2',3'-dideoxyuridine indicated that active anti-HIV nucleosides assume the (AZDU or CS-87, see, Chu, C.K.; et al., J. Med. Chem., 25 C3'-exo or similar carbohydrate conformations while in- 1989, 32, 612; and Eriksson, B.F.H.; et al., Antimicrob. active compounds prefer the C3'-endo conformation. Agents Chemother., 1989, 33, 1927), 2',3'-dideoxyino- (Endo and exo refer to the conformations in which the sine (DDI) and 2',3'-dideoxycytidine (DDC) (see Yarcho- atoms are at the same or opposite side of the sugar ring an, R. et. al., Science, 1989, 245, 412), 3'-deoxy-2',3'- in relation to the base). The C3'-exo and C3'-endo con- didehydrothymidine (D4T, Lin, T.S., et al., Biochem. 30 formations place the C5' atom in axial and equitorial po- Pharmacol., 1987, 36, 311; Hamamoto, Y., et al., An- sitions, respectively. The position of the C5' atom affects tinicrob. Agents Chemother., 1987, 31, 907; Balzarini, the location of the 5'-hydroxyl group in relation to the J., et al., Biochem. Biophys. Res. Commun., 1987, 140, base. Since the 5'-hydroxyl group is the site of phospho- 735), and 2'-fluoro-arabinofuranosyl-2'-3'-dideoxycyti- rylation of the nucleoside, its location with respect to the dine (Martin, T.A., et al., J. Med. Chem., 1990, 33, 2137; 35 rest of the nucleoside is important. Watanabe, K.A., et al., J. Med. Chem., 1990, 33, 2145; [0009] There has been recent interest in the synthesis Sterzycki, R.Z., et al., J. Med. Chem., 1990 33, 2150). of nucleoside derivatives in which the 3'-carbon of the [0004] In the 5'-triphosphorylated form, these nucleo- nucleoside has been replaced with a heteroatom. Nor- sides are known to inhibit HIV reverse transcriptase as beck, D.W., et al., in Tet. Lett., 1989, 30, 6263, reported well as cause chain-termination of the growing viral DNA 40 the synthesis of (±)-1-[(2β,4β)-2-(hydroxymethyl)-4-di- chain. Furman, P.A., et al., Proc. Natl. Acad. Sci. U.S. oxolanyl]thymine (referred to below as (±)-dioxolane-T, A., 1986, 83, 8333; Cheng, Y.C., e al., J. Biol. Chem., see Figure 1), that results in a racemic mixture of dias- 1987, 262, 2187; St. Clair, M.H., et al., Antimicrob. tereomers about the C4' atom. The product is a deriva- Agents Chemother., 1987, 31, 1972; and Schinazi, R. tive of 3'-deoxythymidine in which the C3' atom has F., et al., Antimicrob. Agents Chemother., 1989 33, 115. 45 been replaced with an 03' atom. The product was syn- [0005] The stereochemistry of nucleoside derivatives thesized in five steps from benzyloxyaldehyde dimeth- play an important role in their biological activity. The C1' ylacetal and (±)-methyl glycerate to produce a 79% yield position of the ribose in the nucleoside (the carbon of the 1:1 diastereomeric mixture. The X-ray crystallo- bound to the nitrogen of the heterocyclic base) is a chiral graphic analysis of the product revealed that the diox- 50 3 center because the carbon is attached to four different olane ring adopts the T4 conformation commonly ob- moieties. Likewise, there is an optically active center at served in ribonucleosides, with the 03' atom in the endo C4' of the nucleoside (the ring carbon bound to the hy- position. Norbeck reported that the racemic mixture of droxymethyl group that is phosphorylated in nucle- dioxolane-T exhibits an anti-HIV activity of 20 µMin otides). In the naturally occurring nucleosides, both the ATH8 cells, and attributed the low efficacy against the base attached to the C1' atom and the hydroxymethyl 55 virus to an effect of the endo conformation of the 03' group attached to the C4' atom are on the same side of atom. the carbohydrate ring. [0010] Belleau, et al., in the Fifth International Conf. [0006] A carbohydrate configuration in which the C1' on AIDS, Montreal, Canada June 4-9, 1990, paper No. 2 3 EP 1 600 448 A2 4 T.C.O.l., reported a method of synthesis of cytidine nu- HIV in vivo. cleosides that contain oxygen or sulfur in the 3'-position. The dioxolane ring was prepared by the condensation Brief Description of the Figures of RCO2CH2CHO with glycerine. As with the Norbeck synthesis, the Belleau synthesis results in a racemic 5 [0018] mixture of diastereoisomers about the C4' carbon of the nucleoside. Belleau reported that the sulfur analog, re- Figure 1 is an illustration of the chemical structures ferred to as NGBP-21 or (±) BCH-189 (see Figure 1), of (±)-1-[(2β,4β)-2-(hydroxymethyl)-4-dioxolanyl] had high anti-HIV activity. (±) BCH-189 is currently un- thymine (dioxolane-T) and (±)-1-[(2β,4β)-2-(hy- dergoing preclinical toxicology. 10 droxymethyl)-4-(1,3-thioxolane)]thymine (BCH- [0011] To date, no one has reported a method of syn- 189). thesis of a nucleoside analog with an oxygen in the 3'- Figure 2 is an illustration of the method of synthesis position that results in an enantiomerically pure diox- of enantiomerically pure β-D-(-)-dioxolane-thymine. olane nucleoside that has the same stereochemistry as the nucleosides found in nature (the B stereoisomer). 15 Detailed Description of the Invention There is a need for such a synthesis as a research tool to provide more information on the effect of stereochem- [0019] As used herein, the term "protected" refers to istry on the anti-viral activity of nucleoside derivatives, a moiety that has been placed on a functional group of and to provide new anti-HIV agents.