Polymorphic and other crystalline forms cis-FTC

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C544S317000

Reexamination Certificate

active

06723728

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to polymorphic and other crystalline forms of (−)- and (±)-cis-FTC (4-amino-5-fluoro-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone), pharmaceutical compositions thereof, and uses for such compositions.
BACKGROUND OF THE INVENTION
The success of various synthetic nucleosides such as AZT, D4T, DDI, and DDC in inhibiting the replication of HIV in vivo or in vitro led researchers in the late 1980′s 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-[cis-(2,4)-2-(hydroxymethyl)-4-dioxolanyl]thymine (referred to as (±)-dioxolane-T) exhibits a modest activity against HIV (EC
50
of 20 &mgr;M in ATH8 cells), and is not toxic to uninfected control cells at a concentration of 200 &mgr;M.
Tetrahedron Letters
30 (46), 6246, (1989). European Patent Application Publication No. 337 713 and U.S. Pat. No. 5,041,449, assigned to BioChem Pharma, Inc., disclose racemic 2-substituted-4-substituted-1,3-dioxolanes that exhibit antiviral activity. Published PCT application numbers PCT US91/09124 and PCT US93/08044 disclose isolated &bgr;-D-1,3-dioxolanyl nucleosides for the treatment of HIV infection. WO 94/09793 discloses the use of isolated &bgr;-D-1,3-dioxolanyl nucleosides for the treatment of HBV infection.
U.S. Pat. No. 5,047,407 and European Patent Application Publication No. 0 382 526, also assigned to BioChem Pharma, Inc., disclose that a number of racemic 2-substituted-5-substituted-1,3-oxathiolane nucleosides have antiviral activity, and specifically report that the racemic mixture of 2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (referred to below as BCH-189) has approximately the same activity against HIV as AZT, with less toxicity. The (−)-enantiomer of BCH-189 (U.S. Pat. No. 5,539,116 to Liotta, et al.), known as 3TC, is now sold commercially for the treatment of HIV in humans in the United States. See also EP 513 200 B1.
It has also been disclosed that (−)-(cis)-FTC (4-amino-5-fluoro-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-2(1H)-pyrimidinone (2R-cis), or &bgr;-L-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane) has potent HIV activity. See Schinazi, et al., “Selective Inhibition of Human Immunodeficiency viruses by Racemates and Enantiomers of cis-5-Fluoro-1-[2-(Hydroxymethyl)-1,3-Oxathiolane-5-yl]Cytosine”
Antimicrobial Agents and Chemotherapy
, November 1992, page 2423-2431. See also U.S. Pat. Nos. 5,814,639; 5,914,331; 5,210,085; U.S. Pat. No. 5,204,466, WO 91/11186, and WO 92/14743. The chemical structure of (−)-cis-FTC is shown below:
Because of the commercial importance of 1,3-oxathiolane nucleosides such as FTC, a number of processes for their production have been described in patents and scientific literature. The substituents on the chiral carbons (the specified purine or pyrimidine base (referred to as the C5 substituent)) and CH
2
OH (referred to as the C2 substituent)) of 1,3-oxathiolane nucleosides can be either cis (on the same side) or trans (on opposite sides) with respect to the oxathiolane ring system. Both the cis and trans racemates consist of a pair of optical isomers. Hence, each compound has four individual optical isomers. The four optical isomers are represented by the following configurations (when orienting the oxathiolane moiety in a horizontal plane such that the —S-CH
2
— moiety is in back): (1) cis (also referred to as &bgr;), with both groups “up”, which is the naturally occurring L-cis configuration (2) cis, with both groups “down”, which is the non-naturally occurring &bgr;-cis configuration; (3) trans (also referred to as the &agr;-configuration) with the C2 substituent “up” and the C5 substituent “down”; and (4) trans with the C2 substituent “down” and the C5 substituent “up”. The two cis enantiomers together are referred to as a racemic mixture of &bgr;-enantiomers, and the two trans enantiomers are referred to as a racemic mixture of &agr;-enantiomers. In general, it is fairly standard to be able to separate the pair of cis racemic optical isomers from the pair of trans racemic optical isomers. It is a significantly more difficult challenge to separate or otherwise obtain the individual enantiomers of the cis-configuration. For 3TC and FTC, the desired stereochemical configuration is the &bgr;-L-isomer.
The numbering scheme for the 1,3-oxathiolane ring in FTC is given below.
Routes to Condense the 1,3-oxathiolane Ring with a Protected Base
U.S. Pat. No. 5,204,466 discloses a method to condense a 1,3-oxathiolane with a protected pyrimidine base using tin chloride as a Lewis acid, which provides virtually complete &bgr;-stereoselectivity. See also Choi, et al, “In Situ Complexation Directs the Stereochemistry of N-Glycosylation in the synthesis of Oxathiolanyl and Dioxolanyl Nucleoside Analogues,”
J. Am Chem. Soc.
1991, 213, 9377-9379. The use of tin chloride creates undesirable residues and side products during the reaction which are difficult to remove.
A number of U.S. patents disclose a process for the preparation of 1,3-oxathiolane nucleosides via the condensation of a 1,3-oxathiolane intermediate that has a chiral ester at the 2-position of the ring, with a protected base in the presence of a silicon-based Lewis acid. The ester at the 2-position must then be reduced to the corresponding hydroxymethyl group to afford the final product. See U.S. Pat. Nos. 5,663,320; 5,864,164; 5,693,787; 5,696,254; 5,744,596; and 5,756,706.
U.S. Pat. No. 5,763,606 discloses a process for producing predominantly cis-2-carboxylic or thiocarboxylic acid 1,3-oxathiolane nucleosides that includes coupling a desired, previously silylated purine or pyrimidine base with a bicyclic intermediate in the presence of a Lewis acid. U.S. Pat. No. 5,272,151 describes a process for the preparation of 1,3-dioxolane nucleosides that includes reacting a 2-O-protected-5-O-acylated-1,3-dioxolane with an oxygen- or nitrogen-protected purine or pyrimidine base in the presence of a titanium catalyst.
Choi, et al, “In Situ Complexation Directs the Stereochemistry of N-Glycosylation in the synthesis of Oxathiolanyl and Dioxolanyl Nucleoside Analogues,”
J. Am Chem. Soc.
1991, 213, 9377-9379, reported that no coupling of the 1,3-oxathiolane with protected pyrimidine base occurs with HgCl
2
, Et
2
AlCl, or TiCl
2
(O-isopropyl)
2
(see footnote
2
). Choi also reported that the reaction between anomeric 1,3-oxathiolane acetates with silylated cytosine and virtually any common Lewis acid other than tin chloride resulted in the formation of inseparable mixtures of N-glycosylated anomers.
U.S. Pat. No. 5,922,867 discloses a method for preparing a dioxolane nucleoside that includes glycosylating a purine or pyrimidine base with a 2-protected-oxymethyl-4-halo-1,3-dioxolane.
U.S. Pat. Nos. 5,914,331, 5,700,937, 5,827,727, and 5,892,025, among others, to Liotta et al. describe coupling the 1,3-oxathiolanes disclosed therein with silyated 5-fluorocytosine in the presence of SnCl
4
to form the &bgr;(−)isomer of FTC; and optionally removing the protecting a groups.
Routes to Provide the 1,3-oxathiolane Nucleoside in the Desired Stereoconfiguration
Specific methods for preparing FTC in the desired stereoconfiguration in a substantially pure form are described in U.S. Pat. Nos. 5,914,331, 5,700,937, 5,827,727, and 5,892,025, among others, to Liotta et al. In one embodiment, the C5′-hydroxyl group of a mixture of Tao nucleoside racemates is reacted with an acyl compound to form C5′-esters in which the nucleoside is in the “carbinol” end of the ester. The desired enantiomer can be isolated by treatment of the racemic mixture with an enzyme that hydrolyses the desired enantiomer (followed by extraction of the polar hydrolysate with a polar solvent) or by treatment with an enzyme that hydrolyses the undesired enantiomer (followed by removal of the undesired enantiomer with a polar solvent). Enzymes that catalyze the hydro

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