Method of producing tiazofurin and other C-nucleosides

Details Method of producing tiazofurin and other C-nucleosides Method of producing tiazofurin and other C-nucleosides

2000-06-06

2003-09-02

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018700, C514S023000, C514S183000, C514S359000, C514S360000

Reexamination Certificate

active

06613896

ABSTRACT:

BACKGROUND
C-Nucleosides are interesting compounds having potential activity as pharmaceutical agents. One of these compounds, Tiazofurin, [6,2-(&bgr;-D-ribofuranosyl)thiazole-4-carboxamide)], possesses significant activity against both human lymphoid. F. Earle and R. I. Glazer,
Cancer Res
., 1983, 43 133), lung tumor cell lines (D. N. Camex, G. S. Abluwalia, H. N. Jayaram, D. A. Cooney and D. G. Johns, J. Clin. Invest., 1985, 75 175) and murine-implanted human ovarian cancers (J. P. Micha, P. R. Kucera, C. N. Preve, M. A. Rettenmaier, J. A. Stratton, P. J. DiSaia,
Gynecol. Oncol
. 1985, 21, 351). Tiazofurin also demonstrated efficacy in the treatment of acute mycloid leukemia (G. T. Tricot, H N. Jasyaram C. R. Nichols, K. Pennington, E. Lapis, G. Weber and R. Hoffman,
Cancer Res
. 1997, 47 4988). In addition, recent findings has brought interest in Tiazofurin as a possible treatment for patients with chronic myeloid leukemia (CML) in blast crisis (G. Weber, U.S. Pat. No. 5,405,837; 1995). In the cells Tiazofurin is converted to its active metabolite, thiazole-4-carboxaimde adenine dinucleotide (TAD) which inhibits IMP dehydrogenase, and as a result depletes guanosine nucleotide pools. (E. Olah, Y. Natusmeda, T. Ikegami, Z. Kote, M. Horanyi, I Szelenye, E. Paulik, T. Kremmer, S. R. Hollan, J. Sugar and G. Weber,
Proc. Natl. Acad. Sci. USA
, 1988, 85, 6533).
Although Tiazofurin has been known for over 15 years, and is currently under phase II/III trials in humans, there is no suitable synthesis for large scale production. Tiazofurin was first synthesized independently by M. Fuertes et al. (J. Org. Chem., 1976, 41, 4076) and Srivastava et al. (J. Med. Chem., 1977, 20, 256) in low yield. In both methods the authors obtained side products (i.e. compound 12) and used column chromatography at each stage to purify the products. The principal disadvantage of these methods is the formation of the furan derivative as well as the utility of highly toxic hydrogen sulfide gas.
W. J. Hannon et al. (J. Org. Chem., 1985, 50, 1741) developed a somewhat different route for Tiazofurin in 19% yield. The Hannon method also suffers from low yield, the use H
2
S gas and chromatographic purifications. More recently P. Vogel et al. (Helv. Chem. Acta., 1989, 72, 1825) synthesized Tiazofurin in nine steps with 25% yield. Still more recently, D. C. Humber et al. (J. Chem. Soc. Perkin Trans. 1, 1990, 283) worked a synthesis for Tiazofurin starting from benzyl (2,3,5-tri-
O
-benzyoyl-&bgr;-D-ribofuranosyl) penicillinate.
The only known method that is at all suitable for large scale production is by Parsons et al (U.S. Pat. No. 4,451,684). Unfortunately, the Parsons method uses both mercury cyanide and hydrogen sulfide, both of which have safety and environmental problems. The Parsons method also gives a mixture of products.
The problems discussed above which attend large scale production of Tiazofurin are applicable to large scale production of other C-nucleosides. In the production of thiocarboxamides, for example, most of the known methods use gaseous hydrogen sulfide as a reagent to convert a cyano group into a corresponding thicarboxamide group. Such methods have inherent environmental problems. In production of C-nucleosides in general, most or all of the known syntheses give a mixture of products during a ring closure step. Thus, there is a continuing need for a new procedure for large scale production of Tiazofurin and other C-nucleosides.
SUMMARY OF THE INVENTION
The present invention is directed to a novel method for synthesizing C-nucleosides, in which the C
1
position of a sugar is derivatized in a single step to provide a heterocycle, and then the heterocycle is aromatized in another single step.
In one class of preferred embodiments a cyano sugar is converted into thiocarboxamide, and subsequently condensed to form an azole ring. In a second class of preferred embodiments a cyano sugar is condensed with an amino acid to provide the azole ring. In a third class of preferred embodiments a halo sugar is condensed with a preformed heterocycle to provide the azole ring.
There are many advantages to the present method. One advantage is that the method eliminates the need for gaseous hydrogen sulfide, which is environmentally unsafe. Another advantage is that the yield is substantially improved over previous methods. A third advantage is that the present method eliminates the need for chromatographic purification procedures, thereby reducing the cost of production.


REFERENCES:
patent: 4531001 (1985-07-01), Robins et al.
patent: 5907036 (1999-05-01), Ramasamy et al.
Hennen et al., Journal of Organic Chemistry, vol. 50, pp. 1741-1746, 1985.

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