Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-15
2003-05-13
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S200000
Reexamination Certificate
active
06562850
ABSTRACT:
BACKGROUND OF THE INVENTION
In 1982 physicians first became aware of a new sexually transmitted disease that was associated with an unusual form of cancer (Kaposi's sarcoma) and a variety of unusual infections. The disease was named acquired immune deficiency syndrome (AIDS), since both these problems reflected a severe deficiency in the helper T cells of the immune system. A retrovirus, called human immunodeficiency virus (HIV), was found to be the causative agent of AIDS. HIV is a member of a family of viruses called lentiviruses that are part of a large group of viruses known as the Retroviridae. Some of the other members of the group are the closely related simian, feline, and bovine immunodeficiency viruses. This group of viruses displays a variety of common features.
The fact that HIV has an extreme tendency to mutate to forms that are resistant to existing antiviral therapies greatly complicates attempts to treat the infection with antiviral drugs. Most of the current research in AIDS is aimed at understanding the life cycle of HIV. AIDS research has been targeted towards inhibition of the virus at different stages of its life cycle.
The molecular target for HIV inhibitors can be broadly classified into the following classes: reverse transcriptase (RT) enzyme, protease enzyme, integrase enzyme, regulatory proteins, and zinc finger domains in the nucleocapsid p7 protein.
The normal flow of genetic information is from DNA to RNA to protein, and hence HIV, which is a retrovirus, must first convert its genomic RNA into a double-stranded DNA in order to start its replication cycle in the host cell. This conversion takes place in the host cell cytoplasm with the help of a viral enzyme called reverse transcriptase (RT) that catalyzes a series of biochemical reactions involved in this process. This makes reverse transcriptase (RT) enzyme an attractive target for HIV inhibitors. HIV RT inhibitors can be broadly classified into nucleoside (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). The modes of action of these two classes of compounds are different in nature. The nucleoside HIV RT inhibitors are competitive inhibitors that bind to the catalytic site of the enzyme, and their mode of action appears to be through their triphosphates (produced in the cytoplasm of the host cell) that act as RT enzyme inhibitors through incorporation and termination of the growing viral DNA chain. Common nucleoside RT inhibitors are AZT, ddC, ddI, d4T, 3TC, and Abacavir. Non-nucleoside RT inhibitors are non-competitive inhibitors of the RT enzyme; they bind to an allosteric (regulatory) site with a degree of magnitude heretofore not yet observed and influence the RT catalytic site. Hence they are also referred to as second-site inhibitors. In general, at micromolar concentrations NNRTIs inhibit HIV-1 in vitro with minimum or no cytotoxicity but do not inhibit HIV-2 or other retroviruses. NNRTIs include chloro-TIBO, nevirapine, L-697,661, and delavirdine.
1. Field of the Invention
The need and research for active inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) is urgent and ongoing. In 1997, U.S. Pat. No. 5,608,085 issued to Baker et al. entitled Synthesis of Optically Active Calanolides A and B and Enantiomers and Related Compounds, which produces anti-HIV-1 or HIV-2 compounds in high yields and in a high degree of purity. Recently, on Dec. 1, 1998, U.S. Pat. No. 5,843,990 issued to Baker et al. entitled Pyran-Chromenone Compounds, Their Synthesis and Anti-HIV Activity, which deals with a class of compounds, particularly optically active compounds of a high degree of purity and free of the corresponding enantiomers, which are highly potent anti-HIV compounds. Application by Deshpande et al. (Ref. 22) also claims this contribution to the scientific community. The effectiveness of these compounds as HIV-1 inhibitors depends on many factors including the degree of affinity these HIV-1 inhibitors have for the enzyme's allosteric site. In accordance with this invention, novel 2,3-dihydrobenzo[d]isothiazole 1,1-dioxides (sultams) have been discovered that are biologically active, particularly potent HIV-reverse-transcriptase inhibitors. Further, a novel synthesis has been discovered (and a number of variants) by which the sultams are synthesized in an efficient, multi-step process from which the pure enantiomers of the racemates are obtained.
2. Description of Related Art
Publications of interest relating to the subject matter of this invention include:
1. Wilson, S. R., & Czarnik, A. W. (1997)
Combinatorial Chemistry
, John Wiley & Sons, Inc., New York.
2. Gulakowski et al. (1991)
J. Virol. Meth.,
33:87-100.
3. Hermkens, P. H. H., Ottenheijm, H. C. J., & Reeds, D. (1996)
Tetrahedron
52:4527-4554.
4. Hermkens, P. H. H., Ottenheijm, H. C. J., & Reeds, D. (1997)
Tetrahedron
53:5643-5678.
5. Watanabe, H., Gay, R. L., & Hauser, C. R. (1968)
J. Org. Chem.
33:900-903.
6. Plunkett, M., Ellman, J. A. (1997)
J. Org. Chem.
62:2885-2893.
7. Woolard, F. X., Paetsch, J., & Ellman, J. A. (1997)
J. Org. Chem.
62:6102-6103.
8. Beaver, K. A., Siegmund, A. C., & Spear, K. L. (1996)
Tetrahedron
37:1145-1148.
9. Halm, C., Evarts, J., & Kurth, M. J. (1997)
Tetrahedron Lett.
38:7709-7712.
10. Seeberger, P. H., Beebe, X., Sukenick, G. D., Pochapsky, S., & Danishefsky, S. J. (1997)
Angew. Chem., Int. Ed. Engl.,
36:491-493.
11. Kim, S. W., Hong, C. Y., Lee, K., Lee, E. J., & Koh, J. S. (1998)
Bioorg. Med. Chem. Lett.
8:735-738.
12. Beaver, K. A., et al. (1989) U.S. Pat. No. 4,859,736.
13. Nicolaou, K. C., Xiao, X.-Y., Pasandoosh, Z., Senyei, A., & Nova, M. P. (1995)
Angew. Chem., Int. Ed. Engl.
34:2289-2291.
14. Moran, E. J., Sarshar, S., Cargill, J. F., Shahbaz, M. M., Lio, A., Mjalli, A. M. M., & Armstrong, R. W. (1995)
J. Am. Chem. Soc.
117:10787-10788.
15. European Patent Application No. O 422 944 A1, published on Apr. 17, 1991, entitled
Chiral Sultams.
16. Snieckus, V. (1996)
Chemical Synthesis: Gnosis to Prognosis
, Chatagilialoglu, C. & Snieckus, V. (eds.) Kluwer Academic Publishers, Dordrecht, 191-221.
17. Alerton, E., et al. (1981)
Proc. Am. Pept. Symp
., Pierce Chemical Company, Rockford, Ill., 163-195.
18. Weislow, O. W., et al. (1989)
J. Natl. Cancer Inst.
81:577-586.
19. Eliel, E. L. & Wilen, S. H. (1994)
Stereochemistry of Organic Compounds
, John Wiley & Sons Inc., New York, 24.
20. Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., USA.
21. Corbett, J. W. (1998)
Org. Prep. Proc. Int.
30:489-550.
22. Deshpande, P. P., Tagliaferri, F., Victory, S. F., Yan, S., & Baker, D. C. (1995)
J. Org. Chem.
60:2964-2965.
23. Watanabe, H., et al. (1968)
J. Org. Chem.
33:900-903.
24. DeClercq, E. (1993)
Med. Res. Rev.
13:229.
25. Kilby, M. J., Saag, M. S. (1996)
Antiviral Chemotherapy
4
: New Directions for Clinical Application and Research
, Mills, J., Volberding, P. A., & Corey, L. (eds) Plenum Press, New York, 291-298.
26. Romero, D. L., Morge, R. A., Genin, M. J., Biles, C., Busso, M., Resnick, L., Altaus, I. W., Reusser, F., Thomas, R. C., Tarpley, W. G. (1993)
J. Med. Chem.
36:1505.
27. Dueweke, T. J., Poppe, S. M., Romero, D. L., Swaney, S. M., So, A. G., Downey, K. M., Althaus, I. W., Reusser, F., Busso, M., Resnick, L., Mayers, D. L., Lane, J., Aristoff, P. A., Thomas, R. C., Tarpley, W. G. (1993)
Antimicrob. Agents Chemother.
37:1127.
28. Vasudevachari, M. B., Battista, C., Lane, H. C., Psallidopoulos, M. C., Zhao, B., Cook, J., Palmer, J. R., Romero, D. L., Tarpley, W. G., Salzman, N. P. (1992)
Virology
190:269.
29. Merluzzi, V. J., Hargrave, K. D., Labadia, M., Grozinger, K., Skoog, M., Wu, J. C., Shih, C. K., Eckner, K., Hattox, S., Adams, J., Rosehthal, S. A., Frances, R., Eckner, R. J., Koup, R. A., Sullivan, J. L. (1990)
Science
250:1411.
30. Lehninger, A. L., Nelson, D. L., Cox, M. M. (1993)
Principles of Biochemistry,
2nd ed., Worth Publishers, New York.
31. Carey, F. A. & Sundberg, R. S. (1977)
Advanced Organic Chemistry,
3rd ed., Plenum Press, New York, 677-699.
All references r
Baker David C.
Johnson Stephen C.
Mao Jianmin
Mayasundari Anand
Yan Shijia
Gerstl Robert
Piper Rudnick LLP
The University of Tennessee Research Corporation
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