Sultams: Solid phase and other synthesis of anti-HIV...

Details Sultams: Solid phase and other synthesis of anti-HIV... Sultams: Solid phase and other synthesis of anti-HIV...

1999-05-19

2002-03-05

Gerstl, Robert (Department: 1613)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06353112

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 to 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.
This invention deals with non-nucleoside RT inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) 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 RT 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. Some non-nucleoside RT inhibitors are 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. discloses a 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 (Ref 25). 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 solid-phase combinatorial synthesis has been discovered in which a solid support is used.
Combinatorial organic synthesis (COS) is a known methodology for creating huge, searchable libraries of small organic molecules suitable for both drug-discovery screening and drug-development optimization. Frequently, the use of a solid support in the synthesis will usually eliminate the need for difficult-to-automate procedures like extractions, filtrations and chromatography. Multistep syntheses are typically carried out to completion without purification of the products at intermediate stages. Further, the use of a solid support facilitates the use of a split-pool technique, which offers the most efficient manner of synthesizing large libraries (10
3
-10
9
compounds). Combinatorial chemistry processes commonly use automation which provides several advantages: First, automated systems perform functions that are impossible to do by hand, such as delivering exceedingly small volume of liquids to precise locations. Second, the consistency of an errorless process can be enhanced. Third, and perhaps more important, an appropriately designed automated system will perform functions quickly and repeatedly with consistency of quality and output over long periods of time.
The invention lends itself to the use of a solid support and of combinatorial synthesis.
2. Description of Related Art
Publications of interest relating to the subject matter of this invention include:
1. Borman, S., “Combinatorial Chemistry”, special report,
C
&
EN News,
page 47, Apr. 6, 1998.
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3. Wilson, S. R.; Czarnik, A. W.,
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4. Gulakowski et al.,
J. Virol. Meth.
1991, 33, 87-100.
5. Gordon, E. M.; Kerwin, J. F. Jr.,
Combinatorial Chemistry And Molecular Diversity in Drug Discovery,
John Wiley & Sons, Inc.: New York, 1998.
6. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Reeds, D.,
Tetrahedron,
1996, 52, 4527-4554.
7. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Reeds, D.,
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1997, 53, 5643-5678.
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1968, 33, 900-903.
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18. European patent application No. O 422 944 A1, published on Apr. 17, 1991, entitled
Chiral Sultams.
19. Snieckus, V.,
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Chatagilialoglu, C.; Snieckus, V. Eds.; Kluwer Academic Publishers: Dordrecht, 1996, pp 191-221.
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pp 163-195. Pierce Chemical Company: Rockford, Ill. (1981).
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