Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-30
2002-06-04
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S460000, C549S416000, C549S432000, C549S439000, C556S482000, C558S388000, C560S008000, C560S124000, C568S303000, C568S308000, C568S579000, C568S630000, C568S632000, C568S808000
Reexamination Certificate
active
06399785
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods of producing and characterizing compound libraries containing large numbers of multiply-substituted fullerenes. More particularly, the invention relates to chemically synthesizing combinatorial libraries of multiply-substituted fullerenes and to methods for efficiently screening for and identifying fullerene derivatives having pharmaceutical, materials science, or other utility. The invention also relates to the libraries thus produced, multiply-substituted fullerenes in the libraries which possess pharmaceutical, materials science, or other utility, and pharmaceutical formulations thereof.
BACKGROUND OF THE INVENTION
The traditional method of generating compounds with desirable biological activity involves identifying a lead compound with the desired biological activity; creating, one at a time, variants of that lead compound; and evaluating the biological activity of those variants. Usually, these new medicinal chemical lead structures originate from natural products isolated from microbiological fermentations, plant extracts, and animal sources; from pharmaceutical company compound databases containing a historic collection of compounds synthesized in the course of pharmaceutical research; and from the application of both mechanism-based and structure-based approaches to rational drug design.
Accordingly, the traditional method of finding active pharmacological compounds requires the synthesis of individual compounds and the evaluation of their biological activity. Many hundreds of compounds are typically synthesized and screened before a substance with significant activity is identified which can serve as the lead structure for the development of drug candidates. Once a lead compound is found, analogs are synthesized to optimize biological activity. In addition to being a costly method of determining lead compounds, the traditional method of drug discovery has the additional disadvantage that one can never synthesize all of the possible analogs of a given, promising lead compound.
Recent trends in the search for biologically active compounds have focused on the use of combinatorial chemistry for the preparation of potential sources of new leads for drug discovery. Combinatorial chemistry is a strategy which leads to large chemical libraries. It is often defined as the systematic and repetitive, covalent connection of a set of different “building blocks” of varying structures to each other to yield a large array of diverse, potentially pharmaceutically useful, molecular entities. Powerful techniques for the creation and screening of combinatorial libraries have been developed and improved upon rapidly in the past few years. These developments have rapidly expanded beyond their initial peptide and antibody targets to now include a wider range of biologically interesting compounds, as well as non-biological small molecules.
The libraries generated may each contain vast numbers of different molecules. Screening and isolation procedures are available which offer the means to identify and isolate compounds from a library which fulfill specific biological requirements. These methods include inhibition of binding of tritiated radioligands or selected fluorescence-labeled selected ligands to cell surface receptors on intact cells in culture, to cell surface receptors on disaggregated cell membranes, to cell surface receptors on cells in which a cloned neurotransmitter has been transfected, to cell surface receptors on tissue slices mounted upon microscope slides, to cell surface receptors on tissue strips maintained in organ baths, to cell surface receptors on whole organs maintained perfused and oxygenated in vitro, and to whole organs in the animal in vivo. The method also includes inhibition of binding of ligands to purified or cloned, recombinant receptors immobilized upon a chemical sensor, to purified or cloned, recombinant receptors immobilized upon an optical sensor, to purified or cloned, recombinant receptors immobilized upon an electromechanical sensor, and so forth. All of these techniques are well known to those skilled in the art.
The combinatorial chemistry approach does not actually change the medicinal chemistry paradigm. It introduces the new step of creating libraries, and accelerates the otherwise time consuming process of finding these compounds. By greatly increasing the range of molecular diversity available to the medicinal chemist, combinatorial chemistry has the potential to greatly broaden the number of molecules being surveyed for biological activity and other desirable properties.
The essential starting point for the generation of a diverse library of molecules is an assortment of small, reactive molecules which may be considered chemical building blocks. Unlike the traditional method, where the goal is to prepare and isolate individual variants of a lead compound, the combinatorial method deliberately creates a diverse set of variants simultaneously. The variants are then screened for useful properties.
Theoretically, the number of possible different individual compounds, N, prepared by an ideal combinatorial synthesis is determined by the number of blocks available for each step (“b”) and the number of synthetic steps in the reaction scheme (“x”). If an equal number of building blocks are used in each reaction step, then N=b
x
.
For example, it is well known in the art that multiple peptides and oligonucleotides may be simultaneously synthesized. In a single synthesis of a peptide, amino acids are simultaneously coupled to a chemically functionalized solid support. Typically, an N-protected form of the carboxyl terminal amino acid, e.g. a t-butoxycarbonyl protected (Boc-) amino acid, is reacted with the chloromethyl residue of a chloromethylated styrene divinylbenzene copolymer resin to produce a protected amino acyl derivative of the resin, the amino acid being coupled to the resin as a benzyl ester. This derivative is deprotected and reacted with a protected form of the next required amino acid thus producing a protected dipeptide attached to the resin. The amino acid will generally be used in activated form, e.g. a carbodiimide or active ester. The addition step is repeated and the peptide chain grows one residue at a time by condensation of the required N-protected amino acids at the amino terminus until the required peptide has been assembled on the resin. The peptide-resin is then treated with anhydrous hydrofluoric acid to cleave the ester linking the assembled peptide to the resin and liberate the required peptide. The protecting groups on side chain functional groups of amino acids which were blocked during the synthetic procedure, using conventional methods, may also be removed. This entire procedure may be automated. Multiple peptides or oligonucleotides may be synthesized.
One such methodology for peptide synthesis is disclosed in Geysen, et al. International Publication Number WO 90/09395, hereby incorporated by reference. Geysen's method involves functionalizing the termini of polymeric rods and sequentially immersing the termini in solutions of individual amino acids. Geysen's approach has proven to be impractical for commercial production of peptides since only very minute quantities of polypeptides may be generated. In addition, this method is extremely labor intensive.
U.S. Pat. No. 5,143,854 to Pirrung et al., hereby incorporated by reference, discloses another method of peptide or oligonucleotide synthesis. This method involves sequentially using light for illuminating a plurality of polymer sequences on a substrate and delivering reaction fluids to said substrate. A photochemical reaction takes place at the point where the light illuminates the substrates. Reaction at all other places on the substrate is prevented by masking them from the light. A wide range of photochemical reactions can be employed in this method, including addition, protection, deprotection, and so forth, as are well known in the art. This method of synthesis has numerous drawbacks, howev
Lu Quing
Murphy Randall B.
Wilson Stephen R.
C-Sixty, Inc.
Evans, Esq. Barry
Higel Floyd D.
Kramer Levin Naftalis & Frankel LLP
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