Chemical apparatus and process disinfecting – deodorizing – preser – Chemical reactor – Organic polymerization
Reexamination Certificate
1999-04-23
2001-10-30
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Chemical reactor
Organic polymerization
C422S105000, C422S105000, C422S105000, C422S105000, C422S134000, C435S287200, C435S288300, C435S288500, C435S305300, C436S178000, C210S321750, C210S348000
Reexamination Certificate
active
06309608
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to methods and apparatus for generating chemical libraries of organic compounds. More specifically, the invention relates to methods and apparatus for improving the productivity of chemists—in particular, of “combinatorial chemists” involved in drug discovery—by permitting them to conduct large numbers of reactions simultaneously and to perform the associated physical and chemical steps involved in separation and compound recovery (e.g., resin washing and compound transfer, respectively) in an efficient manner that is amenable to various degrees of automation. More particularly, the present invention relates to novel multi-vessel reaction blocks, wash plates, transfer boxes, and associated equipment with which high-throughput chemistry can be conducted.
BACKGROUND OF THE INVENTION
Historically the discovery and optimization of candidate compounds for development as drugs has been extraordinarily expensive and time-consuming. Although the relatively new approach of “rational drug design” has promise for the future, the pharmaceutical industry has generally relied on mass screening of many-membered “libraries” of chemical compounds for the identification of “lead” compounds worthy of further study and structure-activity relationship (SAR) work. To meet this need high-throughput screening (HTS) technology has been developed that permits pharmaceutical companies to evaluate hundreds of thousands of individual chemical entities per year. Typically, these screens involve measuring some interaction (e.g., binding) between a biological target such as an enzyme or receptor and chemical compounds under test. The screens generally commence with the addition of individual compounds (or mixtures of compounds) to the individual wells in a 96 or higher-well “microtiter” plate that contains the biological target of interest (e.g., a receptor, enzyme or other protein). Ligand/receptor binding or other interaction events are then deduced by, for instance, various spectrophotometric techniques. Those chemical entities that exhibit promise in initial screens (e.g., that bind a biological target with some threshhold affinity) are then subjected to chemical optimization, SAR work, other types of testing, and, if warranted, eventual development as drugs.
Now that HTS has simplified and made more cost-effective the task of determining whether large chemical libraries contain promising lead compounds or “hits”, many pharmaceutical companies are limited not by their ability to screen candidate compounds but rather by their ability to synthesize them in the first place. At one point, most pharmaceutical companies relied on their historical collections of natural products and individually synthesized chemical entities as compound libraries to be subjected to mass screening. However, expanding these libraries—especially with a view toward increasing the “diversity” of the chemical space that they probe—has proven problematic. For instance, the cost of having a synthetic organic or medicinal chemist synthesize individual molecules in a serial fashion has been estimated to be several thousand dollars, and this is obviously a painstakingly slow process.
Thus, the advent of high-throughput screening has created a need for correspondingly high-throughput chemical synthesis (HTCS) to feed this activity. “Combinatorial chemistry” and related techniques for high-throughput parallel syntheses of large chemical libraries were created in response to this need (Gallop, M. A. et al, “Applications of Combinatorial Technologies to Drug Discovery: 1. Background and Peptide Combinatorial Libraries,”
J. Med. Chem.,
37 (9) :1233-1251 (1994); Gordon, E. M. et al, “Applications of Combinatorial Technologies to Drug Discovery: 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions,”
J. Med. Chem.,
37 (10):1385-1401 (1994); Baum, R. M., “Combinatorial Approaches Provide Fresh Leads for Medicinal Chemistry,”
C&E News,
pp. 20-26, Feb. 7, 1994; Plunkett, M. J. et al, “Combinatorial Chemistry and New Drugs,”
Scientific American,
276 (4):68-73 (1997); Borman, S., “Combinatorial Chemistry,”
C&E News,
pp. 44-67, Apr. 6, 1998). To simplify the separation of intermediate compounds during multistep organic syntheses, much of this chemistry is generally performed while the compound being synthesized is covalently immobilized on small support beads. Once the chemical building blocks have been properly assembled, the desired compounds are usually cleaved from their supports (often highly swellable polymeric resins) before being carried through to HTS.
Various definitions of “combinatorial chemistry” and “combinatorial synthesis” have been proposed and are in current use. Some synthesis strategies (e.g., “split-and-mix”) are truly “combinatorial” in nature and have as their hallmark the ability to produce very large libraries; indeed, as many as a million library members can be synthesized in a modest number of reactions (and correspondingly small number of reaction vessels) by virtue of the exponential mathematics involved. One of the several limitations of such approaches, however, is the difficulty of identifying the particular individual chemical species responsible for any activity measured in an assay of what is generally a mixture of compounds.
Other approaches such as high-throughput parallel synthesis are typically used to produce somewhat smaller chemical libraries containing, for example, from several hundred to several hundred thousand individual compounds. Here, discrete compounds (and occasionally mixtures) are spatially segregated during chemical synthesis so no ambiguity exists as to the identity of any compound producing a “hit.” However, parallel synthesis requires that chemical reactions be conducted in parallel in a relatively large number of reaction vessels, thus placing a premium on the ability to automate and improve the speed and efficiency of the synthetic process.
The terms “combinatorial chemistry,” “combinatorial synthesis,” and “parallel synthesis” are used herein synonymously and interchangeably to denote various high-throughput approaches for the preparation of chemical libraries, whether by solid-phase or solution-phase synthesis. Although the present invention is described primarily in terms of its capabilities for solid-phase synthesis, the invention is not so limited. Similarly, the present description focuses principally on the parallel synthesis of discrete compounds (i.e., one chemical entity per reaction chamber or vessel), although truly combinatorial, split-and-mix synthesis as well as the synthesis of compound mixtures can be performed equally well with the apparatus and method of the present invention.
There currently exist several different approaches for the parallel, solid-phase synthesis of discrete compounds, with somewhat different types of apparatus being best suited to each approach. The approaches described here can be referred to as “spatially addressable” strategies for the reason that, generally, each unique compound is synthesized (and addressable) at a separate point in space—that is, one compound is synthesized per reaction vessel in a multi-vessel “reaction block”. The devices and equipment used to execute these different spatially addressable synthesis strategies differ considerably in terms of their degree of sophistocation, automation, and cost—ranging from fully automated robotic synthesizers presently costing as much as several hundred thousand dollars to simple, disposable, inexpensive 96-well microtiter plates modified for chemical synthesis.
Most high-throughput chemical syntheses (HTCS) performed in the context of combinatorial chemistry and parallel synthesis are presently conducted in multi-vessel reaction assemblies often referred to as “reaction blocks” by virtue of their monolithic construction. In most solid-phase syntheses, the compound being constructed is covalently attached to resin beads and so many of these multi-vessel reaction blocks include provision for
Matson Stephen
Zhou Peng
Bex Kathryn
Jacobs Bruce F.
Matson Stephen
Warden Jill
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