Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Chemical analysis
Reexamination Certificate
2000-01-21
2002-04-23
Wachsman, Hal (Department: 2857)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Chemical analysis
C702S027000, C702S030000, C702S032000, C703S011000, C703S012000
Reexamination Certificate
active
06377895
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a system and method useful for the generation and representation of chemical libraries and, more particularly, to a computer-implemented system and method useful for the generation and representation of combinatorial chemistry libraries.
Combinatorial chemistry allows scientists to generate large numbers of unique molecules with a small number of chemical reactions. Rather than using the traditional approach of synthesizing novel compounds one at a time, compounds are synthesized by performing chemical reactions in stages, and reacting all of the molecules formed in stage n−1 with each reactant in stage n. An example of this process is shown in FIG.
1
. While, for purposes of this example, it is assumed that R
1
-R
9
of
FIG. 1
represent single reactants which are used to perform single reactions, those skilled in the art will appreciate that any or all of R
1
-Rn can represent multiple reactions with which different types of chemistry or chemical sequences can be performed.
In stage 1 of the example of
FIG. 1
, molecules A and B are reacted with reactant R
1
. Similarly, molecules C and D are reacted with reactant R
2
, and molecules E and F are reacted with reactant R
3
(although only one of each type of molecule is shown in
FIG. 1
, many of each type are used in the first stage and, consequently, many of each type are formed in subsequent stages). Molecules A-F are the “starting molecules,” and the molecules formed after each stage are represented in
FIG. 1
by the starting molecule followed by the sequence of reactants separated by colons.
In stage 2, all of the molecules formed in stage 1 are reacted with reactants R
4
, R
5
and R
6
, and in stage 3, all of the molecules formed in stage 2 are reacted with reactants R
7
, R
8
and R
9
. As is shown in
FIG. 1
, this process generates
54
diverse molecules after stage 3, having started with only six molecules and having performed only nine reactions. The diverse library of molecules thus formed may be used to screen for biological activity against a therapeutic target or for any other desirable property.
A general formula for the maximum number of unique molecules which can be formed using a combinatorial process is
∏
j
=
2
N
R
j
(
∑
n
=
1
k
m
n
)
where N is the number of stages, R is the number of reactants at stage j, K is the total number of reactants in the first stage, and m is the number of molecules reacted with reactant n. This formula represents the maximum number of unique molecules formed because it is possible for different reaction steps to generate the same compounds.
The following references are related to combinatorial chemistry, and are hereby incorporated by reference in their entirety: PCT International Application Number WO 94/08051, filed Oct. 1, 1993; “Combinatorial Approaches Provide Fresh Leads for Medicinal Chemistry,”
Chemical
&
Engineering News
, Vol. 72, Feb. 7, 1994, pp. 20-26; “A Paradigm for Drug Discovery Employing Encoded Combinatorial Libraries,”
Proc. Natl. Acad. Sci. USA
, Vol. 92, pp. 6027-6031, June 1995; “Synthesis of a Small Molecule Combinatorial Library Encoded with Molecular Tags,”
Journal of the American Chemical Society
, Vol. 117, No. 20, pp. 5588-5589, 1995; “A General Method for Molecular Tagging of Encoded Combinatorial Chemistry Libraries,”
The Journal of Organic Chemistry
, Vol. 59, No. 17, pp. 4723-4724, 1994; “Synthetic Receptor Binding Elucidated with an Encoded Combinatorial Library,”
Journal of the American Chemical Society
, Vol. 116, No. 1, pp. 373-374, 1994; “Complex Synthetic Chemical Libraries Indexed with Molecular Tags,”
Proc. Natl. Acad. Sci. USA
, Vol. 90, pp. 10922-10926, December 1993; “The Promise of Combinatorial Chemistry”,
Windhover's In Vivo The Business
&
Medicine Report
, Vol. 12, No. 5, May, 1994, pp. 23-31.
When a compound generated using combinatorial chemistry is found to have a desirable property, it is important to be able to determine either the structure of the compound or the manner in which it was synthesized so that it can be made in large quantities. Until recently, combinatorial chemistry was practical only for generating peptides and other large oligomeric molecules because direct structure elucidation for most compounds is problematic, and such large molecules (made of repeating subunits) offered the advantage of being amenable to sequencing to determine their structure. In contrast, only very small libraries of small (i.e., nonoligomeric) molecules could be generated because, since such small molecules cannot be sequenced, the size of the library had to be kept small enough to allow a scientist to keep track of every compound made.
Combinatorially generated peptide libraries proved to be of limited value. Peptides are poor therapeutic agents, in part because of their lack of stability in vivo. Drug companies preferred libraries of small organic molecules which, unlike most large molecules such as peptides, can frequently act when taken orally.
A need therefore existed for a scheme by which the reaction history of small molecules generated using combinatorial chemistry could be tracked. A method was developed for “tagging” the generated compounds with an identifier for each reaction step in its synthesis. The process is called the “cosynthesis” method because, as a compound is synthesized, a tag linked to the compound (or to the solid support, e.g., bead, upon which the compound is being synthesized) by means of a chemical bond is also synthesized, which encodes the series of steps and reagents used in the synthesis of the library element. When a library compound is found to have a desirable property, the tag is sequenced to determine the series of reaction steps which formed the compound. Because the tags must be sequenced, large molecule tags such as oligonucleotides and oligopeptides have been used.
The cosynthesis method has many inherent problems. For example, the tagging structures themselves are necessarily chemically labile and unstable and as such are incompatible with many of the reagents commonly used in small molecule combinatorial chemistry. Additionally, multiple protecting groups are required and the cosynthesis of a tag may reduce the yield of the library compounds. For these reasons, the cosynthesis method has not made small molecule combinatorial chemistry a commercially viable technology.
The assignee of the instant invention has developed a proprietary, pioneering technology which makes small molecule combinatorial chemistry commercially feasible. This technology is fully described in PCT published application number WO 94/08051 and employs binary coding of the synthesized compounds such that only the presence or absence of tags, and not their sequence, defines the compound's reaction history. The operation of the assignee's binary coding system is depicted in
FIGS. 2A-2C
.
FIG. 2A
shows a three-stage combinatorial synthesis with three reactants in each stage. While, as is known, two binary digits can uniquely identify four reactants, in a preferred embodiment, the binary digits 00 are not used to identify a reactant. Consequently, as shown in
FIG. 2B
, the reaction history of any compound formed in the combinatorial synthesis of
FIG. 2A
can be represented with a six-digit binary code. The two least significant digits represent the reactant employed in stage 1, the next two digits the reactant employed in stage 2, and the two most significant digits the reactant employed in stage 3. The two digit binary code for each reactant in each stage is shown below the reactant in
FIG. 2A
, with underlining representing bits contributed by other stages.
As shown in
FIG. 2C
, then, compound A, which was synthesized with reactants R
3
, R
5
and R
9
, can be represented with the binary code 111011. Similarly, compound B, which was synthesized with reactants R
1
, R
6
and R
8
, can be represented with the binary code 101101 and compound C, which was synthesized with reactants R
2
, R
4
and R
7
, can
Goldstein Ronald B.
Pharmacopeia Inc.
Wachsman Hal
LandOfFree
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