Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-10-09
2004-06-22
Celsa, Bennett (Department: 1639)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C560S205000, C564S204000, C558S251000, C428S407000, C435S006120, C530S334000
Reexamination Certificate
active
06753449
ABSTRACT:
BACKGROUND OF THE INVENTION
Combinatorial chemistry has recently emerged as an effective method for preparing large numbers of chemical compounds for use, e.g., in the discovery of biologically-active agents such as pharmaceutical drugs. In general, combinatorial chemistry is used to prepare collections of compounds, known as libraries, in which all the members of the library share a common core structural element. Such libraries can be prepared by a variety of methods, including solution-phase synthesis and solid-phase synthesis.
Solid-phase synthesis is usually performed by reaction of compounds which have each been immobilized by a covalent linkage to a solid or insoluble support material. The compounds are attached to the support material, which can be a polymeric resin such as polystyrene or polystyrene copolymer, through a linker, and when the synthesis of compounds is complete, the linker can be cleaved to release the final compound or compounds into solution.
The choice of linker for use in a synthesis depends upon the type of synthetic chemistry to be performed and on the conditions to be employed in the synthesis. In general, a linker is preferably inert to the reaction conditions employed during synthesis of the library, so as to avoid loss of compound by premature cleaving of the compound from the solid support. However, the linker should be selected to permit facile cleavage of the compounds from the solid support when the synthesis has been completed.
Numerous linkers have been proposed for use in solid phase combinatorial synthesis (for reviews, see, e.g., F. Guillier et al.
Chem. Rev
. (2000) 100(6): 2091-2158). Frequently, such linkers are cleavable under either acidic conditions or basic conditions. However, such linkers are not suitable for the preparation of compounds which are not stable to the acidic or basic conditions required for cleavage.
Other linkers have been developed which can be cleaved under more nearly neutral conditions. However, such linkers may be expensive to prepare and in some cases are not compatible with conditions which may be encountered during synthesis of a combinatorial library.
Accordingly, it would be desirable to provide new linkers which are easily and inexpensively prepared and which are compatible with a variety of reaction conditions.
SUMMARY OF THE INVENTION
The present invention relates to compositions and methods useful for performing solid-phase chemical synthesis reactions, including synthesis of combinatorial libraries of compounds. The compositions of the invention include linking moieties that can be cleaved under mild conditions, and are suitable for use with a variety of synthetic reaction conditions.
In one aspect, the invention provides a composition comprising an insoluble support covalently attached to a linker moiety. In this aspect, the linker moiety comprises a group represented by the formula (Formula I):
in which n is 0, 1 or 2; X is CH
2
, O, S, or NR, in which R is alkyl (which may be substituted) or aryl (which may be substituted); Y is a leaving group, OR′, NHR′, or SR′, in which R′ is a positively-charged ion, optionally substituted alkyl or optionally substituted aryl; and R
1
-R
5
are each independently selected from the group consisting of H, optionally substituted alkyl or optionally substituted aryl, nitro, alkoxy, aryloxy, cyano, azido, halogen, optionally substituted thioalkyl and optionally substituted thioaryl, and further wherein at least one of R
1
-R
5
is covalently attached to an insoluble support. In certain preferred embodiments, n is 0. In other preferred embodiments, n is 1 and X is CH
2
. In another preferred embodiment, Y is —OH. In certain embodiments, the insoluble support is agarose; in other embodiments, the insoluble support is polystyrene (including cross-linked polystyrene-divinylbenzene). In other embodiments, the insoluble support can be solubilized in a solvent. In certain preferred embodiments, R
2
, R
3
, and R
4
are H. In some preferred embodiments, R
1
is covalently attached to the insoluble suppor; in other preferred embodiment, R
5
is covalently attached to the insoluble support. In certain preferred embodiments, R
5
comprises an aminoalkyl group.
In another aspect, the invention provides a method of preparing a chemical compound on an insoluble support. In this aspect, the method comprises the steps of providing a composition of Formula I (in which n, X, Y, and R
1
-R
5
as are defined above); covalently linking a first reactant to the linker moiety to provide a support-bound first reactant moiety; and reacting the support-bound first reactant moiety with a second reactant, under conditions such that a chemical compound on an insoluble support is prepared. In certain preferred embodiments of this method, n is 0. In other preferred embodiments, n is 1 and X is CH
2
. In another preferred embodiment, Y is —OH, while in other preferred embodiments, Y is a leaving group. In certain embodiments, the insoluble support is agarose; in other embodiments, the insoluble support is polystyrene (including cross-linked polystyrene-divinylbenzene). In other embodiments, the insoluble support can be solubilized in a solvent. In certain preferred embodiments, R
2
, R
3
, and R
4
are H. In some preferred embodiments, R
1
is covalently attached to the insoluble suppor; in other preferred embodiment, R
5
is covalently attached to the insoluble support. In certain preferred embodiments, R
1
comprises an aminoalkyl group.
In another aspect, the invention provides a method of preparing a chemical compound. This method includes the steps of providing a composition of Formula I; covalently linking a first reactant to the linker moiety to provide a support-bound first reactant moiety; reacting the support-bound first reactant moiety with a second reactant, under conditions such that a chemical compound on an insoluble support is prepared; and cleaving the chemical compound from the insoluble support. In a preferred embodiment, the step of cleaving comprises contacting the chemical compound on an insoluble support with an electrophilic reagent under substantially neutral conditions. In a more preferred embodiment, the electrophilic reagent is I
2
.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
For convenience, certain terms used in the specification and claims are defined below.
The terms “insoluble support” or “solid support”, as used herein, refer to a solid or insoluble support, commonly a polymeric support, to which a linker moiety can be covalently bonded by reaction with a functional group of the support. Many suitable supports are known, and include materials such as polystyrene resins, polystyrene/divinylbenzene copolymers, agarose, and other materials known to the skilled artisan. It will be understood that an insoluble support can be soluble under certain conditions and insoluble under other conditions; however, for purposes of this invention, a polymeric support is “insoluble” if the support is insoluble or can be made insoluble in a reaction solvent and under conditions used to effect the synthesis of chemical compounds on the support, or cleavage of compounds from the support, as described herein.
A variety of supports are known in the art and can be prepared by known techniques. For example, polymers including the carboxylic acid chloride functionality (e.g., —COCl) are known (see, e.g., P. Hodge and D.C. Sherrington, “Polymer-supported Reactions in Organic Synthesis”, Chapter 1, (1980)) and can be prepared by treatment of conventional polymer-supported carboxylic acids (e.g., polyacrylic acids) with, e.g., thionyl chloride, oxalyl chloride, and the like. Polymeric supports including sulfonyl chloride functionalities can be obtained by the reaction of a polymer including sulfonic acid moieties with, e.g., thionyl chloride, or by other known methods, for example, the method described in U.S. Pat. No. 5,118,766. Benzyl halide-containing polymers are well known and include chloromethylated polystyrene (e.g., Merrifield resin). Such reactive
ArQule, Inc.
Celsa Bennett
Epperson Jon D.
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