Compounds and methods

Details Compounds and methods Compounds and methods

1996-06-12

1998-06-30

Dean, Karen A.

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Mixing of two or more solid polymers; mixing of solid...

525105, 525106, C08F 800, C08L 8300

Patent

active

057735123

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to libraries of non-peptide compounds each comprised of a core structure and methods for making such libraries. This invention also relates to novel silicon-based polymer resins and silane linkers, methods for their preparation and their use in the synthesis of libraries of aromatic carbocycles to be screened as pharmaceutical agents.


BACKGROUND OF THE INVENTION

In the continuing search for new chemical moieties that can effectively modulate a variety of biological processes, the standard method for conducting a search is to screen a variety of pre-existing chemical moieties, for example, naturally occurring compounds or compounds which exist in synthetic libraries or databanks. The biological activity of the pre-exiting chemical moieties is determined by applying the moieties to an assay which has been designed to test a particular property of the chemical moiety being screened, for example, a receptor binding assay which tests the ability of the moiety to bind to a particular receptor site.
In an effort to reduce the time and expense involved in screening a large number of randomly chosen compounds for biological activity, several developments have been made to provide libraries of compounds for the discovery of lead compounds. The chemical generation of molecular diversity has become a major tool in the search for novel lead structures. Currently, the known methods for chemically generating large numbers of molecularly diverse compounds generally involve the use of solid phase synthesis, in particular to synthesize and identify peptides and peptide libraries. See, for example, Lebl et al., Int. J. Pept. Prot. Res., 41, p. 201 (1993) which discloses methodologies providing selectively cleavable linkers between peptide and resin such that a certain amount of peptide can be liberated from the resin and assayed in soluble form while some of the peptide still remains attached to the resin, where it can be sequenced; Lam et al., Nature, 354, p. 82 (1991) and (WO 92/00091) which disclose a method of synthesis of linear peptides on a solid support such as polystyrene or polyacrylamide resin; Geysen et al., J. Immunol. Meth., 102, p. 259 (1987) which discloses the synthesis of peptides on derivatized polystyrene pins which are arranged on a block in such a way that they correspond to the arrangement of wells in a 96-well microtiter plate; and Houghten et al., Nature, 354, p. 84 (1991) and WO 92/09300 which disclose an approach to de novo determination of antibody or receptor binding sequences involving soluble peptide pools.
The major drawback, aside from technical considerations, with all of these methods for lead generation is the quality of the lead. Linear peptides historically have represented relatively poor leads for pharmaceutical design. In particular, there is no rational strategy for conversion of a linear peptide into a non-peptide lead. As noted above, one must resort to screening large databanks of compounds, with each compound being tested individually, in order to determine non-peptide leads for peptide receptors.
It is known that a wide variety of organic reactions can be carried out on substrates immobilized on resins. These include, in addition to peptide synthesis reactions which are well known to those of ordinary skill in the art, nucleophilic displacements on benzylic halides, halogenation, nitration, sulfonation, oxidation, hydrolysis, acid chloride formation, Friedel-Crafts reactions, reduction with LiAlH.sub.4, metallation, and reaction of the organometallic polymer with a wide variety of reagents. See, for example, N. K. Mathur et al., Polymers as Aids in Organic Chemistry, Academic Press, New York, p. 18 (1980). In addition, Farrall et al., J. Org. Chem., 41, p. 3877 (1976) describe the experimental details of some of these reactions carried out with resins.
The above-mentioned known organic reactions when applied to solid phase synthesis using known polymeric resins, yield non-peptide compounds containing auxiliary functional groups s

REFERENCES:
patent: 3139409 (1964-06-01), Meston et al.
patent: 4912170 (1990-03-01), Niwa et al.
patent: 4933391 (1990-06-01), Long et al.
patent: 5369012 (1994-11-01), Koontz et al.

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