Solid phase synthesis of heterocycles

Details Solid phase synthesis of heterocycles Solid phase synthesis of heterocycles

1997-11-21

2002-03-26

Venkat, Jyothsna (Department: 1627)

Chemistry: analytical and immunological testing

Involving an insoluble carrier for immobilizing immunochemicals

C436S523000, C436S524000, C436S525000, C436S526000, C436S527000, C436S528000, C436S529000, C436S530000, C436S531000, C435S091500, C546S001000, C546S249000, C546S290000, C546S297000, C546S298000, C546S299000, C546S304000, C546S310000, C546S314000, C546S347000, C546S348000

Reexamination Certificate

active

06362009

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods of creating libraries of compounds using combinatorial synthesis. In particular, the provides methods for synthesizing compounds using a resin activation/capture approach (REACAP technology). The method is amenable to adaptation for use in combinatorial synthetic schemes. Libraries, compounds and pharmaceutical compositions containing compounds produced by the methods are also contemplated herein.
BACKGROUND OF THE INVENTION
Solid phase and combinatorial methods
Solid phase and combinatorial chemistry are very important in the production and screening of collections or “libraries” of compounds. These libraries are of increasing importance in medicinal chemistry and the discovery of new therapeutic agents. See, generally, Backes et al.
Current Opinion in Chem. Biol.
1997, 1, 86-93. Although these synthetic methods were initially developed for the generation of peptides and oligonucleotides, focus has recently shifted to the area of small molecule synthesis, due to the improved pharmacokinetics of such compounds and the greater potential of small molecules as therapeutic agents.
Generally, the methods used in solid phase and combinatorial chemistry involve immobilizing or capturing the substrate to be modified on a resin or other solid support. Immobilization has the advantage over solution phase chemistry in that purification of the modified substrate is greatly simplified. Additionally, the use of multiple solid supports (e.g., pins, beads, etc.) in a combinatorial approach allows for the production of a large number of diverse compounds, i.e., libraries, in a single operation. See, generally, Chaiken et al.
Molecular Diversity and Combinatorial Chemistry: Libraries and Drug Discovery
1996, 328 pp. (American Chemical Society: Washington, D.C.). The immobilization or capture of the substrate is usually, but not always, accomplished by covalent attachment of the substrate to the resin or other solid support through a linker.
Linkers are chosen such that the substrate is easily and efficiently immobilized and, following modification, cleaved from the resin or other solid support to provide the libraries and compounds of interest. Linkers which have been reported for use in solid phase and combinatorial synthesis include linkers based on protecting groups used in solution phase synthesis (see, e.g., Leznoff et al.
Can. J. Chem.
1972, 50, 2892-2893; Frechet et al.
Can. J. Chem.
1976, 54, 926-934; Chan et al.
J. Chem. Soc., Chem. Commun.
1995, 1475-1476; Krchnak et al.
Mol. Divers.
1995, 1, 149-164; Burgess et al.
J. Org. Chem.
1997, 62, 5165-5168), “traceless” linkers (see, e.g., Plunket et al.
J. Org. Chem.
1995, 60, 6006-6007; Han et al.
Tetrahedron Lett.
1996, 37, 2703-2706; Lorsbach et al.
J. Org. Chem.
1996, 61, 8716-8717; Newlander et al.
J. Org. Chem.
1997, 62, 6726-6732), support-bound chiral auxiliaries (see, e.g., Worster et al.
Angew. Chem. Int. Ed. Eng.
1979, 18, 221-222; Allin et al.
Tetrahedron Lett.
1996, 37, 8023-8026), photolabile linkers (see, e.g., Lloyd-Williams et al.
Tetrahedron
1993, 49, 11065-11133; Brown et al.
Mol. Divers.
1995, 1, 4-12), linkers devised to assist in deconvolution of combinatorial libraries (see, e.g., Salmon et al.
Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 11708-11712; Cardno et al.
Tetrahedron Lett.
1996, 37, 135-138), diversification linkers (see, e.g., Kaldor et al.
Tetrahedron Lett.
1996, 37, 7193-7196; DeGrado et al.
J. Org. Chem.
1980, 45, 1295-1300), “safety-catch” linkers (see, e.g., Backes et al.
J. Am. Chem. Soc.
1996, 118, 3055-3056; Gayo et al.
Tetrahedron Lett.
1997, 38, 211-214; Morphy et al.
Tetrahedron Lett.
1996, 37, 3209-3212, Patek et al.
Tetrahedron Lett.
1991, 32, 3891-3894) and linkers which allow for release of the substrate from the resin or other solid support by cyclization onto the support attachment site (see, e.g., Bhargava et al.
J. Am. Chem. Soc.
1983, 105, 3247-3251; Van Maarseveen et al.
Tetrahedron Lett.
1996, 37, 8249-8252; Entwistle et al.
Tetrahedron Lett.
1979, 555-558; Maeji et al.
J. Immunol. Meth.
1990, 134, 23-33; Bray et al.
J. Org. Chem.
1991, 56, 6659-6666). While the use of linkers is a common method, linkers are not required for combinatorial synthesis and, in certain instances, are not preferred due to added complexity in the combinatorial method.
In known solid phase and combinatorial methods, the immobilization or capture of the substrate on the resin generally does not modify the reactivity of the substrate. This has the advantage of allowing the use of known organic chemistry in a predictable fashion for producing libraries and compounds of interest. Chemical methods which have been used successfully in solid phase or combinatorial chemistry include aldol condensations (Ruhland et al.
Tetrahedron Lett.
1996, 37, 2757), including asymmetric aldol reactions (Reggelin et al.
Tetrahedron Lett.
1996, 37, 6851), Knovenagel-type condensations (Zaragoza
Tetrahedron Lett.
1996, 37, 6213), sequential Knoevenagel and Hantzsch condensations (Gordeev et al.
Tetrahedron Lett.
1996, 37, 2809), Claisen condensations (Marzinzik et al.
Tetrahedron Lett.
1996, 37, 1003), tandem Michael addition reactions (Ley et al.
Synlett.
1995, 1017), Staudinger cycloadditions (Ruhland et al.
J. Am. Chem. Soc.
1996, 118, 253), 1,3-dipolar cyloadditions (Mjalli et al.
Tetrahedron Lett.
1996, 37, 2943), Diels-Alder reactions (International Patent Publication Number WO 96/03424), including hetero-Diels-Alder reactions (International Patent Publication Number WO 95/28640), intramolecular ene reactions (Tietze et al.
Angew. Chem., Int. Ed. Eng.
1996, 35, 651), Fischer indole syntheses (Hutchins et al.
Tetrahedron Lett.
1996, 37, 4869), electrophilic aromatic substitutions (Yang et al.
Tetrahedron Lett.
1996, 37, 5041), Bischler-Napieralski reactions (Meutermans et al.
Tetrahedron Lett.
1995, 36, 7709), Suzuki, Stille, Heck and Sonogashira palladium-catalyzed coupling reactions (Koh et al.
J. Org. Chem.
1996, 61, 4494; Beaver et al.
Tetrahedron Lett.
1996, 37, 1145), Pauson-Khand cyclizations (Bolton
Tetrahedron Lett.
1996, 37, 3433), Ugi reactions (Zhang et al.
Tetrahedron Lett.
1996, 37, 751), Horner-Wadsworth-Emmons olefinations (Johnson et al.
Tetrahedron Lett.
1996, 37, 9253), reductive alkylations of amines with carbonyl compounds (Khan et al.
Tetrahedron Lett.
1996, 37, 4819), Reissert condensation/alkylation (Lorsbach et al.
J. Org. Chem.,
1996, 61, 8716), Mitsunobu reactions (Patel et al.
Drug Disc. Today
1996, 1, 134), oxymercurations (International Patent Publication Number WO 96/03418) and rhodium carbenoid reactions (Zaragoza et al.
Tetrahedron
1996, 52, 5999).
The disadvantage of this type of immobilization or capture is that a substrate may need to be activated in a subsequent step in order to afford the requisite activity with a reagent of interest. For example, a pyridine must be activated by reaction with, e.g., a chloroformate to allow for reaction of the resulting N-acylpyridinium ion with a Grignard reagent. In the absence of such activation, a pyridine will generally be unreactive toward this type of reagent.
Libraries and pharmaceutical compositions
Libraries of compounds produced by combinatorial methods are a powerful tool in the discovery of new therapeutic agents. Such libraries, which are designed to provide diverse mixtures of compounds, allow for, in combination with high throughput screening, the rapid screening of a large number of a variety of compounds based on a common scaffold or pharmacophore. This diversity is a valuable feature of the libraries. For example, libraries are recognized to have commercial value through the sales or licensing of the libraries. See, e.g., “CombiChem Seeks $27M In IPO; Signs Agreement With Athena” in
BioWorld Today
vol. 8, no. 202 (Oct. 17, 1997); “Bristol-Meyers To Pay ICAgen $75M For Heart Drugs” in
BioWorld Today
vol. 8, no. 190 (Oct. 1, 1997); “Bayer Buys Into GI's DiscoverEase Program For

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