The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested, one or more structure(s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as the instant compounds composed of two or more monomers, each monomer possessing more than one variable substituent.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides. The preparation and use of synthetic peptide combinatorial libraries has been described, for example, by Dooley in U.S. Pat. No. 5,367,053, Huebner in U.S. Pat. No. 5,182,366, Appel et al. in WO PCT 92/09300, Geysen in published European Patent Application 0 138 855 and Pirrung in U.S. Pat. No. 5,143,853. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such libraries and the rapid screening of the library which identifies lead pharmaceutical peptides.
Substituent limitations have been overcome for mixtures of peptides and peptidomimetics through the use of solid phase techniques instead of the more traditional solution-phase ones. An important step in the development of solid-phase techniques was the discovery of methods to identify active individual compounds from soluble mixtures of large numbers of compounds, as described, for example by Rutter in U.S. Pat. No. 5,010,175 and Simon in WO PCT 91/19735. These soluble mixtures, however, have never before been applied to compounds with amide backbones that have different substituent on each amide nitrogen. Until now, it was possible by previously known methods to add only the same specific substituent to each and every nitrogen atom of the amide backbone. Thus, improved methods were needed to synthesize such selectively N-alkylated amide compounds.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to the shortcomings of combinatorial chemistry with respect to selective N-alkylation. The present invention combines the techniques of solid-phase synthesis of peptidomimetic compounds and the general techniques of synthesis of combinatorial libraries to prepare new selective N-alkylated compounds.
USPTO Backgrounds
USPTO Backgrounds