Solid-phase technology for the preparation of amides

Details Solid-phase technology for the preparation of amides Solid-phase technology for the preparation of amides

1999-05-20

2002-04-16

Venkat, Jyothsna (Department: 1627)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Synthesis of peptides

C435S007100, C435S007200, C435S091500, C436S501000, C436S518000, C530S333000, C530S335000, C544S168000, C564S152000, C564S155000, C564S158000, C564S161000, C564S163000, C564S168000

Reexamination Certificate

active

06372885

ABSTRACT:

INTRODUCTION
With the identification of a molecular target associated with a particular disorder, the medicinal chemist works towards a drug molecule which intervenes in a particular pathway preventing progression of the disorder. The route towards a potent and selective drug proceeds through a number of stages. For example, when faced with an aberrant protease the protease is initially isolated and purified. An assay for activity is then established and a molecule that inhibits the proteolytic activity developed and systematically refined to provide a drug candidate with the desired potency and selectivity. This route is time consuming and expensive, thus tools which expedite a part of the whole process of drug development are extremely attractive commercially.
Combinatorial chemistry techniques, which are methods for the parallel preparation of many molecules compared to traditional single serial techniques, have the potential to play a pivotal role in the design and development of drug-like molecules. Co-pending UK Patent Application No. 9608457.9 describes a combinatorial library technology which has been developed as a tool to accelerate the development of inhibitors of proteolytic enzymes. A protease is screened against a large addressable library of potential protease substrates, swiftly providing an assay for proteolytic activity based upon internally quenched fluorescence. Along with the establishment of a sensitive assay, a wealth of substrate structure-activity data is gathered which may be used in the design oil an inhibitor. (Where legally permissible GB 9608457.5 is incorporated herein by reference).
A large proportion of the molecules that have previously or are currently being developed as protease inhibitors or in fact many other drug classes can be represented by the simple general formula (1)
Two fundamental approaches towards the preparation of molecules such as (1) are available. Traditionally, solution phase based serial chemistries have been used to provide single molecules. Recently these serial solution chemistries have begun to develop into parallel combinatorial methods in which R1 and/or R2 are varied providing 10's-100's of molecules swiftly. Over the last 30 years, the expedient methods of solid phase chemistry have also developed. Solid phase methods have the potential to rapidly produce many thousands of molecules. However, the ease with which different classes of the general formula (1) can be varied in both R1 and R2 simultaneously depends upon the specific nature and functionality of R1 and R2. For example, when R1 and R2 are standard amino acid structures, providing the general class ‘peptides’, solid phase methods have developed sufficiently to provide single peptides or thousands/millions of peptides in a combinatorial library format with relative ease.
Generally, protease inhibitors are designed with recognition elements from the substrate (i. e. R1), and are often coupled with a chemical moiety (i.e. R2) which interacts with the protease to inhibit proteolytic activity.
The combinatorial protease inhibitor library assay technique of GB 9608457.9 provides an example of parallel preparation of molecules (1) in which there is flexible combinatorial variation of R1. Chosen specific effective examples of (1) from the combinatorial library must then be assayed for effectiveness as a protease inhibitor with individually serially varied moieties R2.
The solid phase techniques currently available are not sufficiently developed to enable flexible combinatorial variation of both R1 and R2 in the majority of classes of (1), even in a simple serial manner as single entities, let alone as combinatorial libraries. Thus a solid phase combinatorial library method, enabling the rapid preparation of hundreds or thousands of compounds across many classes of (1) would potentially be extremely attractive for physicochemical/structure-activity profiles in the development of drug candidates. Additionally, such a methodology would expedite the transformation of R1 substrate data derived from the library described in GB 9608457.9 into an effective inhibitor, a process which is currently time consuming using solution based techniques.
It will readily be appreciated by those skilled in the art that a general solid phase combinatorial route to molecules of structure (1) would not be restricted to the development of protease inhibitors. Any type of interaction e.g. receptor agonists, antagonists for which molecules of type (1) exhibit activity may be developed in a combinatorial manner. Here, a novel solid-phase methodology is described allowing the flexible variation of R1 and R2 in many classes of general structure (1), and allowing a combinatorial approach leading to parallel preparation of many molecules.
Background Chemistry—The Current Problem
Solid phase based synthesis utilise cross-linked polymers (a resin support) which is functionalised with a chemically reactive unit (a linker). A functional group (carboxylic acid, amine, hydroxyl, sulphydryl etc) from an initial intermediate of the final desired compound is reversibly and covalently attached to the resin through the linker. Sequential chemical transformations of this now resin-bound intermediate to the final compound are then performed. At each stage, excess and spent reagents are removed from the growing resin-bound product by simple filtration and washing—this being the overriding factor providing expedient synthesis compared to solution based synthesis. As a final step, the fully assembled product is released from the solid support by cleavage of the covalent bond between the linker and product functional group.
To date, peptides provide the vast majority of compounds of general formula (1) prepared. Traditional solid phase peptide synthesis utilises a linker derivatised resin support to which the C&agr; carboxyl of the C-terminal residue is covalently attached. The desired sequence is sequentially assembled (using individual elements at each stage to give a single final product or using mixtures of elements at each stage to give a mixture or ‘library’ of final products). Then the product is released into solution by cleavage of the C-terminal residue—linker bond. This provides the free C-terminal carboxylic acid. To provide alternative C-terminal functionalities different linkers have been developed. However virtually all linkers described to date release a functional group (carboxylic acid, amine, hydroxyl, sulphydryl etc) present in the final product. Thus an obvious problem arises if the desired compound is devoid of one of the above functionalities, as many classes of (1) are. For example peptidyl acyloxymethyl ketones, of the general formula (2), a potent class of inhibitor of the cysteinyl protease Der p I, a major allergen of the house dust mite, are a member of the general class (1), but contain no obvious functional group to which a linker can attach an intermediate to a resin. Therefore current solid phase techniques cannot prepare potential drug candidates of the general structure (2) as single discrete compounds let alone defined libraries of analogues.
Co-pending PCT Application No. PCT/GB96/01707 describes in more detail the cysteinyl protease Der p I inhibitors (2) and their preparation. (Where legally permissible PCT/GB96/01707 is incorporated herein by reference).
A Novel Solid—Phase Based Solution
i)Strategy
The only functional element that is always present in (1) is the secondary amide group (3). Thus, the attachment of initial intermediates of general formula (1) through the conserved secondary amide group to a resin support provides a unique route to any class of (1). Following subsequent solid phase assembly of the desired compound/s, the covalent bond between the linker and now tertiary amide is cleaved to regenerate the conserved secondary amide (3). Scheme 1 below. During the sequential chemical transformations leading to the final secondary
amide product, one has two options. Coupling reactions (the addition of a new chemical moiety providing a part of the fin

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