Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 25 or more amino acid residues in defined sequence
Reexamination Certificate
1998-11-09
2002-04-09
Celsa, Bennett (Department: 1627)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
25 or more amino acid residues in defined sequence
C530S300000, C530S333000, C530S338000, C530S340000, C435S007100, C435S091500, C560S019000, C560S020000, C560S021000, C560S022000, C560S023000, C560S038000, C560S039000, C560S042000, C560S043000, C560S045000, C560S051000, C560S053000, C560S116000, C560S117000, C560S118000, C560S119000, C560S120000, C560S121000, C560S122000, C560S123000, C560S124000, C560S125000, C560S126000, C560S150000, C560S169000, C560S170000, C560S174000
Reexamination Certificate
active
06369194
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to tricarbonyl compounds, and, in particular, to &agr;,&bgr;-diketo acids, esters, and amides and a method of synthesis thereof. In addition, the present invention also relates to a method for the modular development of tricarbonyl compounds that have selected properties for a particular application. The &agr;,&bgr;-diketo compounds are developed from (cyanomethylene)phosphoranes, carboxylic acids, and nucleophiles that include selected substituent groups that provide the desired properties in the &agr;,&bgr;-diketo compounds. The iterative application of the method of the invention facilitates the synthesis of compounds having selected properties to meet the requirements of the particular application.
BACKGROUND OF THE INVENTION
The discovery of new molecules has traditionally focused in two broad areas, biologically active chemical compounds, which are used as drugs for the treatment of life-threatening diseases, and new materials, which are used in commercial, and, especially, in high technological applications. In both areas, the strategy used to discover new compounds has involved two basic operations: the more or less random choice of a molecular candidate, prepared either via chemical synthesis or isolated from natural sources, and the testing of the molecular candidate for useful properties. This discovery cycle is repeated indefinitely until a molecule of a compound possessing the desirable property, i.e., a “lead molecule”, is isolated or synthesized. This “lead molecule” discovery process is inherently ad hoc in nature, and is time-consuming, laborious, unpredictable and costly.
Once a candidate lead molecule has been determined for a particular application, the synthetic chemist must subsequently find ways to synthesize structural variants of the lead molecule to optimize its properties for the application. In the case where the lead molecule is a synthesized organic species or a natural product, the chemist is usually limited to certain structural and synthetic reaction schemes. These schemes are dictated largely by the structural composition of the lead molecule and by the specific requirements of the application. For example, in cases where the lead molecule possesses a functionally important aromatic ring, various electrophilic and nucleophilic substitutions may be carried out on the ring to produce variants. However, each such case must be approached as a specific independent design and synthesis problem, starting each time from the beginning, because of the lack of availability of an appropriate chemistry to simply alter the structure of the lead compound to produce the variant.
Recently, some attempts have been made to modularize certain synthetic organic reaction schemes to facilitate modification and transformation of a lead or base compound. See, e.g., 1993 Proc. Natl. Acad. Sci. USA, 90, 6909. However, the molecules that can be produced by such attempts are extremely limited in their achievable diversity, and are still bounded by factors dictated by the choice of specific structural themes. In the case where the lead molecule is a naturally occurring, biological molecule, such as a peptide, a protein, an oligonucleotide or a carbohydrate, simple synthetic point-modifications to the lead molecule to produce variants are quite difficult to achieve.
A brief account of the strategies and tactics used in the discovery of new molecules is described below. Although the emphasis of the discussion is on molecules of biological interest, the technical problems encountered in the discovery of biologically active molecules is also illustrative of the problems encountered in the discovery of molecules that can serve as building blocks for the development of new tools and materials for a variety of high technological applications. Furthermore, as discussed below, these problems are also illustrative of the problems encountered in the development of fabricated structures and materials for high technological applications.
Modern theories of biological activity state that biological activities and, therefore, physiological states are the result of molecular recognition events. For example, nucleotides can form complementary base pairs so that complementary single-stranded molecules hybridize, resulting in double- or triple-helical structures that appear to be involved in regulation of gene expression. In another example, a biologically active molecule, referred to as a ligand, binds with another molecule, usually a macromolecule referred to as ligand-acceptor (e.g., a receptor, an enzyme, etc.), and this binding elicits a chain of molecular events which ultimately gives rise to a physiological state, e.g., normal cell growth and differentiation, abnormal cell growth leading to carcinogenesis, blood-pressure regulation, nerve-impulse generation and propagation, etc. The binding between ligand and ligand-acceptor is geometrically characteristic and extraordinarily specific, involving appropriate three-dimensional structural arrangements and chemical interactions.
A currently favored strategy for the development of agents which can be used to treat diseases involves the discovery of forms of ligands of biological receptors, enzymes, or related macromolecules, which mimic such ligands and either boost, i.e., agonize, or suppress, i.e., antagonize, the activity of the ligand. The discovery of such desirable ligand forms has traditionally been carried out either by random screening of molecules (produced through chemical synthesis or isolated from natural sources), or by using a so-called “rational” approach involving identification of a lead-structure, usually the structure of the native ligand, and optimization of its properties through numerous cycles of structural redesign and biological testing. Since most useful drugs have been discovered not through the “rational” approach, but through the screening of randomly chosen compounds, a hybrid approach to drug discovery has recently emerged which is based on the use of combinatorial chemistry to construct huge libraries of randomly-built chemical structures which are screened for specific biological activities. Brenner et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 5381.
Most lead-structures which have been used in the “rational” drug design approach are native polypeptide ligands of receptors or enzymes. The majority of polypeptide ligands, especially the small ones, are relatively unstable in physiological fluids, due to the tendency of the peptide bond to undergo facile hydrolysis in acidic media or in the presence of peptidases. Thus, such ligands are decisively inferior in a pharmacokinetic sense to non-peptidic compounds, and are not favored as drugs. An additional limitation of small peptides as drugs is their low affinity for ligand acceptors. This phenomenon is in sharp contrast to the affinity demonstrated by large, folded polypeptides, e.g., proteins, for specific acceptors, such as receptors or enzymes, which often exist in the sub-nanomolar concentration range. For peptides to become effective drugs, they must be transformed into non-peptidic organic structures, i.e., peptide mimetics, which bind tightly, preferably in the nanomolar range, and can withstand the chemical and biochemical rigors of coexistence with biological tissues and fluids.
Despite numerous incremental advances in the art of peptidomimetic design, no general solution to the problem of converting a polypeptide-ligand structure to a peptidomimetic has been defined. At present, “rational” peptidomimetic design is done on an ad hoc basis. Using numerous redesign/synthesis/screening cycles, peptidic ligands belonging to a certain biochemical class have been converted by groups of organic chemists and pharmacologists to specific peptidomimetics. However, in the majority of cases, results in one biochemical area, such as, peptidase inhibitor design using the enzyme substrate as a lead, cannot be transferred for use in another area, such as, tyrosine-kinase inhibitor design using the kinase substrate
Celsa Bennett
Pennie & Edmonds LLP
Yale University
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