Methods for solid-phase synthesis of hydroxylamine compounds...

Details Methods for solid-phase synthesis of hydroxylamine compounds... Methods for solid-phase synthesis of hydroxylamine compounds...

1998-05-06

2001-08-28

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

Reexamination Certificate

active

06281245

ABSTRACT:

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH
Not applicable.
TECHNICAL FIELD
This invention is directed to methods for producing combinatorial chemistry libraries containing hydroxylamines and hydroxylamine derivatives, including hydroxamic acid derivatives, hydroxylurea derivatives, and hydroxylsulfonamide derivatives. This invention is further directed to synthesis of combinatorial chemistry libraries of hydroxylamines and hydroxylamine derivatives, including hydroxamic acid derivatives, hydroxylurea derivatives, and hydroxylsulfonamide derivatives, using solid-phase techniques. This invention is still further directed to the libraries of hydroxylamines and hydroxylamine derivatives, including hydroxamic acid derivatives, hydroxylurea derivatives, and hydroxylsulfonamide derivatives, produced by the solid-phase synthetic method disclosed. This invention is still further directed to utilizing the libraries of hydroxylamines and hydroxylamine derivatives (including hydroxamic acid derivatives, hydroxylurea derivatives, and hydroxylsulfonamide derivatives) to identify and select compounds which bind to, inhibit, or otherwise affect enzymes, receptors, or other biological molecules implicated in disease processes (including disease-related metalloproteinases and other metalloenzymes). The hydroxylamines and hydroxylamine derivatives (including hydroxamic acid derivatives, hydroxylurea derivatives, and hydroxylsulfonamide derivatives) thus selected have potential therapeutic value.
BACKGROUND ART
The techniques of combinatorial chemistry have been increasingly exploited in the process of drug discovery. Combinatorial chemistry allows for the synthesis of a wide range of compounds with varied molecular characteristics. Combinatorial synthetic techniques enable the synthesis of hundreds to millions of distinct chemical compounds in the same amount of time required to synthesize one or a few compounds by classical synthetic methods. Subjecting these compounds to high-throughput screening allows thousands of compounds to be rapidly tested for desired activity, again saving time expense and effort in the laboratory.
Chemical combinatorial libraries are diverse collections of molecular compounds. Gordon et al. (1995)
Acc. Chem. Res
. 29:144-154. These compounds are formed using a multistep synthetic route, wherein a series of different chemical modules can be inserted at any particular step in the route. By performing the synthetic route multiple times in parallel, each possible permutation of the chemical modules can be constructed. The result is the rapid synthesis of hundreds, thousands, or even millions of different structures within a chemical class.
For several reasons, the initial work in combinitorial library construction focused on peptide synthesis. Furka et al. (1991)
Int. J. Peptide Protein Res
. 37:487-493; Houghton et al. (1985)
Proc. Natl. Acad. Sci. USA
82:5131-5135; Geysen et al. (1984)
Proc. Natl. Acad. Sci. USA
81:3998-4002; Fodor et al, (1991)
Science
251:767. The rapid synthesis of discrete chemical entities is enhanced where the need to purify synthetic intermediates is minimized or eliminated; synthesis on a solid support serves this function. Construction of peptides on a solid support is well-known and well-documented. Obtaining a large number of structurally diverse molecules through combinatorial synthesis is furthered where many different chemical modules are readily available; hundreds of natural and unnatural amino acid modules are commercially available. Finally, many peptides are biologically active, making them interesting as a class to the pharmaceutical industry.
The scope of combinatorial chemistry libraries has recently been expanded beyond peptide synthesis. Polycarbamate and N-substituted glycine libraries have been synthesized in an attempt to produce libraries containing chemical entities that are similar to peptides in structure, but possess enhanced proteolytic stability, absorption and pharmacokinetic properties. Cho et al. (1993)
Science
261:1303-1305; and Simon et al. (1992)
Proc. Natl. Acad. Sci. USA
89, 9367-9371. Furthermore, benzodiazepine, pyrrolidine, and diketopiperazine libraries have been synthesized, expanding combinatorial chemistry to include heterocyclic entities. Bunin et al. (1992)
J. Am. Chem. Soc
. 114:10997-10998; Murpy et al. (1995)
J. Am. Chem. Soc
. 117:7029-7030; and Gordon et al. (1995)
Biorg. Medicinal Chem. Lett
. 5:47-50.
Hydroxylamines and their derivatives, including hydroxamic acids, hydroxyl ureas, and hydroxyl sulfonamides, have been the subject of much research focused on their properties as metalloproteinase inhibitors. Izquierdo-Martin et al. (1992)
J. Am. Chem. Soc
. 114:325-331; and Cushman et al. (1981) Chapter 5 “Specific Inhibitors of Zinc Metallopeptidases” in
Topics in Molecular Pharmacology
(Burgen & Roberts, eds.).
Metalloproteinases are members of a superfamily of enzymes which share a number of features. Their activity depends on the peptide nature of their substrates; full enzymatic activity requires a metal ion (generally zinc, cobalt, or iron) bound by the side chains of conserved amino acids at or near the active site; among the conserved metal-binding residues are histidines belonging to a motif, HEXXH. The enzyems are sensitive to metal-chelating reagents. Vallee and Auld (1990)
Biochem
. 29:5647-5659; and Stöcker et al. (1995)
Protein Sci
. 4: 823-840. Currently, the family comprises two subclasses, exemplified by thermolysin and metzincins.
The metalloproteinase superfamily encompasses metalloproteinases from a wide variety of organisms. For example, matrix metalloproteinases in mammals act to modify or degrade extracellular matrix components such as collagens, fibronectin, and laminin. Birkedal-Hansen et al. (1993)
Crit. Rev. Oral Biol. Med
. 4:197-250. MMP's are believed to be involved in the development of arthritis, tumor angiogenesis, retinopathy, and many other disease processes. While many MMP's are secreted from the cell, others remain membrane bound. Takino et al. (1995)
J. Biol. Chem
. 270:23013-23020; Will and Hinzmann (1995)
Eur. J. Biochem
. 231:602-608; and Tuner and Tanzawa (1997)
FASEB J
. 11:355-364. Other metalloproteinases isolated from mammals include endopeptidase EC 3.4.24.15, which is believed to be involved in the regulated metabolism of a number of neuropeptides (Papastoitsis et al. (1994)
Biochem
. 33:192-199; and McDermott et al. (1992)
Biochem. Biophys. Res. Comm
. 185:746-753); angiotensin-converting enzyme; endothelin-converting enzyme; and neutral endopeptidase. Homologues of these various human metalloproteinases have been reported in a variety of animal species. Snake venom metalloproteinases also degrade major proteins of the extracellular matrix, and further have been reported to degrade platelet integrin VLA-2 and von Willebrand factor. Jia et al. (1996)
Toxicon
34:1269-1276; and Kamiguti et al. (1996)
Toxicon
34:627-642. Fungi such as Aspergillus and Fusarium have been reported to synthesize metalloproteinases. Sekine (1973)
Agric. Biol. Chem
. 37:1945-1952; and U.S. Pat. No. 5,691,162. Metalloproteinases have also been isolated from parasitic organisms which can be pathogenic toward mammals, including protozoan parasites such as helminths (U.S. Pat. No. 5,691,186). Bacteria also synthesize metalloproteinases. Häse et al. (1993)
Microbiol. Rev
. 57:823-837. Metalloproteinases have been isolated from various bacteria including Bacillus species such as
Bacillus subtilis
(McConn et al. (1964)
J. Biol. Chem
. 239:3706); Serratia (Miyata et al. (1971)
Agr. Biol. Chem
. 35:460);
Legionella pneumophila
(Moffat et al. (1994)
Infection and Immunity
62:751-753); Vibrio species (Takahashi et al. (1996)
Biosci. Biotech. Biochem
. 60:1651-1654; and Clostridium species such as
Clostridium perfringens
(Minami et al. (1997)
Microbiol. Immunol
. 41:527-535. Activities of some of these enzymes can produce deleterious effects in mammals. For example, the &lgr;-toxin of
C. perfringens
ac

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