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...

1997-10-27

2003-04-01

Ponnaluri, Padmashri (Department: 1627)

Chemistry: analytical and immunological testing

Involving an insoluble carrier for immobilizing immunochemicals

C435S091500, C435S091500, C435S091500, C530S335000

Reexamination Certificate

active

06541276

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 metalloproteases). 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 combinatorial 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 metalloprotease 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.). Metalloproteases are believed, to be involved in the development of arthritis, tumor angiogenesis, retinopathy, and many other disease processes.
U.S. Pat. No. 5,268,384 discloses hydroxamates and hydroxyl ureas used to treat inhibit angiogenesis by inhibiting matrix metalloproteases. Among metalloproteases disclosed as targets of inhibitors are collagenases, including human skin fibroblast collagenase and purulent human sputum collagenase; gelatinases, including human skin fibroblast gelatinase and purulent human sputum gelatinase; and stromelysin. Disclosed disorders amenable to treatment by matrix metalloprotease (MMP) inhibitors include ocular pathologies such as diabetic retinopathy and neovascular glaucoma; cancer, including Kaposi's sarcoma, glioblastoma, and angiosarcoma; immune system disorders such as rheumatoid arthritis; and skin disorders such as psoriasis.
Patent publication WO 96/26918 discloses hydroxamates for inhibiting MMPs. The publication also discusses the inhibition of the production or the action of the cytokine tumor necrosis factor (TNF) by hydroxamic acid MMP inhibitors. See also, Mohler et al.
Nature
370:218-220 (1994); Gearing et al.,
Nature
370:555-557 (1994); and McGeehan et al.,
Nature
370:558-561 (1994). These MMP inhibitors are described as useful for treating inflammatory, infectious, immunological or malignant diseases due to their effect on TNF. Among the specific diseases described are septic shock, hemodynamic shock, malaria, meningitis, fibrotic disease, cachexia, autoimmune diseases, and graft rejection.
Patent publication WO 96/25156 discloses hydroxamates for inhibiting matrix metalloproteases. The publication also discusses inhibition of production or processing of transforming growth factor alpha (TGF-&agr;) by MMP inhibitors, and describes potential applications of the MMP inhibitors in treating inflammation; wound healing, including scar and keloid formation; diabetic retinopathy; neovascular glaucoma; atherosclerosis; vascular adhesions; systemic lupus erythrematosus; various carcinomas; and other diseases amenable to treatment by modulating production or processing of TGF-&agr;.
U.S. Pat. No. 5,552,419 discloses aryl sulfonamido-substituted hydroxamic acids. The compounds are described as inhibitors of stromelysin, gelatinase and/or collagenase. Disorders described as amenable to treatment by the hydroxamic acid derivatives are osteoarthritis and rheumatoid arthritis; tissue ulceration; periodontal disease; bone diseases, including Paget's disease and osteoporosis; HIV infection; and tumor metastasis, tumor progression or tumor invasion.
Patent publication EP 423943 describes the use of inhibitors of certain matrix metalloproteases, such as collagenases, gelatinases, and stromelysins, as useful for treatment of demyelinating diseases such as multiple sclerosis and other scleroses; demyelinating peripheral neuropathies; acute disseminated encephalomyelitis; and other neural disorders.
Other hydroxamic acid-based metalloprotease inhibitors are described in the following patent publications: U.S. Pat. Nos. 4,599,361 and 5,256,657; European patent publications EP 236872, EP 274453, EP 489577, EP 489579, EP

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