Synthesis of hydroxamic acid derivatives

Details Synthesis of hydroxamic acid derivatives Synthesis of hydroxamic acid derivatives

1997-03-24

1999-08-03

Celsa, Bennett

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Synthesis of peptides

530331, 530334, 525 5411, 525374, 525377, C07K 104, C08G 6348

Patent

active

059326956

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a solid phase reaction component, and to a process for the use of such a component in the synthesis of individual hydroxamic acid derivatives or a combinatorial library of such compounds. In particular, the solid phase reaction component may be used for the synthesis of hydroxamic acids that are inhibitors of zinc metalloproteinase enzymes. Such enzymes are involved in tissue degradation and the release of tumour necrosis factor from cells.


BACKGROUND OF THE INVENTION

Solid phase synthesis is an established and effective method for the preparation of peptides, and offers advantages over conventional solution phase chemistry in terms of purification and simplicity (Atherton E, Sheppard R C, Solid Phase Peptide Synthesis: A Practical Approach; IRL Press at Oxford University Press: Oxford, 1989). Solid phase synthesis may also be used for the preparation of non-peptide molecules (Leznoff C C, Acc. Chem. Res., 1978, 11, 327-333) and recently there has been considerable interest in the application of this methodology to the synthesis of combinatorial libraries for biologically active lead compound optimisation and discovery (Moos W H et al., Annu. Rep. Med. Chem., 1993, 28, 315-324).
Solid phase synthesis requires an appropriate solid substrate which carries a plurality of functional groups to which the first reactive entity in the proposed synthesis may be covalently coupled, and from which the desired molecule may be cleaved after assembly. The solid substrate should be compatible with the solvents and reaction conditions that are to be used in the peptide or non-peptide synthesis.
The final step in solid phase synthesis is the cleavage of the covalent bond between the desired peptide or non-peptide molecule and the linker. It is desirable that the conditions for the cleavage are orthogonal to those used during the reactions employed for the synthesis of the peptide or non-peptide on the solid support such that inadvertent cleavage does not occur during the synthesis. Furthermore, the conditions for cleavage should be relatively mild such that they do not result in degradation of the desired peptide or non-peptide. Solid substrates which present hydroxyl groups as the points of attachment for the first stage of the synthesis are commonly used, for example substrates which present hydroxyl groups as derivatives of benzyl alcohol, the peptide or non-peptide being attached as a benzyl ester and cleaved by hydrolysis, transesterification or aminolysis to release the peptide or non-peptide as a carboxylic acid, carboxylate ester or as a carboxamide. Also used are substrates which present amino groups, for example as derivatives of diphenylmethylamine, the peptide or non-peptide being attached as a carboxamide and cleaved by hydrolysis to release the peptide or non-peptide as a carboxamide. Substitution of such linkers by a nitro group can enable the photolytic cleavage of the peptides or non-peptides from the residue of the solid substrate.
Certain hydroxamic acid derivatives possess useful biological activities. Examples of such hydroxamic acids include compounds that inhibit urease (Odake S et al., Chem. Pharm. Bull., 1992, 40, 2764-2768), trypanosome glycerol-3-phosphate oxidase (Grady et al., Mol. Biochem. Parasitol., 1986, 19, 231-240), dehydropeptidase-1 (EP-B-276,947), ribonucleotide reductase (Farr R A et al., J. Med. Chem., 1989, 32, 1879-1885), 5-lipoxygenase (Kerdesky F A J et al., Tetrahedron Lett., 1985, 26, 2134-2146; U.S. Pat. No. 4,731,382), substance P degradation (Laufer R et al., Eur. J. Biochem., 1985, 150, 135-140), cardiovascular metalloproteinase enzymes (Turbanti L et al., J. Med. Chem., 1993, 36, 699-707; WO-9428012) and matrix metalloproteinase enzymes (Schwartz M A. Van Wart H E, Prog. Med. Chem., 1992, 29, 271-334).
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs)

REFERENCES:
patent: 4461876 (1984-07-01), Lieberman
patent: 4868248 (1989-09-01), Sparapany
International Search Report for PCT/GB96/00428.
PCT Written Opinion for PCT/GB96/00428.
Letter by Applicant in reply to PCT written opinion for PCT/GB96/00428.
PCT International Preliminary Examination Report for PCT/GB96/00428.
(1) Chemical Abstracts, vol. 77, No. 24, Dec. 11, 1972, Abstract No. 153114e, Chernyshev, V.P.: "Maleic Anhydride Copolymer", p. 39, col. 2 & SU,A,342 865 (Institute of Fine Chemical Technology, Moscow) Jun. 22, 1972.
(2) Polymer Bulletin, vol. 32, No. 3, 1994, pp. 273-279, XP002003868, Taek Seung Lee: "Synthesis of Porous Poly(Hydroxamic Acid) from Poly(Ethyl Acrylate-Co-Divinylbenzene)".

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