Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Patent
1995-01-26
1998-04-14
Luxton, David
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
514 17, A61K 3808
Patent
active
057392790
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention is concerned with new antiinflammatory agents. In particular, this invention relates to compounds which are derivatives of 4-amino-2,2-difluoro-8-oxo-1,6-hexanedioic acid; to the pharmaceutically acceptable base salts of such derivatives; to methods of using such derivatives in inhibiting interleukin 1.beta. converting enzyme (ICE) and for treating inflammatory conditions in mammals, especially man; and to pharmaceutical compositions useful therefor.
Current therapies for arthritis are severely limited by the side effects of available drugs and their ineffectiveness beyond treatment for disease symptoms. The most widely used drugs are agents (the non-steroidal antiinflammatory drugs, NSAIDS) which inhibit the cyolooxygenase pathway of arachidonic acid metabolism. While these compounds are effective in controlling the symptoms of arthritis, they are not disease remittive. Furthermore, cyclooxygenase inhibition is invariably associated with the major side-effect of NSAID therapy, gastrointestinal irritation. Steroids are used in the more severe cases of arthritis and are very effective. However, long term therapy using steroids is seldomly tolerable. Second line antiinflammatory agents such as gold, penicillamine, chloroquine and methotrexate are also beset with side effect issues which severely limit their general utility.
Interleukin-1 (IL-1) has been strongly implicated as a key mediator of tissue damage in osteo- and rheumatoid arthritis. Lowering levels of IL-1 in a diseased joint would be expected to halt continued degeneration and perhaps allow joint repair to take place. One approach to reducing levels of IL-1 is to block the generation of mature IL-1.beta. from its biologically inactive precursor, pro-IL-1.beta., by inhibition of the interleukin-1.beta. converting enzyme (ICE). This invention relates to a novel series of compounds which inhibit ICE. The compounds should act as disease remittive antiinflammatory agents and are not expected to elicit the side effects associated with NSAID therapy (due to cyclooxygenase inhibition), steroids or other treatments currently in use.
Peptidyl derivatives containing difluorostatone are described in: S. Thaisrivongs et al., J. Med. Chem., 1986, 29, 2080-2087 and K. Fearon et al., J. Med. Chem., 1987, 30, 1617-1622.
SUMMARY OF THE INVENTION
This invention is concerned with new compounds which are useful for the treatment of diseases associated with elevated levels of interleukin-1 (IL-1). The compounds block the formation of biologically active mature IL-1.beta. from its precursor pro-IL-1.beta. by inhibiting interleukin 1.beta. converting enzyme (ICE).
The compounds of the present invention and their pharmaceutically acceptable salts are of the formula A ##STR2## and the pharmaceutically acceptable base salts thereof wherein A.sup.1 is L-Pro--NR.sup.1 R.sup.2 or --NR.sup.1 R.sup.2, where R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl and benzyl; or R.sup.1 and R.sup.2 are taken together with the nitrogen to which they are attached and form ##STR3## wherein n is an integer from 2 to 6; A.sup.2 is selected from the group consisting of L-His, L-Cys, L-Cys(Me), L-Phe, L-Phe-R.sup.3, L-Val, L-Ala, L-lle, L-Leu and L-Tyr;
A.sup.3 is selected from the group consisting of L-Val, L-Leu, L-lle, L-Tyr, L-Phe and L-Phe- R.sup.3 ; L-Phe-R.sup.3, L-Tyr, and L-Leu; for each occurrence is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, benzyl, fluoro, trifluoromethyl and chloro; and
Q.sup.1 is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, R.sup.4 CO and phenylcarbonyl, wherein R.sup.4 is hydrogen, C.sub.1 -C.sub.6 alkyl or benzyl.
The abbreviations used to denote the amino acids are well known and standard in the art and are as follows: Ala, alanine; Pro, proline; His, histidine; Cys, cystine; Cys (Me), methylcystine; Phe, phenylalanine; Val, valine; lle, isoleucine; Leu, leucine; and Tyr, tyrosine.
A
REFERENCES:
R. P. Robinson and K. M. Donahue, J. O. Chem., 1992, 57, No. 26, pp. 7309-7314.
Doherty, A. M., et al., J. Med. Chem., 1992, 35, pp. 2-14.
Thaisrivongs, S., et al., J. Med. Chem., 1985, 28, pp. 1553-1555.
Thaisrivongs, S., et al.., J. Med. Chem., 1986, 29, pp. 2080-2087.
Fearon, K., et al., J. Med. Chem., 1987, 30, pp. 1617-1622.
Benson Gregg C.
Luxton David
Pfizer Inc.
Richardson Peter C.
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