Pharmaceutical compositions

Details Pharmaceutical compositions Pharmaceutical compositions

1996-04-08

1999-01-26

Owens, Amelia

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514 19, 549512, A61K 31335, A61K 3800

Patent

active

058639373

DESCRIPTION:

BRIEF SUMMARY
This invention relates to novel derivatives of N.sup.3 -D-trans-2,3-epoxysuccinamoyl-L-2,3-diaminopropanoic acid of value as antimicrobial agents.
Fungal infections, caused mainly by Candida albicans, have increased rapidly in the last decade, especially in immunocompromised patients such as those with AIDS, those receiving organ transplants and cancer patients undergoing chemotherapy. Such infections can lead to secondary infections that are life threatening. Amphotericin B is still the drug of choice for most fungal diseases and the more recently developed antifungal drugs do not in general offer any substantial improvement as compared with amphotericin B. There is still therefore a need for new antifungal drugs.
The compound N.sup.2 -L-alanyl-N.sup.3 -D-trans-2,3-epoxysuccinamoyl-L-2,3-diamino-propanoic acid, identified as Sch 37137, is produced by fermentation from Micromonospora sp. (Cooper et al., J. Antibiotics, 1988, 41, 13 and the absolute configuration of all the chiral centres in this compound has been established through a correlation of the product of fermentation with a synthetic compound (Rane et al., Tetrahedron Letters, 1993, 34(20), 3201). Sch 37137 displays biological activity against certain fungi and gram-positive and gram-negative bacteria although the activity reported by Cooper et al. was at only a relatively low level.
Nevertheless, we have now found that Sch 37137, and more particularly novel analogues of Sch 37137 in which the L-alanine residue is replaced by certain alternative amino acid residues or in which other variations in structure are made, possess good levels of antimicrobial activity, the activity of the analogues generally being enhanced as compared with that of the corresponding isomeric form of Sch 37137.
Accordingly, the present invention comprises a compound being a derivative of N.sup.3 -D-trans-2,3-epoxysuccinamoyl-L-2,3-diaminopropanoic acid of formula (1) ##STR2## wherein R.sub.1 is hydrogen; or R.sub.1 is the residue of an amino acid selected from L-valine, L-norvaline, L-leucine, L-isoleucine, L-norleucine, L-methionine, L-lysine, L-2-aminobutanoic acid, L-aspartic acid and L-glutamic acid; L-norvalyl-L-norvaline, L-lysyl-L-norvaline, L-methionyl-L-norvaline, L-glutamyl-L-norvaline, L-norvalyl-L-methionine, L-methionyl-L-methionine, L-leucyl-L-norvaline, L-norleucyl-L-norvaline, L-valyl-L-norvaline, L-glutamyl-L-leucine, L-asparginyl-L-norvaline and L-leucyl-L-leucine; L-methionine, L-valine, L-norvaline, L-leucine, L-isoleucine, L-norleucine and L-2-aminobutanoic acid; with the provisos that when R.sub.1 is hydrogen then R.sub.2 is an amino acid residue and that when R.sub.1 is an amino acid residue or a peptide residue then R.sub.2 is hydroxyl; the compound optionally being in the form of a physiologically acceptable salt.
It will be appreciated that the amino acid and dipeptide residues R.sub.1 are formed at the C-terminus of the amino acid or dipeptide whilst the amino acid residues R.sub.2 are formed at the N-terminus.
A preferred group of compounds of formula (1) has the formula (2) ##STR3## wherein R.sub.1 is the residue of an amino acid selected from L-valine, L-norvaline, L-leucine, L-isoleucine, L-norleucine, L-methionine, L-lysine, L-2-aminobutanoic acid, L-aspartic acid and L-glutamic acid; L-norvalyl-L-norvaline, L-lysyl-L-norvaline, L-methionyl-L-norvaline, L-glutamyl-L-norvaline, L-norvalyl-L-methionine, L-methionyl-L-methionine, L-leucyl-L-norvaline, L-norleucyl-L-norvaline, L-valyl-L-norvaline, L-glutamyl-L-leucine, L-asparginyl-L-norvaline and L-leucyl-L-leucine.
Preferred compounds of formula (2) in which R.sub.1 is a dipeptide residue comprise a norvaline residue, as one of the residues of the dipeptide, particularly at its C-terminus. Thus a dipeptide residue R.sub.1 of particular interest is that of L-lysyl-L-norvaline. However it is generally preferred that R.sub.1 is an amino acid residue rather than a dipeptide residue, particularly the residue of L-methionine or L-leucine and especially that of L-norvaline.
A further preferred group

REFERENCES:
R. Andruszkiewicz et al. "Anticandidal properties of N.sup.3 -(4-Methoxyfumaroyl). . ." J. Med. Chem. 1990, 33, pp. 132-135.
R. Andruszkiewicz et al. "Synthesis and biological properties of N.sup.3 -. . . ." J. Med. Chem., 1987, 30, pp. 1715-1719.
D.F. Rane et al. "Total synthesis and absolute. . . " Tetrahedron Letters, vol 34 No 30, pp. 3201-3204, 1993.
R. Andruszkiewicz et al. "Synthesis and Anticandiadal activites. . ." The Journal of Antibiotics, vol 17 No 6, pp. 715-723.
J. Shoji et al. "Isolation of CB-25-l, and antifungal. . ." The Journal of Antibiotics, vol XLII No 6, pp.869-873.
R. Cooper et al. "Sch 37137, a novel antifungal compound. . ." The Journal of Antibiotics, vol XLI No. 1, pp. 13-19.

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