Tetrapeptide derivative

Details Tetrapeptide derivative Tetrapeptide derivative

1994-02-09

1999-12-21

Huff, Sheela

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530330, A61K 3800

Patent

active

060049340

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to a novel tetrapeptide derivative having an antitumor activity, and relates more detailedly to a tetrapeptide derivative represented by the following formula or a salt thereof: ##STR5## wherein, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are the same or different and each represent a hydrogen atom, a lower alkyl group or an aralkyl group; ##STR6## or a group of -A.sub.2 -R.sub.7, wherein, A.sub.1 represents a direct bond or ##STR7## Y represents a hydrogen atom or --COR.sub.6, R.sub.5 represents a hydrogen atom, a lower alkyl group or an aralkyl group, group or ##STR8## wherein, R.sub.8 and R.sub.9 are the same or different and each represent a hydrogen atom, a lower alkyl group, a phenyl group or a 4- to 7-membered heterocyclic group containing one or two hetero atoms selected from S, O and N, or alternatively they are bonded to form a 4- to 7-membered heterocyclic ring optionally further containing one hetero atom selected from S, O and N, isopropyl groups, R.sub.3 represents a sec-butyl group, R.sub.4 represents a methyl group, and Q represents an .alpha.-(2-thiazolyl)phenethyl group.


BACKGROUND ART

Peptides having a cytostatic activity and/or an antineoplasm activity have been isolated from marine molluscs, sea hare Dolabella auricularia and these peptides are called dolastatins 1 to 15. Among them, dolastatin 10 is a pentapeptide extracted from Dolabella auricularia from the Indian Ocean in 1987 by G. R. Pettit, et al. and having the following structural formula, and is said to be the strongest cytostatic substance presently known (see G. R. Pettit, et al., J. Am. Chem. Soc., 109, 6883 (1987) and Japanese Laid-Open Patent Publication No. 167278/1992). ##STR9##
Further, recently, publication was made on the total synthesis of dolastatin 10 itself (see, U.S. Pat. No. 4,978,744), but its derivatives have not so far been known at all.
The present inventors had intensely studied about derivatives of dolastatin 10, and as a result they found that certain dolastatin analogs represented by the above formula (I) have a higher cytostatic activity than dolastatin 10. They further found that many of these compounds have a larger therapeutic ratio (maximum effective dose/dose at 30% prolongation of life) and a lower toxicity than dolastatin 10, and are thus excellent as an antitumor agent.
Namely, they found not only that amino acid analogs of dolastatin 10 exhibit a higher activity than the native dolastatin 10, but that the activity is, unexpectedly, extremely increased by introducing a carboxyl derivative into the thiazole ring. Further, they found, throughly astoundingly, that derivatives wherein the thiazole ring is eliminated show extremely higher activity than dolastatin 10.


DISCLOSURE OF INVENTION

The embodiments of this invention completed based on these findings can be classified into the following three categories.
(1) Amino acid-substituted compounds of dolastatin 10 and synthesis thereof
(2) Carboxyl derivatives of the thiazole ring and synthesis thereof
(3) Tetrapeptide derivatives wherein the thiazole ring is eliminatd and synthesis thereof
The synthesis of compounds belonging to category (1) is described in the later-shown Flow sheets 1, 2 and 3, and synthesis of compounds belonging to category (2) is described in the later-shown Flow sheets 4 and 5. Further, synthesis of compounds belonging to category (3) is described in the later-shown Flow sheet 6.
In the present description, the term "lower" means that the number of the carbon atoms of a group or compound to which this term is attached is 6 or less, preferably 4 or less.
In the above formula (I), the "lower alkyl group" may be either of straight-chain and branched-chain, and there can, for example, be mentioned a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl or isohexyl group, or the like and the "aralkyl group" means an aryl-lower alkyl group, and there can, for example, be mentioned a benzyl or phenethyl group, or the like. Further, the "lower alko

REFERENCES:
patent: 4816444 (1989-03-01), Pettit et al.
patent: 4978744 (1990-12-01), Pettit et al.
patent: 5017691 (1991-05-01), Lee et al.
Pettit et al., J. Am. Chem. Soc., "The Isolation and Structure of a Remarkable Marine Animal Antineoplastic Constituent: Dolastain 10.sup.1a ", vol. 109, pp. 6883-6885 (1987).
Schroder et al., The Peptides, vol. 1, "Formation of the Peptide Bond", pp. 76-136 (1965).
Bai et al., Biochemical Pharmacology, "Structure-Activity Studies with Chiral Isomers and with Segments of the Antimitotic Marine Peptide Dolastatin 10", vol. 40, No. 8, pp. 1859-1864 (1990).
Pettit et al., J. Med. Chem., "Chiral Modifications of Dolastatin 10: The Potent Cytostatic Peptide (19aR)-Isodolastatin 10.sup.1 ", vol. 33, pp. 3132-3133 (1990).
Johnson et al, Cancer Treatment Reviews vol. 2 p. 1-31 (1975).

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