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
1996-04-01
1998-06-16
Tsang, Cecilia J.
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 3800, C07K 500, C07K 700, C07K 1700
Patent
active
057672377
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a novel peptide derivative having an antitumor activity, and, more detailedly, relates to a peptide derivative represented by the following formula or a salt thereof ##STR2## wherein A and B each represent either of the following (a) and (b), (a) A represents a hydrogen atom, and B represents a phenyl group substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, or a heteroaryl group, lower alkoxycarbonyl group or a carboxyl group, wherein, R.sup.1 represents a lower alkyl group or a heteroaryl group, and B represents a phenyl group optionally substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy 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 U.S. Pat. No. 4,816,444). ##STR3##
Further, recently, publication was made on the total synthesis of dolastatin 10 itself (see, U.S. Pat. No. 4,978,744).
In this connection, the present inventors previously disclosed certain dolastatin 10 derivatives (see, WO93/03054 Pamphlet).
The present inventors found that certain dolastatin 10 derivatives wherein the dolaphenine (which means an .alpha.-(thiazolyl)phenethylamino group) at the C-terminus of dolastatin 10 is substituted with another substituent have a much stronger antitumor activity than that of dolastatin 10.
DISCLOSURE OF INVENTION
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), as the "lower alkyl group", there can, for example, be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-hexyl groups, etc. and as the "lower alkoxy group", there can, for example, be mentioned methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy groups, etc. Further, the "halogen atom" includes fluorine, chlorine, bromine and iodine atoms.
The "heteroaryl group" means an aromatic heterocyclic group containing hetero atom(s) selected from O, S and N, preferably, 5 or 6-membered heterocyclic group containing 1 to 4 hetero atoms, such as thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, triazinyl groups, etc.
The "phenyl group substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group" represented by the symbol B includes a phenyl group substituted with one halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, and there can, for example, be mentioned 2-fluorophenyl, 2-chloro-phenyl, 2-bromophenyl, 3-fluorophenyl, 3-iodophenyl, 4-chlorophenyl, 4-bromophenyl, 2-hydroxyphenyl, 2-methylphenyl, 4-ethylphenyl, 2-methoxyphenyl, 4-ethoxyphenyl groups, etc. Further, the "phenyl group optionally substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group" includes an unsubstituted phenyl group besides the above substituted phenyl groups.
A group of preferred compounds in the invention are compounds of the above formula (I) wherein A represents a hydrogen atom and B represents a phenyl group substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group, or a heteroaryl group, particularly compounds of the above formula (I) wherein B represents a phenyl group substituted with a halogen atom, hydroxyl group, lower alkyl group or lower alkoxy group; a thienyl group; or a pyridyl group.
Another group of preferred compounds are compounds of the above formula (I) wherein A represents --CONH--R.sup.1, --CSNH--R.sup.1, a hydroxym
REFERENCES:
patent: 4816444 (1989-03-01), Pettit et al.
patent: 4978744 (1990-12-01), Pettit et al.
patent: 5410024 (1995-04-01), Pettit et al.
patent: 5635483 (1997-06-01), Pettit et al.
Pettit et al., The Isolation and Structure of a Remarkable Marine Animal Antineoplastic Constituent: Dolastatin 10.sup.1a, J. Am. Chem. Soc., 1987, 109, 6883-6885.
Gondo Masaaki
Ito Takeshi
Kobayashi Motohiro
Miyazaki Koichi
Sakakibara Kyoichi
Borin Michael
Teikoku Hormone Mfg. Co. Ltd.
Tsang Cecilia J.
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