Mitomycin derivatives

Details Mitomycin derivatives Mitomycin derivatives

1988-10-31

1992-04-07

Rizzo, Nicholas S.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D48704, A61K 3140

Patent

active

051030187

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to mitomycin derivatives having anti-tumour activity and pharmaceutical compositions containing the same.


BACKGROUND ART

Mitomycins have excellent anti-tumour activity, whilst they are liable to exhibit certain undesired side effects such as the decrease of leucocytes. Thus, attempts have been made to provide various mitomycin derivatives to increase anti-tumour activity and/or to decrease toxicity.
The known mitomycin derivatives include mitomycin C derivatives and porfiromycin derivatives, which contain a substituted 7-amino group, disclosed, for example, in U.S. Pat. No. 4,268,676; Japanese laid open Patent Applications 92288/81 and 188590/82; Journal of Medicinal Chemistry, 24, 975-981 (1981); ibid., 26, 16-20 (1983) and ibid., 26, 1453-1457 (1983)]. These prior art literatures disclose that mitomycin derivatives containing a substituted amino group at the 7th position exhibit anti-tumour activity in the living body.
Among various mitomycin derivatives containing a substituted 7-amino group, those having a 7-amino group substituted with a sulphur atom are exemplified by the mitomycin derivatives containing at the 7th position 2-thiazolamino group, 2-thienylmethylamino group and (4-sulfonamidophenyl)methylamino group (disclosed in Japanese laid open Patent Application 92288/81), 2-mercaptoethylamino group, 2-ethylthioethylamino group, thiomorpholino group, thiazolidinyl group, 4-mercaptoanilino group, 2-(4-methylthiazolyl)amino group, 2-(5-methyl-1,3,4-thiadiazolyl)amino group and 4-(2,1,3-benzothiadiazolyl)amino group (disclosed in Japanese laid open Patent Application 188590/82).
Examples of the known mitomycin derivatives containing at the 7th position a substituent of the formula: 7-N-propyldithioethylmitomycin C, 7-N-methoxycarbonylmethyldithioethylmitomycin C and 7-N-[2-(2-hydroxyethyldithio)ethyl]mitomycin C (disclosed, for example, in EP0116208A1 and Japanese laid open Patent Application 175493/84). Those, of which R contains an aromatic ring having a substituent, are exemplified by 7-N-[2-(4-acetamidophenyldithio)ethyl]mitomycin C (disclosed in EP 0116208A1 and Japanese laid open Patent Application 175493/84) and 7-N-[2-(4-fluorophenyldithio)ethyl]mitomycin C (disclosed in EP 0163550A2 and Japanese laid open Patent Application 255789/75). Those, of which R contains a structural component of an amino acid having a thiol group or a peptide having the foregoing amino acid are exemplified by 7-N-[2-[(L-cystein-S-yl)thio]ethyl]mitomycin D and 7-N-[2-[(glycino-L-cystein-S-yl)thio]ethyl]mitomycin C, etc. (disclosed in EP0163550A2 and Japanese laid open Patent Application 255789/85 etc.)
Mitomycin derivatives containing at the 7th position a substituent of the formula: 7'-N'-dithiodiethylenedimitomycin D, 7-N-[2-(2-aminoethyl)dithioethyl]mitomycin C, 7-N-[2-(2-aminoethyl)dithioethyl]mitomycin D (disclosed in EP 0116208A1, Japanese laid open Patent Applications 104386/84 and 175493/84) etc.
Derivatives of mitomycin C containing the 7th position ##STR1## in which R is exemplified by ##STR2## (disclosed in Japanese laid open Patent Application 205382/84). However, in the executional examples, only the derivatives of mitomycin C and la-acetylmitomycin C, both containing at the 7th position ##STR3## are disclosed, and other compounds and their physico-chemical characteristics and anti-tumour effects are not disclosed.
An object of the present invention is to provide mitomycin derivatives containing a substituted amino group at the 7th position having higher anti-tumour activity, lower side effects and/or higher solubility which is desirable in pharmaceutical preparation and anti-tumour compositions containing the same.


DISCLOSURE OF THE INVENTION

The present invention provides mitomycin derivatives represented by the following formula (I): ##STR4## wherein X' and X" each independently represents hydrogen or lower alkyl; when Z is hydrogen, Y is methyl; represents hydrogen; which OH of the carboxyl group has been removed, lower alkanoyl and halogen-substit

REFERENCES:
patent: 4927943 (1990-05-01), Vyas et al.

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