US 4,399,282 A · Camptothecin derivatives

Abstract

New camptothecin derivatives possessing either or both of high anti-tumor activity and slight toxicity, represented by the general formula: ##STR1## wherein X is H, CH.sub.2 OH, COOH, an alkyl group, an aralkyl group or the grouping CH.sub.2 OR.sup.1 or COOR.sup.2 wherein R.sup.1 is an alkyl group or an acyl group and R.sup.2 is a lower alkyl group, Y is H, OH or the grouping OR.sup.3 wherein R.sup.3 is a lower alkyl group or an acyl group, and Z is H or an acyl group, with the proviso that when X is CH.sub.2 OH, an alkyl group or an aralkyl group, both Y and Z are H, that when X is the grouping CH.sub.2 OR.sup.1 or COOR.sup.2, Y is H, that when Y is OH, both X and Z are H, and that when Y is the grouping OR.sup.3, X is H, and water-soluble alkali metal salts thereof. These camptothecin derivatives are prepared by treating camptothecin with sulfuric acid and a persulfate or with sulfuric acid and a peroxide, if necessary, with an organic compound corresponding to the organic moiety of the substituent to be introduced directly into camptothecin, in an aqueous medium in the presence or absence of a transition metal ion, and optionally treating the resultant products, if necessary, after oxidation of the introduced substituent, with an alkylating agent or an acylating agent.

Claims40

Dependent claims

A camptothecin derivative of the formula:

##STR9## wherein X is H, CH.sub.2 OH, COOH, a straight or branched chain alkyl group with 1-18 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, or the group CH.sub.2 OCOR.sup.1 or COOR.sup.2 where R.sup.1 is a straight or branched chain alkyl group with 1-17 carbon atoms, trifluoromethyl, phenyl, a phenylalkyl group having 1 to 2 carbon atoms in the alkylene portion thereof or the group HOOC--(CH.sub.2).sub.n where n is an integer of 2 to 4 and where R.sup.2 is a lower alkyl group;
Y is H, OH or OR.sup.3, where R.sup.3 is a lower alkyl group, an alkanoyl group with 1-5 carbon atoms, benzoyl or a phenylalkanoyl group with 1-2 carbon atoms in the alkylene portion thereof;
and Z is H, acetyl or trifluoroacetyl;
with the proviso (1) that when X is CH.sub.2 OH, the straight or branched alkyl group, the cycloalkyl group or the phenylalkyl group, both Y and Z are H, (2) that when X is CH.sub.2 OCOR.sup.1 or COOR.sup.2, Y is H, (3) that when Y is OH, both X and Z are H, and (4) that when Y is OR.sup.3, X is H;
or a water-soluble alkali metal salt thereof.

2 more elements

A process for the preparation of a camptothecin derivative of the formula:

##STR10## wherein X' is the group COOR.sup.4 or CH.sub.2 OR where R.sup.4 is H, lower alkyl or benzyl and R is H or R'CO where R' is a straight or branched chain alkyl group with 1-17 carbon atoms, trifluoromethyl, phenyl, a phenylalkyl group having 1 to 2 carbon atoms in the alkylene portion thereof or the group HOOC(CH.sub.2).sub.n where n is an integer of 2 to 4, and Z is H, acetyl or trifluoroacetyl, or a water-soluble alkali metal salt thereof, which comprises subjecting camptothecin to a radical reaction with a hydroxymethyl compound of the general formula:
A--CH.sub.2 OH (II)
wherein A is H, COOH or CH.sub.2 OH, by the aid of sulfuric acid and an inorganic or organic peroxide in an aqueous medium, the inorganic and organic peroxide being selected from the group consisting of hydrogen peroxide, persulfuric acid and ammonium and alkali metal salts thereof, Caro's acid and alkali metal salts thereof, alkali metal and alkaline earth metal peroxides, tert-butyl hydroperoxide, benzoyl peroxide and dialkanoyl peroxides.

A process for the preparation of a camptothecin derivative of the formula:

##STR11## wherein X"' is a straight or branched chain alkyl group with 1-18 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, or the group --COOR.sup.4 where R.sup.4 is H or a lower alkyl group, or a water-soluble alkali metal salt thereof, which comprises subjecting camptothecin to a radical reaction with an organic compound of the general formula:
X"--Q (II')
wherein Q is --CH.sub.2 OH, --COOH, --CHO, --COX" or ##STR12## and X" is a straight or branched chain alkyl group with 1-10 carbon atoms, a cycloalkyl group with 5-7 carbon atoms, or a phenylalkyl group having 1 to 3 carbon atoms in the alkylene portion thereof, by the aid of sulfuric acid and an inorganic or organic peroxide in an aqueous medium in the presence of a transition metal ion supplied in the medium from a transition metal salt selected from the group consisting of silver, iron (II), copper, cobat, nickel, lead, mercury, cadmium, thallium and zinc salts in the form of halides, carbonates, nitrates, sulfates and acetates, the inorganic or organic peroxide being selected from the group consisting of hydrogen peroxide, persulfuric acid and ammonium and alkali metal salts thereof, Caro's acid and alkali metal salts thereof, alkali metal and alkaline earth metal peroxides, tert-butyl hydroperoxide, benzoyl peroxide and dialkanoyl peroxides.

Dependencies are inferred from the claim text.

Camptothecin derivatives

Life of this patent

Camptothecin derivatives

Life of this patent

Abstract

Claims40