Kabushiki Kaisha Yakult Honsha

Kenichiro Nokata

Tadashi Miyasaka

Seigo Sawada

Masahiko Mutai

Takashi Yaegashi

Kenichi Tezuka

Satoru Okajima

Teruo Yokokura

Hiroshi Nagata

Hisao Hagiwara

Eiichi Sugino

Hisako Nagai

New campotothecin derivatives and a process for preparing same are disclosed, which are represented by the general formula: ##STR1## wherein R.sup.1 represents a lower alkyl group, R.sup.2 represents a hydrogen atom or an amino, hydroxyl, lower acylamino or lower alkoxy group, R.sup.3 represents a hydrogen or halogen atom or a lower alkyl, hydroxyl, lower alkoxy, nitro, amino, cyano or di(lower alkyl)amino group, R.sup.4 represents a hydrogen or halogen atom or a lower alkyl, hydroxyl, lower alkoxy, lower alkylthio, amino, cyano or di(lower alkyl)amino group, and R.sup.5 represents a hydrogen or halogen atom or a hydroxyl or lower alkoxy group, with the proviso that all of the R.sup.2, R.sup.3, R.sup.4 and R.sup.5 substituents should not be a hydrogen atom and also that if any one of the R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is a hydroxyl or lower alkoxy group, all of the other three substituents should not be a hydrogen atom.

Camptothecin derivatives

New camptothecin derivatives, useful as antitumor agents or intermediates therefor, of the general formula (I) ##STR1## wherein X is a lower alkyl group, and R is a hydrogen atom or the grouping -COY where Y is a linear or branched unsubstituted C.sub.1 -C.sub.18 alkyl group; a lower alkyl group substituted by a halogen atom or a lower alkylthio, amino, acylamino, hydroxyl, lower alkoxy, aryloxy or lower alkoxycarbonyl group; a C.sub.3 -C.sub.19 alkenyl, C.sub.3 -C.sub.19 alkynyl or C.sub.3 -C.sub.8 cycloalkyl group; a C.sub.3 -C.sub.8 cycloalkyl group substituted by an acylamino-lower alkyl group; an N-acylpyrrolidyl group; a phenyl group; a phenyl group substituted by a halogen atom or a trifluoromethyl, nitro, amino, lower alkoxycarbonyl, lower alkyl, phenyl or lower alkoxy; a cinnamyl group; a benzyl group; a naphthyl group; a pyridyl group; a furyl group; or a thienyl group, as well as acid addition salts and quaternary ammonium salts thereof, and a process for preparing the new camptothecin derivatives by subjecting 7-ethylcamptothecin to the treatment with an N-di-X-ethylenediamine followed by acylation.

New camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R.sup.1 is a hydrogen atom, a halogen atom or an alkyl group with 1-4 carbon atoms and X is a chlorine atom or --NR.sup.2 R.sup.3 where R.sup.2 and R.sup.3 are the same or different and each represents a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted carbocyclic or heterocyclic group, with the proviso that when both R.sup.2 and R.sup.3 are the substituted or unsubstituted alkyl groups, they may be combined together with the nitrogen atom, to which they are bonded, to form a heterocyclic ring which may be interrupted with --O--, --S-- and/or &gt;N--R.sup.4 in which R.sup.4 is a hydrogen atom, a substituted or unsubstituted alkyl group with 1-4 carbon atoms or a substituted or unsubstituted phenyl group and wherein the grouping --O--CO--X is bonded to a carbon atom located in any of the 9-, 10- and 11-positions in the ring A of camptothecin, as well as an ammonium salt or an alkali metal salt thereof. These new camptothecin derivatives are prepared by reacting a 7-R.sup.1 -camptothecin derivative having a hydroxyl group in any of the 9-, 10- and 11-positions on the ring A thereof with phosgen and then reacting, if necessary, the resultant 7-R.sup.1 -camptothecin derivative having a chlorocarbonyloxy group in the same position on the ring A thereof with an amine HNR.sup.2 R.sup.3 or by reacting a 7-R.sup.1 -camptothecin derivative having a hydroxyl group in any of the 9-, 10- and 11-positions on the ring A thereof with a carbamoyl chloride Cl-CONR.sup.2 R.sup.3.

Camptothecin derivatives and process for preparing same

New Camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R.sup.1 stands for a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group, R.sup.2 for a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, a carboxymethyl group or an acyloxymethyl group, and R.sup.3 for the grouping --XR' (where R' is a hydrogen atom, an alkyl group or an acyl group and X is an oxygen atom or a sulfur atom), a nitro group, an amino group, an alkylamino group, an acylamino group or a halogen atom, with the proviso that when both of R.sup.1 and R.sup.2 are hydrogen atoms, R.sup.3 should not be hydroxyl group, methoxy group or acetoxy group. These new camptothecin derivatives are prepared by treating a 5-R.sup.1 -7-R.sup.2 camptothecin derivative with a peroxidant and then reacting the resultant 5-R.sup.1 -7-R.sup.2 -camptothecin-1-oxide with an active hydrogen compound under irradiation of UV-rays or by catalytically hydrogenating the ring B of camptothecin in a solvent, treating the resultant tetrahydro product with an acylating agent, introducing nitro group into 10-position of the acylated product by the reaction with nitric acid, splitting off the acyl group in the 10-nitro product by hydrolysis and treating the hydrolyzed tetrahydro product with an oxidizing agent for dehydrogenation, and if desired, reducing the nitro group in the resultant product to amino group and modifying the amino group by N-alkylation, N-acylation or by diazotization followed by hydrolysis or Sandmeyer reaction, before or after the oxidation of the 10-nitro-tetrahydro product.

Photochemical process for preparing camptothecin derivatives

New 5- and/or 7-substituted camptothecin-1-oxide derivatives possessing anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group and R' is a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, an acyloxymethyl group or a carboxymethyl group, with the proviso that both of R and R' should not be hydrogen atoms. These 5- and/or 7-substituted camptothecin-1-oxide derivatives are prepared by treating the corresponding 5- and/or 7-substituted camptothecins with a peroxidant as an N-oxidizing reagent.

Camptothecin-1-oxide derivatives

New Camptothecin derivatives possessing high anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R.sup.1 is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxy group or an acyloxy group, R.sup.2 for a hydrogen atom, an alkyl group, an aralkyl group, a hydroxymethyl group, a carboxymethyl group or an acyloxymethyl group, and R.sup.3 is the grouping --XR' (where R' is a hydrogen atom, an alkyl group or an acyl group and X is an oxygen atom or a sulfur atom), a nitro group, an amino group, an alkylamino group, an acylamino group or a halogen atom, with the proviso that when both of R.sup.1 and R.sup.2 are hydrogen atoms, R.sup.3 should not be a hydroxyl group, methoxy group or acetoxy group. These new camptothecin derivatives are prepared by treating a 5-R.sup.1 -7-R.sup.2 -camptothecin derivative with a peroxidant and then reacting the resultant 5-R.sup.1 -7-R.sup.2 -camptothecin-1-oxide with an active hydrogen compound under irradiation of UV-rays or by catalytically hydrogenating the ring B of camptothecin in a solvent, treating the resultant tetrahydro product with an acylating agent, introducing a nitro group into the 10-position of the acylated product by the reaction with nitric acid, splitting off the acyl group in the 10-nitro product by hydrolysis and treating the hydrolyzed tetrahydro product with an oxidizing agent for dehydrogenation, and if desired, reducing the nitro group in the resulting product to an amino group and modifying the amino group by N-alkylation, N-acylation or by diazotization followed by hydrolysis or the Sandmeyer reaction, before or after the oxidation of the 10-nitro-tetrahydro product.

New 7-substituted camptothecin derivatives possessing anti-tumor activity with slight toxicity, represented by the general formula: ##STR1## wherein R stands for --CHO, --CH.sub.2 OR', --CH(OR').sub.2 or --CH.dbd.N--X where R' is a lower alkyl group with 1-6 carbon atoms or a phenylalkyl group with 1-3 carbon atoms in the alkylene moiety thereof, and X is a hydroxyl group or --NR.sup.1 R.sup.2 where R.sup.1 and R.sup.2 are the same or different and each represents a hydrogen atom or a lower alkyl group with 1-6 carbon atoms, or when R.sup.1 is hydrogen, R.sup.2 may be a lower alkyl group with 1-6 carbon atoms, a substituted or unsubstituted aryl group, a carbamoyl group, an acyl group, an aminoalkyl group or an amidino group, or when R.sup.1 is the lower alkyl group, R.sup.2 may be an aminoalkyl group, or R.sup.1 and R.sup.2 may be combined together with the nitrogen atom, to which R.sup.1 and R.sup.2 are bound, to form a heterocyclic group, and quaternary salts thereof. These 7-substituted camptothecin derivatives are prepared by treating 7-hydroxymethyl- or 7-dialkoxymethyl-camptothecin with a catinoid reagent, or treating 7-formyl- or 7-hydroxymethyl-camptothecin with an acid in the presence of a lower alkanol or phenylalkanol, or treating 7-formylcamptothecin or an acetal thereof with a nitrogen-containing carbonyl reagent and optionally treating the resulting product with a quaternating agent.

7-Substituted camptothecin derivatives

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.

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Tokyo, Japan

Kenichiro Nokata