# US 5,352,689 A · Rhizoxin derivatives and their use as anti-tumor agents

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- Number: US 5,352,689 A
- Document ID: US5352689A
- Status: Granted
- Kind: A
- Application number: 08/128,046
- Filed: 1993-09-27
- Granted: 1994-10-04
- Earliest claimed: 1988-07-06
- Assignees: Sankyo Company, Limited
- Inventors: Masakatsu Kaneko; Makoto Kamokari; Tomowo Kobayashi; Kazuhiko Sasagawa
- Web page: https://patentgrep.com/patent/US5352689A

## CPC

- C07D 493/18: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Rhizoxin and rhizoxin-2-ene derivatives of formula ##STR1## in which: n is 1 to 25; A is an extra bond or oxygen, X is oxygen, sulfur, nitrogen or carbonyl; and R is hydrogen, carboxylic acyl having from 1 to 25 carbon atoms, alkoxycarbonyl group having from 2 to 26 carbon atoms, phosphono, alkylphosphono group in which the alkyl part has from 1 to 25 carbon atoms, dialkylphosphono group in which each alkyl part has from 1 to 25 carbon atoms, alkyl group having from 1 to 25 carbon atoms, aralkyl, cycloalkyl, heterocyclic, alkylthio group in which the alkyl part has from 1 to 25 carbon atoms, aralkylthio, or heterocyclylthio, or when X represents a nitrogen atom, R is R.sup.1 and R.sup.2, where R.sup.1 and R.sup.2 are hydrogen, alkyl, acyl, alkoxycarbonyl, phosphono, alkylphosphono or dialkylphosphono, have valuable anti-tumor activity. They may be prepared by acylation of rhizoxin or rhizoxin-2-ene.

## Claims

### Claim 1

A compound of the formula (I): ##STR13## in which: n represents an integer of from 1 to 25,
A represents an oxygen atom,
X represents a sulfur atom or NR and
when X represents a sulfur atom,
R represents a hydrogen atom; an aliphatic carboxylic acyl group having from 1 to 25 carbon atoms, which group is unsubstituted or has at least one substituent selected from the group consisting of substituents (a), defined below; an alkoxycarbonyl group in which the alkoxy part has from 1 to 25 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a), defined below; an alkylthio group in which the alkyl part has from 1 to 25 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a), defined below; or a benzylthio group;
when X represents NR,
R is independently selected from the group consisting of R.sup.1 and R.sup.2, where R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen atoms, alkyl groups, aliphatic carboxylic acyl groups, alkoxycarbonyl groups, in which said acyl and alkyl groups and the alkyl part of said alkoxycarbonyl has from 1 to 25 carbon atoms and is unsubstituted or has at least one substituent (a) selected from the group consisting of
a halogen atom, a carboxy group, a hydroxy group, a group of the formula --COO--Rhz, where Rhz is as defined below, a 2,4-dicyclohexylallophanyl group, a phenyl group, a nitrophenyl group, and a cyanophenyl group;
RhZ represents a group of the formula (II): ##STR14## and a ring-opened acid corresponding to said compound of formula (I) and salts and esters of said acid.

### Claim 2 (depends on 1)

The compound of claim 1, wherein n is an integer from 1 to 20.

### Claim 3 (depends on 1, 2, 4)

The compound of claim 1, wherein X represents NR and R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen atoms; C.sub.1 -C.sub.10 alkyl groups; C.sub.2 -C.sub.24 aliphatic carboxylic acyl groups; alkoxycarbonyl groups in which the alkoxy part has from 2 to 20 carbon atoms in which said acyl and alkyl groups and the alkyl part of said alkoxycarbonyl is unsubstituted or have at least one substituent (a.sup.1) selected from the group consisting of halogen atoms, hydroxy groups, groups of formula --COO--Rhz, where Rhz is as defined in claim 1, 2,4-dicyclohexylallophanyl groups and phenyl groups which are unsubstituted or have at least one substituent selected from the group consisting of nitro and cyano groups.

### Claim 4 (depends on 1)

The compound of claim 1, wherein n is an integer from 2 to 15.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X represents NR and R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen atoms; C.sub.1 -C.sub.6 alkyl groups; C.sub.2 -C.sub.16 aliphatic carboxylic acyl groups; alkoxycarbonyl groups in which the alkoxy part has from 2 to 6 carbon atoms in which said acyl and alkyl groups and the alkyl part of said alkoxycarbonyl are unsubstituted or have at least one substituent (a.sup.2) selected from the group consisting of halogen atoms, hydroxy groups, groups of formula --COO-Rhz, where Rhz is as defined in claim 1 below, and 2,4-dicyclohexylallophanyl groups.

### Claim 6 (depends on 1)

The compound of claim 1, wherein n is an integer from 2 to 11.

### Claim 7 (depends on 1)

The compound of claim 1, wherein X represents NR and R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen atoms; C.sub.1 -C.sub.4 alkyl groups; C.sub.2 -C.sub.16 aliphatic carboxylic acyl groups; alkoxycarbonyl groups in which the alkoxy part has from 2 to 6 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a.sup.3), defined below; substituents (a.sup.3): halogen atoms, groups of formula -COO-Rhz, where Rhz is as defined in claim 1, and 2,4-dicyclohexylallophanyl groups.

### Claim 8 (depends on 1)

The compound of claim 1, wherein: X represents NR and R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen atoms; C.sub.1 -C.sub.4 alkyl groups; C.sub.2 -C.sub.16 aliphatic carboxylic acyl groups; alkoxycarbonyl groups in which the alkoxy part has from 2 to 6 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a.sup.3), defined below; substituents (a.sup.3): halogen atoms, groups of formula --COO-Rhz, where Rhz is as defined in claim 1, and 2,4-dicyclohexylallophanyl groups.

### Claim 9 (depends on 1)

The compound of claim 1, wherein:
X represents a carboxy group and R represents a C.sub.8 -C.sub.14 alkoxy group.

### Claim 10

Rhizoxin-13-yl 12-hydroxydodecanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 11

Rhizoxin-13-yl 12-propionyloxydodecanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 12

Rhizoxin-13-yl 12-valeryloxydodecanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 13 (depends on 1)

The compound of claim 1 selected from the group consisting of rhizoxin-13-yl 3-(benzyldithio)propionate and pharmaceutically acceptable salts and esters thereof.

### Claim 14 (depends on 1)

The compound of claim 1, selected from the group consisting of dirhizoxin-13-yl 3,3'-dithiodipropionate and pharmaceutically acceptable salts and esters thereof.

### Claim 15 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 3-(lauroylthio)propionate and pharmaceutically acceptable salts and esters thereof.

### Claim 16 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 3-aminopropionate and pharmaceutically acceptable salts and esters thereof.

### Claim 17 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 3-(decanoylamino)propionate and pharmaceutically acceptable salts and esters thereof.

### Claim 18 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 6-aminohexanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 19 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 6-(2,2,2-trichloroethoxycarbonylamino)hexanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 20 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 6-undecanoylaminohexanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 21 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 12-aminododecanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 22 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 12-valeramidododecanoate and pharmaceutically acceptable salts and esters thereof.

### Claim 23 (depends on 1)

The compound of claim 1, selected from the group consisting of rhizoxin-13-yl 3-[2-(2,4-dicyclohexylallophanyl)ethyldithio]propionate and pharmaceutically acceptable salts and esters thereof.

### Claim 24 (depends on 1, 2, 4)

The compound of claim 1, wherein X represents a sulfur atom and R represents: a hydrogen atom; an alkoxycarbonyl group in which the alkoxy part has from 1 to 20 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a.sup.1), defined below; an alkylthio group in which the alkyl part has from 1 to 10 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a.sup.1), defined below or a benzylthio group;
substituents (a.sup.1):
halogen atoms, hydroxy groups, groups of formula -COO-Rhz, where Rhz is as in claim 1, 2,4-dicyclohexylallophanyl groups and phenyl groups which are unsubstituted or have at least one substituent selected from the group consisting of nitro and cyano groups.

### Claim 25 (depends on 1)

The compound of claim 1, wherein X represents a sulfur atom and R represents: a hydrogen atom an alkoxycarbonyl group in which the alkoxy part has from 1 to 10 carbon atoms; an alkylthio group in which the alkyl part has from 1 to 6 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a.sup.2), defined below; or a benzylthio group;
substituents (a.sup.2):
halogen atoms, hydroxy groups, groups of formula -COO-Rhz, where Rhz is as defined in Claim 1, and 2,4-dicylclohexylallophanyl groups.

### Claim 26 (depends on 1)

The compound of claim 1, wherein X represents a sulfur atom and R represents: a hydrogen atom; an alkoxycarbonyl group in which the alkoxy part has from 1 to 10 carbon atoms; or an alkylthio group in which the alkyl part has from 1 to 6 carbon atoms and is unsubstituted or has at least one substituent selected from the group consisting of substituents (a.sup.3), defined below;
substituents (a.sup.3):
halogen atoms, groups of formula -COO-Rhz, where Rhz is as defined in claim 1, and 2,4-dicyclohexylallophanyl groups.

### Claim 27 (depends on 1)

The compound of claim 1, wherein X is a sulfur atom or NR and R is an acyl group selected from the group consisting of acetyl, propionyl, butyryl, iso-butyryl, 2-methylpropionyl, pentanoyl, 2-methylbutyryl, pivaloyl, hexanoyl, 2-methylpentanoyl, 3-methylpentanoyl, 4-methylpentanoyl, heptanoyl, 2-methylhexanoyl, 3-ethylhexanoyl, octanoyl, 2-methylheptanoyl, 3-ethylheptanoyl, 2-ethyl-3-methylpentanoyl, 3-ethyl-2-methylpentanoyl, nonanoyl, 2-methyloctanoyl, 7-methyloctanoyl, 4-ethylheptanoyl, 3-ethyl-2-methylhexanoyl, 2-ethyl-1-methylhexyl, 2-methylnonanoyl, 8-methylnonanoyl, 5-ethyloctanoyl, 3-ethyl-2-methylheptanoyl, 3,3-diethylhexanoyl, undecenoyl, 2-methyldecenoyl, 9-methyldecenoyl, 4-ethylnonanoyl, 3,5-dimethylnonanoyl, 3-propyloctanoyl, 5-ethyl-4-methyloctanoyl, dodecanoyl, 1-methylundecanoyl, 10-methylundecanoyl, 3-ethyldecenoyl, 5-propylnonyl, 3,5-diethyloctanoyl, tridecanoyl, 11-methyldodecanoyl, 7-ethylundecenoyl, 4-propyldecenoyl, 5-ethyl-3-methyldecenoyl, 3-pentyloctanoyl, tetradecyl, 12-methyltridecanoyl, 8-ethyldodecyl, 6-propylundecyl, 4-butyldecenoyl, 2-pentylnonanoyl, pentadecanoyl, 13-methyltetradecenoyl, 10-ethyltridecenoyl, 7-propyldodecanoyl, 5-ethyl-3-methyldodecanoyl, 4-pentyldecanoyl, hexadecanoyl, 14-methylpentadecanoyl, 6-ethyltetradecanoyl, 4-propyltridecanoyl, 2-butyldodecanoyl, n-heptadecanoyl, 15-methylhexadecanoyl, 7-ethylpentadecanoyl, 3-propyltetradecanoyl, 5-pentyldodecanoyl, octadecanoyl, 16-methylheptadecanoyl, 5-propylpentadecanoyl, nonadecanoyl, 17-methyloctadecanoyl, 4-ethylheptadecanoyl, icosanoyl, 18-methylnonadecanoyl, 3-ethyloctadecanoyl, henicosanoyl, docosanoyl, tricosanoyl, tetracosanoyl and pentacosanoyl.

### Claim 28 (depends on 1)

The compound of claim 1, wherein X is a sulfur atom and R is a hydrogen atom.

### Claim 29 (depends on 1)

A pharmaceutical composition comprising an effective anti-tumor amount of an anti-tumor agent in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anti-tumor agent is at least one compound selected from the group consisting of compounds of formula (I), ring-opened acids corresponding to said compounds of formula (I) and pharmaceutically acceptable salts and esters of said ring-opened acids, as defined in claim 1.

### Claim 30 (depends on 29)

The composition of claim 29, wherein said anti-tumor agent is selected from the group consisting of:
rhizoxin-13-yl 12-hydroxydodecanoate;
rhizoxin-13-yl 12-propionyloxydodecanoate;
rhizoxin-13-yl 12-valeryloxydodecanoate;
rhizoxin-13-yl 3-(benzyldithio)propionate;
dirhizoxin-13-yl 3,3'-dithiodipropionate;
rhizoxin-13-yl 3-(lauroylthio)propionate;
rhizoxin-13-yl 3-aminopropionate;
rhizoxin-13-yl 3-(decanoylamino)propionate;
rhizoxin-13-yl 6-aminohexanoate;
rhizoxin-13-yl 6-(2,2,2-trichloroethoxycarbonylamino)hexanoate;
rhizoxin-13-yl 6-undecanoylaminohexanoate;
rhizoxin-13-yl 12-aminododecanoate;
rhizoxin-13-yl 12-valeramidododecanoate;
rhizoxin-13-yl 3-propionate;
and pharmaceutically acceptable salts and esters thereof.

### Claim 31 (depends on 1)

A method of treating an animal suffering from tumors, by administering thereto an effective anti-tumor amount of an anti-tumor agent, wherein said anti-tumor agent is at least one compound selected from the group consisting of compounds of formula (I), ring-opened acids corresponding to said compounds of formula (I) and pharmaceutically acceptable salts and esters of said ring-opened acids, as defined in claim 1.

### Claim 32 (depends on 31)

The method of claim 31, wherein said anti-tumor agent is selected from the group consisting of:
rhizoxin-13-yl 12-hydroxydodecanoate;
rhizoxin-13-yl 12-propionyloxydodecanoate;
rhizoxin-13-yl 12-valeryloxydodecanoate;
rhizoxin-13-yl 3-(benzyldithio)propionate;
dirhizoxin-13-yl 3,3'-dithiodipropionate;
rhizoxin-13-yl 3-(lauroylthio)propionate;
rhizoxin-13-yl 3-aminopropionate;
rhizoxin-13-yl 3-(decanoylamino)propionate;
rhizoxin-13-yl 6-aminohexanoate;
rhizoxin-13-yl 6-(2,2,2-trichloroethoxycarbonylamino)hexanoate;
rhizoxin-13-yl 6-undecanoylaminohexanoate;
rhizoxin-13-yl 12-aminododecanoate;
rhizoxin-13-yl 12-valeramidododecanoate;
rhizoxin-13-yl 3-propionate;
and pharmaceutically acceptable salts and esters thereof.