# US 5,346,918 A · Milbemycin ether derivatives, their preparation and their therapeutic and agrochemical uses

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- Number: US 5,346,918 A
- Document ID: US5346918A
- Status: Granted
- Kind: A
- Application number: 07/661,833
- Filed: 1991-02-27
- Granted: 1994-09-13
- Earliest claimed: 1990-03-01
- Assignees: Sankyo Company, Limited
- Inventors: Yasuhiro Morisawa; Akio Saito; Toshimitsu Toyama; Susumu Kaneko
- Web page: https://patentgrep.com/patent/US5346918A

## CPC

- C07D 493/22: in which the condensed system contains four or more hetero rings
- A01N 43/90: having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
- A61P 33/00: Antiparasitic agents
- A61P 33/10: Anthelmintics
- C07H 19/01: sharing oxygen
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Compounds of formula (I): ##STR1## in which: R.sup.1 is a variety of organic groups; R.sup.5 is methyl, ethyl, isopropyl or sec-butyl; and X is hydroxy, alkanoyloxy or hydroxyimino and salts and esters thereof have valuable anthelmintic, acaricidal and insecticidal activities. Methods of preparing the compounds are also provided.

## Claims

### Claim 1

A compound of the formula (I): ##STR28## in which: R.sup.1 represents: a cycloalkyl group having from 4 to 8 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and substituted by a cycloalkyl group having from 3 to 8 carbon atoms, said cycloalkyl group being unsubtituted or having at least one substituent selected from the group consisting of substituents (c); or a group having the following formula: ##STR29## wherein: R.sup.2 represents: a hydrogen atom; a halogen atom; a cyano group; a nitro group; an alkyl group having from 1 to 4 carbon atoms; a substituted alkyl group which has from 1 to 4 carbon atoms and which has at least one substituent selected from the group consisting of substituents (a); an alkoxy group having from 1 to 4 carbon atoms; an alkoxyalkoxy group having a total of from 2 to 6 carbon atoms; or a group having one of the following formulae:
--(CH.sub.2).sub.n NHR.sup.9
--(CH.sub.2).sub.n NR.sup.9 COR.sup.6
--(CH.sub.2).sub.n NR.sup.9 COCOR.sup.6
--(CH.sub.2).sub.n NR.sup.9 COCOOR.sup.7
--(CH.sub.2).sub.n NR.sup.9 CHR.sup.6 NHCOR.sup.6
--(CH.sub.2).sub.n NR.sup.9 CHR.sup.6 NHCONHR.sup.6
--(CH.sub.2).sub.n NR.sup.9 CHR.sup.6 NHCOOR.sup.7
--(CH.sub.2).sub.n NR.sup.9 C(=Y)YR.sup.6
--(Ch.sub.2).sub.n NR.sup.9 C(=Y)NR.sup.6 R.sup.6
--(CH.sub.2).sub.n NR.sup.9 C(=Y)NR.sup.6 NR.sup.6 R.sup.6
--(CH.sub.2).sub.n NR.sup.9 C(=Y)NR.sup.6 NHZ
--(CH.sub.2).sub.n NR.sup.9 C(=NR.sup.10)NHR.sup.10
--(CH.sub.2).sub.n NR.sup.9 C(=NR.sup.10)R.sup.6 or
--(CH.sub.2).sub.n NR.sup.9 SO.sub.m R.sup.6
wherein:
m is 1 or 2;
n is 0, 1 or 2;
R.sup.6 represents a hydrogen atom; an alkyl group having from 1 to 8 carbon atoms; a substituted alkyl group having from 1 to 8 carbon atoms and having at least one substituent selected from the group consisting of substituents (b); an aliphatic hydrocarbon group having from 2 to 8 carbon atoms and having one or two carbon-carbon double or triple bonds; a cycloalkyl group having from 3 to 8 carbon atoms; a substituted cycloalkyl group having from 3 to 8 carbon atoms and having at least one substituent selected from the group consisting of substituents (c); an aryl group which has from 6 to 14 ring carbon atoms and which is unsubstituted or which has at least one substituent selected from the group consisting of substituents (c); an aryloxy group which has from 6 to 14 ring carbon atoms and which is unsubstituted or which has at least one substituent selected from the group consisting of substituents (c); an arylthio group which has from 6 to 14 ring carbon atoms and which is unsubstituted or which has at least one substituent selected from the group consisting of substituents (c); and, where there are two or more groups or atoms represented by R.sup.6, these are the same or different from each other;
R.sup.7 represents an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, or an aralkyl group in which an alkyl group having from 1 to 4 carbon atoms is substituted by from 1 to 3 aryl groups which have from 6 to 10 ring carbon atoms and which have at least one substituent selected from the group consisting of substituents (c);
R.sup.9 represents a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;
R.sup.10 represents any of the groups or atoms defined above for R.sup.6, or it represents a cyano group, a nitro group, a group of formula --COOR.sup.7, wherein R.sup.7 is as defined above, or a group of formula --COR.sup.6, wherein R.sup.6 is as defined above;
Y represents an oxygen atom or a sulfur atom; and, where there are two or more groups represented by Y, these are the same or different from each other;
Z represents a group of formula --COOR.sup.7, wherein R.sup.7 is as defined above, a group of formula --COR.sup.6, wherein R.sup.6 is as defined above, or a group of formula --SO.sub.2 R.sup.6, wherein R.sup.6 is as defined above;
Q represents a methylene group, an ethylene group or a group of formula --OCH.sub.2 --;
R.sup.5 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; and
X represents: a hydroxy group; an alkanoyloxy group which has from 1 to 5 carbon atoms, and which is unsubstituted or has at least one substituent selected from the group consisting of substituents (d); or a hydroxyimino group;
substituents (a):
halogen atomes, alkoxy groups having from 1 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, and alkanoyloxy groups having from 1 to 5 carbon atoms;
substituents (b):
cycloalkyl groups having from 3 to 8 carbon atoms; alkoxy groups having from 1 to 4 carbon atoms; alkylthio groups having from 1 to 4 carbon atoms; cyanoalkylthio groups having from 2 to 5 carbon atoms; alkoxycarbonyl groups having from 2 to 5 carbon atoms; halogen atoms; cyano groups; nitro groups; amino groups; aryl groups which have from 6 to 14 ring carbon atoms and which are unsubstituted or have at least one substitutent selected from the group consisting of substituents (c); aryloxy groups which have from 6 to 14 ring carbon atoms and which are unsubstituted or have at least one substituent selected from the group consisting of substituents (c); and arylthio groups which have from 6 to 14 ring carbon atoms and which are unsubstituted or have at least one substituent selected from the group consisting of substitutents (c);
substituents (c):
alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, alkanoyloxy groups having from 1 to 5 carbon atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms, halogen atoms, cyano groups, nitro groups, amino groups, alkylamino groups in which the alkyl parts has from 1 to 4 carbon atoms, dialkylamino groups in which each alkyl part is independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, carbamoyl groups, alkylcarbamoyl groups in which the alkyl part has from 1 to 4 carbon atoms, dialkylcarbamoyl groups in which each alkyl part is independently selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms, and alkanoylamino groups having from 1 to 5 carbon atoms;
substituents (d):
halogen atoms, alkoxy groups having from 1 to 4 carbon atoms, alkoxycarbonyl groups having from 2 to 5 carbon atoms, and carboxy groups.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R.sup.1 represents a group of formula: ##STR30## wherein R.sup.2 represents a hydrogen atom or a group of formula --NR.sup.9a COR.sup.6a
wherein:
R.sup.9a represents a hydrogen atom or a methyl group;
R.sup.6a represents: a hydrogen atom; an alkyl group having from 1 to 4 carbon atoms; a cycloalkyl group having from 3 to 5 carbon atoms; an alkyl group having from 1 to 3 carbon atoms and substituted with a halogen atom, a cyano group, an alkoxy group having from 1 to 3 carbon atoms, an alkylthio group having from 1 to 3 carbon atoms, a cyanomethylthio group or a phenoxy group; an alkenyl group having from 2 to 4 carbon atoms; a phenyl group; a phenyl group substituted with an alkyl grouup having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom or a nitro group; and
Q represents a methylene group or an ethylene group.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R.sup.1 represents a group of formula: ##STR31## wherein R.sup.2 represents a group of formula:
R.sup.6b --CO--CO--N(R.sup.9a)--
wherein:
R.sup.9a represents a hydrogen atom or a methyl group; and
R.sup.6b represents an alkyl group having from 1 to 4 carbon atoms; a cycloalkyl group having from 3 to 5 carbon atoms; an alkenyl group having from 2 to 4 carbon atoms; a phenyl group; or a phenyl group substituted with an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom or a nitro group.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R.sup.1 represents a group of formula: ##STR32## wherein R.sup.2 represents a group of formula:
R.sup.6c --Y--CY--N(R.sup.9a)--
wherein:
R.sup.9a represents a hydrogen atom or a methyl group;
Y represents an oxygen atom; and
R.sup.6c represents: an alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 4 carbon atoms and substituted with a halogen atom or an alkoxy group having from 1 to 3 carbon atoms; a vinyl group; an allyl group; a benzyl group; a methoxybenzyl group; or a nitrobenzyl group.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R.sup.1 represents a group of formula: ##STR33## wherein R.sup.2 represents a group of formula:
R.sup.6d N(R.sup.6e)--CY--N(R.sup.9a)--
wherein:
R.sup.9a represents a hydrogen atom or a methyl group;
Y represents an oxygen atom or a sulfur atom; and
R.sup.6d and R.sup.6e are the same or different and each represents: a hydrogen atom; an alkyl group having from 1 to 4 carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; a phenyl group; or a phenyl group substituted with an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom or a nitro group.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R.sup.1 represents a group of formula: ##STR34## wherein R.sup.2 represents a group of formula:
R.sup.6h N(R.sup.6g)N(R.sup.6f)--CY--N(R.sup.9a)--
wherein:
R.sup.9a represents a hydrogen atom or a methyl group;
Y represents an oxygen atom; and
R.sup.6f, R.sup.6g and R.sup.6h are the same or different and each represents: a hydrogen atom; an alkyl group having from 1 to 4 carbon atoms; a cycloalkyl group having from 3 to 6 carbon atoms; a phenyl group; or a phenyl group substituted with an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 carbon atoms, a halogen atom or a nitro group.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R.sup.1 represents a group of formula: ##STR35## wherein R.sup.2 represents a group of formula:
R.sup.6r --S(O).sub.m --N(R.sup.9a)--
wherein:
R.sup.9a represents a hydrogen atom or a methyl group;
m is 1 or 2; and
R.sup.6r represents an alkyl group having from 1 to 4 carbon atoms; an alkyl group having from 1 to 3 carbon atoms group and substituted with a cyano group; a phenyl group; or a phenyl group substituted with an alkyl group having from 1 to 3 carbon atoms, an alkoxy group having from 1 to 3 to carbon atoms, a halogen atom or a nitro group.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R.sup.5 represents an ethyl group.

### Claim 9 (depends on 1)

The compound of claim 1, wherein X represents a hydroxy group.

### Claim 10 (depends on 1)

The compound of claim 1, selected from the group consisting of:
13-(5-ethoxycarbonylamino-2-indanyloxy)milbemycin A.sub.4 and
13-[5-(3-methylureido)-2-indanyloxy]milbemycin A.sub.4
and salts thereof.

### Claim 11 (depends on 1)

The compound of claim 1, selected from the group consisting of 13-[5-(3-methylureido)-2-indanyloxy]milbemycin A.sub.4.

### Claim 12 (depends on 1)

An anthelmintic, acaricidal and insecticidal composition comprising an anthelmintic, acaricidal and insecticidal compound in admixture with a pharmaceutically, argiculturally, veterinarily or horticulturally acceptable carrier or diluent, wherein said compound is selected from the group consisting of the compounds of formula (I) as defined in claim 1.

### Claim 13 (depends on 12)

The composition of claim 12, wherein said compound is selected from the group consisting of:
13-(5-ethoxycarbonylamino-2-indanyloxy)milbemycin A.sub.4 and
13-[5-(3-methylureido)-2-indanyloxy]milbemycin A.sub.4
and salts thereof.

### Claim 14 (depends on 1)

A method of treating an animal parasitized by a parasite selected from the group consisting of helminths, acarids and insects by administering thereto at least one compound selected from the group consisting of compounds of the formula (I) as defined in claim 1.

### Claim 15 (depends on 14)

The method of claim 14, wherein said compound is selected from the group consisting of:
13-(5-ethoxycarbonylamino-2-indanyloxy)milbemycin A.sub.4 and
13-[5-(3-methylureido)-2-indanyloxy]milbemycin A.sub.4
and salts thereof.

### Claim 16 (depends on 1)

A method of protecting animals or plants from damage by parasites selected from the group consisting of acarids, helminths and insects, which comprises applying an active compound to said animals, to said plants or to seeds of said plants or to a locus including said animals, plants or seeds, wherein the active compound is selected from the group consisting of at least one compound of formula (I) and as defined in claim 1.

### Claim 17 (depends on 16)

The method of claim 16, wherein said compound is selected from the group consisting of:
13-(5-ethoxycarbonylamino-2-indanyloxy)milbemycin A.sub.4 and
13-[5-(3-methylureido)-2-indanyloxy]milbemycin A.sub.4
and salts thereof.