13-Halomilbemycin derivatives, their preparation and compositions containing them

Claim 2

A milbemycin compound of formula (I): ##STR5## in which: R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; X represents a halogen atom; and Y represents an oxygen atom or a group of formula ═N--OR 2 , wherein R2 represents a hyrogen atom, a C 1 -C 6 alkyl group, a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents or a group of formula --CH 2 COOR 3 , in which R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group; and, when R 2 represents a hydrogen atom, a salt or ester thereof.

Claim 3

A compound as claimed in claim 1, wherein X represents a chlorine or fluorine atom.

Claim 4

A compound as claimed in claim 1, wherein Y represents a group of formula ═N--OH.

Claim 5

A compound as claimed in claim 1, wherein: X represents a chlorine or fluorine atom; and Y represents a group of formula ═N--OH.

Claim 6

A milbemycin compound of formula (Ia): ##STR6## wherein: R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; X represents a halogen atom; and R 2a represents: a group of formula --COR 4 , in which R 4 represents a C 1 -C 20 alkyl group, a C 2 -C 20 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents, a phenyl group, a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl, halogen, nitro, carboxy and C 2 -C 7 alkoxycarbonyl substituents or a group of formula --(CH 2 ) n COOR 5 , wherein n is an integer from 1 to 3 and R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group; a group of formula --CZ.NR 6 R 7 , wherein R 6 and R 7 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a phenyl group or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen and Z represents an oxygen or sulfur atom; a group of formula --COOR 8 , wherein R 8 represents: a C 1 -C 6 alkyl group; a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents; a phenyl group; a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; a group of formula --CH 2 (--O--CO) m --B where m is 0 or 1 and B represents an oxygen-containing heterocyclic group having 5 or 6 ring atoms or said heterocyclic group having at least one C 1 -C 4 alkyl substituent; or a group derived by removing an omega-hydroxy group from a sugar alcohol selected from the group consisting of glycerol, erythritol, threitol, arabinitol, adenitol, xylitol, sorbitol, mannitol and dulcitol or said sugar alcohol being protected by a group selected from the group consisting of formyl, acetyl, tetrahydro-2-furanyl, tetrahydro-2-pyranyl, 1-methoxyethyl, 1-ethoxyethyl, trimethylsilyl, triethylsilyl and dimethyl-t-butylsilyl; a group of formula --SO 2 R 9 , wherein R 9 represents a C 1 -C 6 alkyl group, a phenyl group, or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; or a group of formula --(Z═)P(--OR 10 ) 2 , in which Z is as defined above, and each of the groups represented by R 10 , which may be the same or different, is a C 1 -C 6 alkyl group.

Claim 7

A milbemycin compound of formula (Ia): ##STR6## wherein: R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; X represents a halogen atom; and R 2a represents: a group of formula --COR 4 , in which R 4 represents a C 1 -C 20 alkyl group, a C 2 -C 20 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents, a phenyl group, a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl, halogen, nitro, carboxy and C 2 -C 7 alkoxycarbonyl substituents or a group of formula --(CH 2 ) n COOR 5 , wherein n is an integer from 1 to 3 and R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group; a group of formula --CZ.NR 6 R 7 , wherein R 6 and R 7 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a phenyl group or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen and Z represents an oxygen or sulfur atom; a group of formula --COOR 8 , wherein R 8 represents: a C 1 -C 6 alkyl group; a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents; a phenyl group; a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; a group of formula --CH 2 (--O--CO) m --B where m is 0 or 1 and B represents an oxygen-containing heterocyclic group having 5 or 6 ring atoms or said heterocyclic group having at least one C 1 -C 4 alkyl substituent; or a group derived by removing an omega-hydroxy group from a sugar alcohol selected from the group consisting of glycerol, erythritol, threitol, arabinitol, adenitol, xylitol, sorbitol, mannitol and dulcitol or said sugar alcohol being protected by a group selected from the group consisting of formyl, acetyl, tetrahydro-2-furanyl, tetrahydro-2-pyranyl, 1-methoxyethyl, 1-ethoxyethyl, trimethylsilyl, triethylsilyl and dimethyl-t-butylsilyl; a group of formula --SO 2 R 9 , wherein R 9 represents a C 1 -C 6 alkyl group, a phenyl group, or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; or a group of formula --(Z═)P(--OR 10 ) 2 , in which Z is as defined above, and each of the groups represented by R 10 , which may be the same or different, is a C 1 -C 6 alkyl group.

Claim 8

A compound as claimed in claim 5, wherein X represents a chlorine or fluorine atom.

Claim 9

A compound as claimed in claim 5, where R 2a represents: a group of formula --CO.NR 6 R 7 where R 6 and R 7 are independently selected from the group consisting of hydrogen atoms and C 1 -C 6 alkyl groups; a group of formula --COR 4 where R 4 represents a C 1 -C 20 alkyl group, a benzyl group or a phenyl group; or a group of formula --COOR 8 where R 8 represents a C 1 -C 6 alkyl group, a benzyl group or a phenyl group.

Claim 10

A compound as claimed in claim 5, where R 2a represents: a group of formula --CO.NR 6 R 7 where R 6 and R 7 are independently selected from the group consisting of C 1 -C 4 alkyl groups; or a group of formula --COR 4 where R 4 represents a C 1 -C 5 alkyl group.

Claim 11

A compound as claimed in claim 5, where R 2a represents: a group of formula --CO.NR 6 R 7 where R 6 and R 7 are independently selected from the group consisting of C 1 and C 2 alkyl groups; or a group of formula --COR 4 where R 4 represents a C 1 -C 3 alkyl group.

Claim 12

A compound as claimed in claim 9, where X represents a chlorine or fluorine atom.

Claim 13

A compound as claimed in claim 5, where R 2a represents a dimethylcarbamoyl group or a propionyl group.

Claim 14

A compound as claimed in claim 1, wherein R 1 represents an ethyl or isopropyl group.

Claim 15

A compound as claimed in claim 5, wherein R 1 represents an ethyl or isopropyl group.

Claim 16

A compound as claimed in claim 9, wherein R 1 represents an ethyl or isopropyl group.

Claim 17

The compound as claimed in claim 1, which is 13β-fluoro-5-ketomilbemycin D oxime or a salt thereof.

Claim 18

The compound as claimed in claim 1, which is 13β-fluoro-5-ketomilbemycin A 4 oxime or a salt thereof.

Claim 19

The compound as claimed in claim 1, which is 13β-chloro-5-ketomilbemycin D oxime or a salt thereof.

Claim 20

The compound as claimed in claim 1, which is 13β-chloro-5-ketomilbemycin A 4 oxime or a salt thereof.

Claim 21

The compound as claimed in claim 5, which is 13β-fluoro-5-ketomilbemycin D 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 22

The compound as claimed in claim 5, which is 13β-fluoro-5-ketomilbemycin A 4 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 23

The compound as claimed in claim 5, which is 13β-chloro-5-ketomilbemycin D 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 24

The compound as claimed in claim 5, which is 13β-chloro-5-ketomilbemycin A 4 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 25

The compound as claimed in claim 5, which is 13β-fluoro-5-ketomilbemycin D 5-O-propionyloxime.

Claim 26

The compound as claimed in claim 5, which is 13β-fluoro-5-ketomilbemycin A 4 5-O-propionyloxime.

Claim 27

The compound as claimed in claim 5, which is 13β-chloro-5-ketomilbemycin D 5-O-propionyloxime.

Claim 28

The compound as claimed in claim 5, which is 13β-chloro-5-ketomilbemycin A 4 5-O-propionyloxime.

Claim 29

An anthelmintic, acaricidal and insecticidal composition comprising an active compound in admixture with a pharmaceutically, agriculturally or horticulturally acceptable carrier or diluent, wherein said active compound is selected from the group consisting of milbemycin compounds of formula (I): ##STR7## in which: R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; X represents a halogen atom; and Y represents an oxygen atom or a group of formula ═N--OR 2 , wherein R2 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents or a group of formula --CH 2 COOR 3 , in which R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group; and, when R 2 represents a hydrogen atom, a salt or ester thereof.

Claim 30

An anthelmintic, acaricidal and insecticidal composition comprising an active compound in admixture with a pharmaceutically, agriculturally or horticulturally acceptable carrier or diluent, wherein said active compound is selected from the group consisting of milbemycin compounds of formula (I): ##STR7## in which: R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; X represents a halogen atom; and Y represents an oxygen atom or a group of formula ═N--OR 2 , wherein R2 represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents or a group of formula --CH 2 COOR 3 , in which R 3 represents a hydrogen atom or a C 1 -C 6 alkyl group; and, when R 2 represents a hydrogen atom, a salt or ester thereof.

Claim 31

A composition as claimed in claim 27, wherein X represents a chlorine or fluorine atom.

Claim 32

A composition as claimed in claim 27, wherein Y represents a group of formula ═N--OH.

Claim 33

A composition as claimed in claim 27, wherein: X represents a chlorine or fluorine atom; and Y represents a group of formula ═N--OH.

Claim 34

An anthelmintic, acaricidal and insecticidal composition comprising an active compound in admixture with a pharmaceutically, agriculturally or horticulturally acceptable carrier or diluent, wherein said active compound is selected from the group consisting of milbemycin compounds of formula (Ia): ##STR8## wherein: R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; X represents a halogen atom; and R 2a represents: a group of formula --COR 4 , in which R 4 represents a C 1 -C 20 alkyl group, a C 2 -C 20 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents, a phenyl group, a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl, halogen, nitro, carboxy and C 2 -C 7 alkoxycarbonyl substituents or a group of formula --(CH 2 ) n COOR 5 , wherein n is an integer from 1 to 3 and R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group; a group of formula --CZ.NR 6 R 7 , wherein R 6 and R 7 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a phenyl group or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen and Z represents an oxygen or sulfur atom; a group of formula --COOR 8 , wherein R 8 represents: a C 1 -C 6 alkyl group; a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents; a phenyl group; a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; a group of formula --CH 2 (--O--CO) m --B where m is 0 or 1 and B represents an oxygen-containing heterocyclic group having 5 or 6 ring atoms or said heterocyclic group having at least one C 1 -C 4 alkyl substituent; or a group derived by removing an omega-hydroxy group from a sugar alcohol selected from the group consisting of glycerol, erythritol, threitol, arabinitol, adenitol, xylitol, sorbitol, mannitol and dulcitol or said sugar alcohol being protected by a group selected from the group consisting of formyl, acetyl, tetrahydro-2-furanyl, tetrahydro-2-pyranyl, 1-methoxyethyl, 1-ethoxyethyl, trimethylsilyl, triethylsilyl and dimethyl-t-butylsilyl; a group of formula --SO 2 R 9 , wherein R 9 , wherein R 9 represents a C 1 -C 6 alkyl group, a phenyl group, or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; or a group of formula --(Z═)P(--OR 10 ) 2 , in which Z is as defined above, and each of the groups represented by R 10 , which may be the same or different, is a C 1 -C 6 alkyl group.

Claim 35

An anthelmintic, acaricidal and insecticidal composition comprising an active compound in admixture with a pharmaceutically, agriculturally or horticulturally acceptable carrier or diluent, wherein said active compound is selected from the group consisting of milbemycin compounds of formula (Ia): ##STR8## wherein: R 1 represents a methyl group, an ethyl group, an isopropyl group or a sec-butyl group; X represents a halogen atom; and R 2a represents: a group of formula --COR 4 , in which R 4 represents a C 1 -C 20 alkyl group, a C 2 -C 20 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents, a phenyl group, a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl, halogen, nitro, carboxy and C 2 -C 7 alkoxycarbonyl substituents or a group of formula --(CH 2 ) n COOR 5 , wherein n is an integer from 1 to 3 and R 5 represents a hydrogen atom or a C 1 -C 6 alkyl group; a group of formula --CZ.NR 6 R 7 , wherein R 6 and R 7 are the same or different and each represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl group, a phenyl group or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen and Z represents an oxygen or sulfur atom; a group of formula --COOR 8 , wherein R 8 represents: a C 1 -C 6 alkyl group; a C 7 -C 9 phenylalkyl group, a C 7 -C 9 phenylalkyl group having at least one substituent on the phenyl ring selected from the group consisting of C 1 -C 6 alkyl, halogen and nitro substituents; a phenyl group; a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; a group of formula --CH 2 (--O--CO) m --B where m is 0 or 1 and B represents an oxygen-containing heterocyclic group having 5 or 6 ring atoms or said heterocyclic group having at least one C 1 -C 4 alkyl substituent; or a group derived by removing an omega-hydroxy group from a sugar alcohol selected from the group consisting of glycerol, erythritol, threitol, arabinitol, adenitol, xylitol, sorbitol, mannitol and dulcitol or said sugar alcohol being protected by a group selected from the group consisting of formyl, acetyl, tetrahydro-2-furanyl, tetrahydro-2-pyranyl, 1-methoxyethyl, 1-ethoxyethyl, trimethylsilyl, triethylsilyl and dimethyl-t-butylsilyl; a group of formula --SO 2 R 9 , wherein R 9 , wherein R 9 represents a C 1 -C 6 alkyl group, a phenyl group, or a phenyl group having at least one substituent selected from the group consisting of C 1 -C 6 alkyl and halogen; or a group of formula --(Z═)P(--OR 10 ) 2 , in which Z is as defined above, and each of the groups represented by R 10 , which may be the same or different, is a C 1 -C 6 alkyl group.

Claim 36

A composition as claimed in claim 31, wherein X represents a chlorine or fluorine atom.

Claim 37

A composition as claimed in claim 31, where R 2a represents: a group of formula --CO.NR 6 R 7 where R 6 and R 7 are independently selected from the group consisting of hydrogen atoms and C 1 -C 6 alkyl groups; a group of formula --COR 4 where R 4 represents a C 1 -C 20 alkyl group, a benzyl group or a phenyl group; or a group of formula --COOR 8 where R 8 represents a C 1 -C 6 alkyl group, a benzyl group or a phenyl group.

Claim 38

A composition as claimed in claim 31, where R 2a represents: a group of formula --CO.NR 6 R 7 where R 6 and R 7 are independently selected from the group consisting of C 1 -C 4 alkyl groups; or a group of formula --COR 4 where R 4 represents a C 1 -C 5 alkyl group.

Claim 39

A composition as claimed in claim 31, where R 2a represents: a group of formula --CO.NR 6 R 7 where R 6 and R 7 are independently selected from the group consisting of C 1 and C 2 alkyl groups; or a group of formula --COR 4 where R 4 represents a C 1 -C 3 alkyl group.

Claim 40

A composition as claimed in claim 35, where X represents a chlorine or fluorine atom.

Claim 41

A composition as claimed in claim 31, where R 2a represents a dimethylcarbamoyl group or a propionyl group.

Claim 42

A composition as claimed in claim 27, wherein R 1 represents an ethyl or isopropyl group.

Claim 43

A composition as claimed in claim 31, wherein R 1 represents an ethyl or isopropyl group.

Claim 44

A composition as claimed in claim 35, wherein R 1 represents an ethyl or isopropyl group.

Claim 45

A method of treating an animal parasitized by a parasite selected from the group consisting of helminths, acarids and insects, which comprises applying to or administering to said animal an active compound, wherein said active compound is selected from the group consisting of compounds of formula (I), as defined in claim 1, and salts and esters thereof.

Claim 46

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, said plants or to seeds of said plants, or to a locus including said animals, said plants or said seeds, wherein said active compound is selected from the group consisting of compounds of formula (I), as defined in claim 1, and salts and esters thereof.

Claim 47

A composition as claimed in claim 27, wherein said active compound is 13β-fluoro-5-ketomilbemycin D oxime or a salt thereof.

Claim 48

A composition as claimed in claim 27, wherein said active compound is 13β-fluoro-5-ketomilbemycin A 4 oxime or a salt thereof.

Claim 49

A composition as claimed in claim 27, wherein said active compound is 13β-chloro-5-ketomilbemycin D oxime or a salt thereof.

Claim 50

A composition as claimed in claim 27, wherein said active compound is 13β-chloro-5-ketomilbemycin A 4 oxime or a salt thereof.

Claim 51

A composition as claimed in claim 31, wherein said active compound is 13β-fluoro-5-ketomilbemycin D 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 52

A composition as claimed in claim 31, wherein said active compound is 13β-fluoro-5-ketomilbemycin A 4 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 53

A composition as claimed in claim 31, wherein said active compound is 13β-chloro-5-ketomilbemycin D 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 54

A composition as claimed in claim 31, wherein said active compound is 13β-chloro-5-ketomilbemycin A 4 5-O-(N,N-dimethylcarbamoyl)oxime.

Claim 55

A composition as claimed in claim 31, wherein said active compound is 13β-fluoro-5-ketomilbemycin D 5-O-propionyloxime.

Claim 56

A composition as claimed in claim 31, wherein said active compound is 13β-fluoro-5-ketomilbemycin A 4 5-O-propionyloxime.

Claim 57

A composition as claimed in claim 31, wherein said active compound is 13β-chloro-5-ketomilbemycin D 5-O-propionyloxime.

Claim 58

A composition as claimed in claim 31, wherein said active compound is 13β-chloro-5-ketomilbemycin A 4 5-O-propionyloxime.