AU621593B2 - Creation of Inventions and Patents with Artificial Intelligence

AU621593B2 – Insecticides and parasiticides
– Google Patents

AU621593B2 – Insecticides and parasiticides
– Google Patents
Insecticides and parasiticides

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Publication number
AU621593B2

AU621593B2
AU31195/89A
AU3119589A
AU621593B2
AU 621593 B2
AU621593 B2
AU 621593B2
AU 31195/89 A
AU31195/89 A
AU 31195/89A
AU 3119589 A
AU3119589 A
AU 3119589A
AU 621593 B2
AU621593 B2
AU 621593B2
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AU
Australia
Prior art keywords
phenyl
formula
hydrogen
methyl
compounds
Prior art date
1988-03-11
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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Application number
AU31195/89A
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AU3119589A
(en

Inventor
Anthony Cornelius O’sullivan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Novartis AG

Original Assignee
Ciba Geigy AG
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1988-03-11
Filing date
1989-03-10
Publication date
1992-03-19

1989-03-10
Application filed by Ciba Geigy AG
filed
Critical
Ciba Geigy AG

1989-09-14
Publication of AU3119589A
publication
Critical
patent/AU3119589A/en

1992-03-19
Application granted
granted
Critical

1992-03-19
Publication of AU621593B2
publication
Critical
patent/AU621593B2/en

1998-04-23
Assigned to NOVARTIS AG
reassignment
NOVARTIS AG
Alteration of Name(s) in Register under S187
Assignors: CIBA-GEIGY AG

2009-03-10
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Classifications

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system

C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings

C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS

C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

A—HUMAN NECESSITIES

A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING

A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS

A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds

A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES

A61K31/00—Medicinal preparations containing organic active ingredients

A61K31/33—Heterocyclic compounds

A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin

A61K31/365—Lactones

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P33/00—Antiparasitic agents

A61P33/10—Anthelmintics

Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE

Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

Y02P20/00—Technologies relating to chemical industry

Y02P20/50—Improvements relating to the production of bulk chemicals

Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to novel derivatives of formula I that can be derived from milbemycins, to their preparation and their use for controlling pests, and also to pesticides that contain at least one of these compounds as active ingredient. The novel compounds have the general formula I (I) in which X is one of the groups -CH(OR1)-, -C(O)- or -C(=N-OR)-; R1 is hydrogen or an OH-protecting group; R is hydrogen, an OH-protecting group, or an alkyl or cycloalkyl group; R2 is methyl, ethyl, isopropyl or sec.-butyl; and Ph is a phenyl ring that is substituted by Ra, Rb, Rc and Rd, wherein each of Ra, Rb, Rc and Rd, independently of the others, is hydrogen, C1-C10alkyl, C2-C10alkoxyalkyl, C2-C10alkenyl, C1-C10alkoxy, C2-C10alkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group C1-C3alkyl and C1-C3alkoxy.

Description

I
621593 S F Ref: 87278 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: Published: Priority: Related Art: I Va Name and Address of Applicant: Address for Service: Ciba-Geigy AG Klybeckstrasse 141 4002 Basle
SWITZERLAND
Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Insecticides and Parasiticides The following statement is a full description of this invention, including the best method of performing it known to me/us 5845/3 5-16940/+ Insecticides and parasiticides Abstract The present invention relates to novel derivatives of formula I that can be derived from milbemycins, to their preparation and their use for controlling pests, and also to pesticides that contain at least one of these compounds as active ingredient.
The novel compounds have the general formula I o 00 9 923 9 o H 3 22/ CH.3 Ph l/ 0\ 000:o :13 17
H
3 C
(I)
X is one of the groups or R, is hydrogen or an OH-protecting group; R is hydrogen, an OH-protecting group, or an alkyl or cycloalkyl group; RI is methyl, ethyl, isopropyl or sec.-butyl; S and B Ph is a phenyl ring that is substituted by R Rb, Rc and R wherein each of R, Rb, Rc and Rd, independently of the others, is hydrogen, C-Calkyl, C-Cloalkoxyalkyl, C-Cloalkenyl, C-Calkoxy, C2-Calkoxyalkoxy in which substX is one of the groups CH(OR)-, or -C(=N-OR)-;-Calkyl and RI is hydrogen or an OH-protecting group; R is hydrogen, an OH-protecting group, or an alkyl or cycloalkyl group; .mi K is methyl, ethyl, isopropyl or sec.-butyl; itr and j Ph is a phenyl ring that is substituted by R a
R
b Rc and R d wherein each of Ra, R, Rc and R d independently of the others, is hydrogen, Ci-Cioalkyl, Cz-Cioalkoxyalkyl, Cz-Cioalkenyl, Ci-Cioalkoxy, Cz-Cioalk- t oxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group Ci-C3alkyl and Ci-C3alkoxy. y 11 t 1A Insecticides and parasiticides The present invention relates to novel derivatives of formula I that can be derived from milbemycins, to their preparation and their use for controlling pests, and also to pesticides that contain at least one of these compounds as active ingredient.
According to a first embodiment of this invention, there is provided compounds of”formula I 9H3 22 3 CH3 Phx I 1 7 1 3 17
H
3 C H O P(I)
CH
3 in which I 10 X is one of the groups -CH(OR or R1 is hydrogen or an OH-protecting group; R is hydrogen, an OH-protecting group, or an alkyl or cycloalkyl group; R is methyl, ethyl, isopropyl or sec.-butyl; and Ph is a phenyl ring that is substituted by R a Rb, Rc and Rd’ wh e re wherein each of R a Rb, R and Rd, independently of the others, Sis hydrogen, C1-C 10 alkyl, C 2
-C
10 alkoxyalkyl, C 2
-C
10 alkenyl,
C
1
-C
10 alkoxy, C2-C 10 alkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from S 20 the group C 1
-C
3 alkyl and C 1
-C
3 alkoxy.
According to a second embodiment of this invention, there is Sprovided a process for the preparation of compounds of formula I, which process comprises reacting a compound of formula II 16 CH3 12: H3C IH 0 1 H (II) KX1 9CH3 i KXW:1296v i i 1B wherein G is one of the groups a or b
CH
3
H
3 or I 13B-halogen-A 14 1 5 15-chloro-A 1 3 1 4 R1 is hydrogen or an ‘OH-protecting group, R 2 is as defined for formula I, and E is chlorine, bromine or iodine, with a diaryl zinc compound of formula III Ph-Zn-Ph (III), wherein Ph is as defined for formula I, in the presence of a transition metal salt, and, if desired, when R 1 is an OH-protecting group, removing that protecting group by hydrolysis.
According to a third embodiment of this invention, there is provided a process for the preparation of compounds of formula lib 0 0 R H23 1 1 i HH H
CCH
3 o 22 in which .is hydrogen an OH-protecting group; and .o I I b
SH
3 CH3 CH 3 S OR Sis hydrogen or an OH-protecting group; and W:;296v C” _d ,44
I,
1C wherein R 2 is methyl, ethyl, isopropyl or sec.-butyl, with a chlorinating agent that brings about the formation of the corresponding 13 14 derivative.
According to a fourth embodiment of this invention, there is provided compounds of formula IIb H 2 23 CH 3 R2 n1
II
*0 HiI~ (IIb),
I
CH3 R1i in which R1 is hydrogen or an OH-protecting group; and
R
2 is methyl, ethyl, isopropyl or sec.-butyl.
According to a fifth embodiment of this invention, there is provided compositions for controlling pests, which contain at least one compound of formula I according to the first embodiment as active ingredient, together with carriers, distributing agents or carriers and distributing agents.
According to a sixth embodiment of this invention, there is provided a method of controlling pests, which comprises applying or administering a pesticidally effective amount of a compound of formula according to the first embodiment to the host animals, host plants or other loci of the pests.
The novel compounds have the general formula I
I
C CH 3 YH 3 22/\2. H Ph Y\ 13 17 *’oBR 2
H
3
CH
\C
ii It
~CH
3 in which SX is one of the groups -CH(OR 1 or W:1296v t
I
~1 ii’ I: i” 1D R1 is hydrogen or an OH-protecting group; R is hydrogen, an OH-protecting group, or an alkyl or cycloalkyl group;
P
2 is methyl, ethyl, isopropyl or sec.-butyl; and Ph is a phenyl ring that is substituted by Ra, Rb, R and Rd’ wherein each of R a Rb, Rc and Rd, independently of the others, is hydrogen, C 1
-C
10 alyl, C 2
-C
10 alkoxyalkyl, C 2
-C
10 alkenyl, C1-Co 1 alkoxy, C2-C 10 alkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group C 1
-C
3 alkyl and C1-C 3 alkoxy.
I
1 3 2t 296v t h i 1 2- The term “alkyl” as an independent substituent or as a component of a substituent is used to mean, depending on the number of carbon atoms indicated, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl, and any suitable isomers thereof, such as, for example, isopropyl, isobutyl, tert.-butyl and isopentyl. R as alkyl is preferably alkyl having from 1 to 8, especially from 1 to 4, carbon atoms.
Cycloalkyl is preferably C3-Cscycloalkyl, that is to say cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Cz-Cioalkoxyalkyl is an alkyl radical having a carbon structure that consists of up to 10 carbon atoms and that is interrupted at one position by an oxygen atom. Preferred alkoxyalkyl groups are those having from 1 Uo2 o° to 6 carbon atoms, such as, for example, -CHz-O-CH 3 -CHz-O-CzHs, =oo -CH 2 CHz-0-C 2 Hs, -CH 2
CH
2
-O-CH
3
-CH(CH
3
)-O-CH
3 -CHz-0-C(CH 3 3
-C(CH
3 2 -0-CH 3 or -CH 2
CH
2
CH
2 -O-nC 3
H
7 0eo0o0 Cz-Cloalkenyl is a straight-chain or branched acyclic, aliphatic radical aQ 0 having a double bond. Especially worthy of mention is Cz-Cqalkenyl, for example vinyl and allyl.
0 1 00 A o, Of the Ci-Cioalkoxy groups, those having from 1 to 6 carbon atoms are preferred. Examples are propoxy, ethoxy and, especially, methoxy.
o0 a0 Cz-Cioalkoxyalkoxy is an alkoxy radical having a carbon structure that consists of up to 10 carbon atoms and that is interrupted at one position by an oxygen atom. Preferred alkoxyalkoxy groups are those having from 2 0 to 6 carbon atoms, such as, for example, -O-CHzCH2-O-C 2 Hs, 0 G -O-CH 2
CH
2 -O-CH3, O-CH 2
CH
2
CH
2 -O-nC 3
H
7
-O-CH
2
-C(CH
3 )2-O-CH3, -O-CH 2 -O-CH3 or -O-CH 2
CH
2
CH
2
CH
2
-O-CH
3 and also -O-CH 2
CH
2
-O-CH
2
-C(CH
3 )3.
Preferred substituted phenyl and phenoxy radicals Ra, Rb, Rc and R d are those which are substituted by from 1 to 3 substituents from the group C1-C 3 alkyl and Ci-C3alkoxy, and especially those in which the total -3number of carbon atoms of all the substituents of one ring when taken together does not exceed the number 5. Preferred substituents of the phenyl and phenoxy radicals are methyl and methoxy.
Ph is especially phenyl, a phenyl radical substituted by from one to three methyl groups, a phenyl radical substituted by from one to three methoxy groups, or a phenyl radical substituted by one phenyl or one phenoxy group.
Suitable structural elements symbolised by “Ph” are those which can be derived from compounds that are obtainable by customary chemical methods.
Throughout this specification, OH-protecting groups for the substituents o 09 *oo R and Ri are to be understood as being the protective functions that are S customary in organic chemistry. These are especially acyl and silyl groups. Suitable acyl groups are, for example, the radicals R4-C(O)-, Swherein R4 is Ci-Cloalkyl, Ci-Ciohaloalkyl, or a group from the series o 0 phenyl and benzyl that is unsubstituted or is substituted by one or more substituents selected from the group consisting of halogen, Ci-C 3 alkyl, Ci-C 3 haloalkyl, Ci-C 3 alkoxy, C 1
-C
3 haloalkoxy, cyano and nitro, and is o° preferably Ci-C 6 alkyl, C 1
-C
6 haloalkyl, or phenyl that is unsubstituted or o 0 o is substituted by halogen, Ci-C 3 alkyl, CF 3 or by nitro. A suitable silyl group for RI and R is the radical -Si(Rs)(R 6
)(R
7 wherein Rs, R 6 and R 7 preferably independently of one another, are Ci-Calkyl, benzyl or phenyl 0 0 and form, for example, together with the silicon atom, one of the groups trimethylsilyl, tris(tert.-butyl)silyl, diphenyl-tert.-butylsilyl, bis(isopropyl)methylsilyl, triphenylsilyl etc. and, especially, tert.- S butyl-dimethyl-silyl. The 5-OH group may also be etherified in the form of benzyl ether or methoxyethoxy methyl ether.
Compounds of formula I wherein X is the group -CH(ORi)- or and Ri and R are each a protecting group can be converted into the highly active free 5-hydroxy derivatives (Ri H) or the 5-oxime derivatives (R H) by simple removal of the protecting function, for example by hydrolysis, and thus have also the character of intermediates. The biological value of these compounds is not, however, reduced at all or to 4 -4any significant extent by the protecting group. The removal of the protecting group by hydrolysis can be effected with a dilute acid, for example with 1 p-toluenesulfonic acid in methanol or with an aqueous HF solution in acetonitrile at from -20 0 C to 50 0 C, preferably at from 0 0 C to 0 C, or alternatively with pyridinium fluoride in pyridine.
The above-mentioned acyl and silyl groups serve as protecting groups not only for hydroxy groups present in the substituent X but also for all other hydroxy groups present in the compounds of the invention or in precursors of those compounds.
Compounds of formula I wherein X is -CH(ORI)- and RI is hydrogen are preferred. Acyl and silyl groups as R and R 1 are generally to be regarded as protecting groups.
Throughout this specification, compounds in which Rz is sec.-butyl are S also to be classified as milbemycin derivatives although, according to conventional classification, they are derived from avermectin derivatives. Avermectin aglycons (having an OH group in the 13a-position) can, however, be converted into milbemycin homologues in accordance with US-PS 4,173,571.
S In naturally occurring milbemycins (X -CH(ORI)-, RI H; Rz CH 3
C
2 Hs or isoC3H7) the 13-position is always occupied only by hydrogen: 29 CH3 CH 3 17 4 4 i13 S H 3 C (M) 0
H
bH CH 3
AH
Rz CHa milbemycin A 3 (US-PS 3,950,360) R2 C 2 Hs milbemycin A4 (US-PS 3,950,360)
I
R2 isoC 3
H
7 milbemycin D (US-PS 4,346,171) Rz sec.-CuH 9 13-deoxy-22,23-dihydro-C-076-Bla-aglycon (US 4,173,571, GB 1,573,955 and DE-OS 2 717 040) In avermectins on the other hand, an a-L-oleandrosyl-a-L-oleandrose radical, which is linked via oxygen in a-configuration to the macrolide molecule, is present in the 13-position. Avermectins also differ struc- 22,23 turally from milbemycins by a 23-OH group or A 23 -double bond and, as a rule, by a substituent R 2 sec.-C4H9. Hydrolysis of the sugar residue of avermectins readily produces the corresponding avermectin aglycons that contain an allylic 13a-hydroxy group. As stated above, avermectin aglycons can be converted into milbemycin homologues. In the milbemycin 22,23 derivatives of this Application, the A 2′-double bond is always in o’ hydrogenated form.
Owing to their pronounced parasiticidal and insecticidal activity, the S following subgroups of compounds of formula I according to the present S invention are especially preferred: Group Ia: Compounds of formula I wherein X is -CH(ORi)- and RI is hydrogen or a protecting group, R 2 is methyl, ethyl, isopropyl or sec.- Sbutyl; and Ph is a phenyl ring that is substituted by R Rb, R and R d wherein each of R R R and Rd, independently of the others, is o, hydrogen, Ci-Cioalkyl, C 2 -Cioalkoxyalkyl, C2-Cioalkenyl, Ci-Cioalkoxy,
C
2 -Cloalkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group Ci-C3alkyl and Cl-C3alkoxy.
Group Ib: Compounds of formula I wherein X is -CH(ORi)- and R 1 is hydrogen, R 2 is methyl, ethyl, isopropyl or sec.-butyl; and Ph is a phenyl ring that is substituted by R, Rb, Rc and R d wherein each of R a Rb, R and Rd, independently of the others, is hydrogen, Ci-Cloalkyl,
C
2 -Cioalkoxyalkyl, Cz-Cioalkenyl, Ci-Cioalkoxy, C 2 -Cloalkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the gro;ip C1-C 3 alkyl and C1-C 3 alkoxy.
-6- 6 Group Ic: Compounds of formula I wherein X is -CH(ORI)- and RI is hydrogen, Rz is methyl or ethyl; and Ph is a phenyl ring that is substituted by R a Rb, R c and R d wherein each of R, Rb, R c and Rd, independently of the others, is hydrogen, Ci-Cioalkyl, Cz-Co1alkoxvalkyl, Cz-Cioalkenyl, C 1 -Cloalkoxy, C 2 -Cioalkoxyalkoxy, or a phenyl or ,.;.noxy radical that is unsubstituted or is substituted by at least one substituent from the group Ci-C 3 alkyl and Ci-C 3 alkoxy.
Group Id: Compounds of formula I wherein X is -CH(ORi)- and Ri is hydrogen, R 2 is methyl or ethyl; and Ph is a phenyl ring that is substituted by R a Rb, R and R d wherein each of R Rb, R and Rd, independently of the others, is hydrogen, C 1 -Co1alkyl, C 2 -Coalkoxyalkyl, Cz-Cioalkenyl, C 1 -Co1alkoxy or C 2 -Co1alkoxyalkoxy.
Group Ie: Compounds of formula I wherein X is -CH(ORI)- and RI is hydrogen, Rz is methyl or ethyl; and Ph is a phenyl ring that is sub- S stituted by R a Rb, R and Rd, wherein each of Ra, Rb, Rc and R d independently of the others, is hydrogen, or a phenyl or phenoxy radical S that is unsubstituted or is substituted by at least one substituent from the group C 1
-C
3 alkyl and Cl-C3alkoxy.
At” S Group If: Compounds of formula I wherein X is -CH(ORI)- and RI is hydrogen, Rz is methyl or ethyl; and Ph is a phenyl ring that is substituted by Ra, R, Rc and Rd, wherein each of Ra, R, Rc and Rd, independently of the others, is hydrogen, C 1
-C
3 alkyl or Ci-C 3 alkoxy, with the proviso that not more than two of the substituents Ra, Rb, Rc and Rd have a meaning other than hydrogen.
Group Ig: Compounds of formula I wherein X is -CH(ORI)- and RI is hydrogen, R 2 is methyl or ethyl; and Ph is a phenyl ring that is substituted by R, Rb, Rc and Rd, wherein each of Ra, Rb, Rc and R d independently of the others, is hydrogen, phenyl or phenoxy, with the proviso that not more than two of the substituents R, R, R and R d have thatthaa’ othsbtt R Rb’ Rc a meaning other than hydrogen.
7- Group Ih: Compounds of formula I wherein X is -CH(ORi)- and R 1 is hydrogen, R 2 is methyl or, especially, ethyl; and Ph is phenyl that is unsubstituted or monosubstituted by methyl, methoxy, phenyl or phenoxy, or disubstituted by methyl or methoxy, or trisubstituted by methyl.
Group Ii: Compounds of formula I wherein X is -CH(0R 1 and R 1 is hydrogen, R 2 is methyl or, especially, ethyl; and Ph is phenyl that is unsubstituted or monosubstituted by methyl, methoxy, phenyl or phenoxy, or disubstituted by methoxy.
Preferred individual compounds (X -CH(OR 1
R
1 H) are: 13-phenyl-milbemycin A4, 13B-(2-methoxyphenyl)-milbemycin A4, o e w 13P1-(3-methoxyphenyl)-milbemycin A4, 13-(4-methoxyphenyl)-milbemycin A, 13f-(4-methoyphenyl)-milbemycin
A
4 0 0 131-(2-ethylphenyl)-mlhmycin A 4 13a-(4-biphenylyl)-milbemycin A4, 131-(4-phenoxyphenyl)-milbemycin A 4 and 131-(3,4-dimethoxyphenyl)-milbemycin A 4 00.40 The following compounds exhibit pronounced activity: S 13a-phenyl-milbemycin
A
3 13B-(2-methylphenyl)-milbemycin A 4 and 13a-(4-methylphenyl)-milbemycin A4.
The present invention relates not only to the compounds of formula I but also to novel processes for their preparation. It has been found that, surprisingly, the substituent “Ph” can be bonded in a deliberate manner stereospecifically in the -configuration to the 13-C atom of the macrolide molecule by reacting the corresponding 131-halogen compound or 13,14 the corresponding 15-halogen-A derivative with an aryl metal compound, in which the aryl moiety corresponds to the substituent “Ph”, in the presence of a catalytic amount of a transition metal salt. The halogen reaction of compounds of the type -9 withi aryl metal -14 a o C a each of Ra, R, Rc and Rd, independently of the others, is hydrogen, Ci-Cioalkyl, C2-Cloalkoxyalkyl, Cz-Cioalkenyl, Ci-Coalkoxy, C-Coalkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group Ci-C 3 alkyl and CI-C3alkoxy. -8i, compounds, catalysed by a transition metal salt, is known from the literature (Acc. Chem. Res. 1982, 15, 340-348), and, as a rule, this reaction takes place with inversion. This means that, for example, when reacting a corresponding 13a-halogen-milbemycin derivative with an aryl metal compound, catalysed by a transition metal salt, the formation of a 13a-arylmilbemycin derivative is to be expected. Surprisingly, however, only 13B-arylmilbemycin derivatives are obtained.
Accordingly, the invention further relates to a process for the preparation of compounds of formula I, which process comprises reacting a compound of formula II 1 6 .CH3 .o S* O 17 4e4s 12: 1 OH R1 4 “r H0C (II) II I
C
4 4 4” CH3 6R, ‘0 wherein G is one of the groups a or b H3 H3 or H3 14,15 13,14 13B-halogen-A14 15-chloro-A 3 14 Ri is hydrogen or an OH-protecting group, R2 is as defined for formula I, .o .and E is chlorine, bromine or iodine, with a diaryl zinc compound of formula
III
Ph-Zn-Ph (III), wherein Ph is as defined for formula I, in the presence of a transition metal salt, and, if desired, when Ri is an OH-protecting group, removing that protecting group by hydrolysis.
-9 Within the scope of the present invention, transition metal salts are to be understood as being those salts which contain as metal component a transition metal of group VIII. Of the 9 metals in this group, namely Fe, Ru, Os, Co, Rh, Ir, Ni, Pd and Pt, there are preferred as metal components of the transition metal salts Co, Ni and Pd. Suitable transition metal salts are purely inorganic transition metal salts and also those which are complexed with organic ligands. Typical organic ligands are phosphines and organically substituted amines. Representative examples of suitable transition metal salts are NiC1 2 Go0 2 [(phenyl) 3
PI
2 NiCl2, [(phenyl) 3
PI
2 PdCl 2 [(phenyl) 2
PCH
2 2 NiCl2, [(phenyl) 2
PCH
2 ]2oBr2, [(phenyl) 2
PCH
2
CH
2
CH
2 P(phenyl) 2 ]NiCl 2 [(phenyl)2PCH 2 CH21 2 NiCl2 and S(cyclohexyl) 3 P 2 NiCl 2 Akad. SSSR 155, 623 (1964); Engl. 299).
0: 9 .i Within the scope of the present invention, transition metal salts are to Here nderstood as being those salts which conta II in whichas metal c omponent a are transition metal of group VIII. Of the 9 metals in this group, namely Fe,Ib.
Ru, Os, Co, Rh, Ir, Ni, Pd and Pt, there are preferred as metal compo- Compounents of the transition metal salts Co, Ni and Pd. Suitable transitionr sec.metal saltsnd R and E arely inorganic transition metal salts formula II, a proess for those preparation thereof are known from EP 180 539. In that process, a correspondwhich are 15-complexed with organic ligands. Typical organic ligands aren phosphines and organically substituted amines. Representative examples of suitable transition metal salts are NiCI2, CoClz, [(phenyl)3P]zNiCl2, [(phenyl)aP]2PdC12, [(phenyl)2PCH] zNiC12, [(phenyl)zPCHz]2CoBr2, [into the 1nyl)PCH-halogen compound.(phenyl)PCHCH NiC and [(cyclohexyl)3P]NiCl2.
The diary zinc compounds of formula III are either known or can be prepared analogously to known methods Sheverdina et al., Doklady t0 0 S Akad. SSSR 155, 623 (1964); Engl.: 299).
0 R2 H3 (IIb),
*H
H CH 3 II a o”to Here and hereinafter, compounds of formula II in which G is a group a are o designated IIa and those having the group b are designated IIb. t Compounds of formula IIa in which Rz is methyl, ethyl, isopropyl or sec.butyl and Ri and E are as defined for formula II, and a process for the preparation thereof are known from EP 180 539. In that process, a corresponding 15-hydroxy-A 1 compound is converted with a halogenating agent 1 into the 13 -halogen compound.
The compounds of formula IIb (lib), r CH C V ‘I O!i ‘i l 5845/3 in which RI is hydrogen or an OH-protecting group; and Rz is methyl, ethyl, isopropyl or sec.-butyl, are novel and also constitute a further aspect of the present invention, as does the process for their preparation. The compounds of formula IIb are prepared by reacting a milbemycin of formula M with a chlorinating agent that brings about the formation of the corresponding
A
13 14 derivative.
It is already known from EP 143 747 that reaction of milbemycins of formula M with hypochlorous acid (HOC1) or sulfuryl chloride (SOzCl2) gives compounds of formula M’ 29 2
SH
2 22 CH 3 oa II .oo, I 6* 1 1 3* 1 *00 sH I 1 I 1 H S H 3 C (M II I/ a 0 CH 3 o 4 o wherein R2 is as defined for formula M. This reaction constitutes a chlorination in the 15-position with the simultaneous formation of an S exocyclic double bond in the 29-14-position.
It is also known that the chlorination of alkenyl and dialkenyl compounds I o and cyclohexylidene can be effected with tert.-butyl hypochlorite or os,.
chlorine Sato et al., Chemistry Lett. 1982, 141-142; M. Yoshioka et al., Tetrahedron Lett. 21, 351-354).
None of the known processes, however, gives any indication of how it would be possible to obtain the compounds of formula IIb of the invention which have endocyclic carbon-carbon double bonds.
C
1
-C
3 all-oxy.
I i i’ chlorite. This process also forms an aspect of the present invention.
The process is generally carried out in an inert solvent. Suitable solvents are, for example, ethers and ethereal compoun such as dialkyl ethers (diethyl ether, diisopropyl ether, tert.-butylmethyl ether, dimethoxyethane, dioxane, tetrahydrofuran or anisole); halogenated hydrocarbons, such as, for example, chlorobenzene, methylene chloride or ethylene chloride; or sulfoxides, such as dimethyl sulfoxide, it also being possible for aromatic or aliphatic hydrocarbons, such as, for example, benzene, toluene, xylenes, petroleum ether, ligroin or cyclohexane, to be present.
roI The reaction is generally carried out in a temperature range of from 0 C to +50 0 C, preferably at from -10 0 C to +20 0
C.
n A further process for the preparation of compounds of formula I comprises o a 0x 14,15 S introducing the substituent “Ph” into corresponding 13-acyloxy-A derivatives or 15-acyloxy-A derivatives by reacting said derivatives with a triarylaluminium compound. This reaction can be carried out analogously to the method described in EP 189 159, which method also oo. includes the preparation of the acylated starting compounds.
Accordingly, the present invention further relates to a process for the preparation of compounds of formula I, which comprises treating a compound of formula V 164 CH3 4 I 17 i 12 I H3C O li
CH
3 biin- S derivatives o R 15 acyoyA’ drvtvsb ecigsi eiaie ,1 12 wherein G’ is one of the groups a’ or b’ H3 H 3 or 1 Oke 14,15 13,14 13B-ester-A 4 15 15-ester-A 13 14 R8 is an acyl group, R 1 is hydrogen or, preferably, a silyl group, and R 2 is as defined for formula I, with a triarylaluminium compound of formula VI Al(Ph)3 (VI), wherein Ph is as defined for formula I, and then, if free 5-hydroxy com- S pounds are desired, removing the R 1 -silyl group by hydrolysis.
The process is generally carried out in an inert solvent. Suitable solvents are, for example, ethers and ethereal compounds, such as dialkyl a ft t ethers (diethyl ether, diisopropyl ether, tert.-butylmethyl ether, di- S methoxyethane, dioxane, tetrahydrofuran or anisole); halogenated hydrocarbons, such as, for example, chlorobenzene, methylene chloride or .s ethylene chloride; and aromatic or aliphatic hydrocarbons, such as, for o, example, benzene, toluene, xylenes, petroleum ether, ligroin or cyclohexane, may also be present.
a a t It can be advantageous to carry out the reaction or partial steps thereof under a protective gas atmosphere (for example argon, helium or nitrogen) ,t and/or in absolute solvents. If desired, intermediates may be isolated from the reaction mixture and, if desired, purified in customary manner, e.g. by washing, digestion, extraction, recrystallisation, chromatography, etc., before being further reacted. It is, however, also possible to dispense with such purification steps and carry them out only with corresponding end products.
K i “1 1 13 The reaction is generally carried out in a temperature range of from -100 0 C to 100 0 C, preferably at from -200C to +60 0 C. The triarylaluminium compound of formula VI is added in an at least equimolar amount, in solid form or in an inert solvent, such as, for example, hexane, toluene or benzene, to a solution of the compound of formula V.
When the reaction is complete, the silyl protecting group can be removed again by treating the compounds of formula I with a dilute acid, such as, for example, with 1 p-toluenesulfonic acid in methanol or with an aqueous HF solution in acetonitrile in a temperature range of from -20 0
C
to 50 0 C, preferably at from 0 0 C to 30 0 C, or with pyridinium fluoride in pyridine.
Suitable acyl groups for Rs are, for example, formyl, acetyl, benzoyl, ethoxycarbonyl or P(=O)(Oalkyl)2, such as P(=O)(OEt)2, alkylsulfonyl radicals, preferably lower alkylsulfonyl, especially mesyl, or, to a limited extent, also tetrahydropyranyl.
The 5-keto-milbemycins in which X is which fall within the scope of formula I, can be obtained, for example, by treating compounds of formula I in which X is -CH(OH)- with a reagent suitable for the purpose Sof oxidation. Suitable oxidising agents are, for example, activated manganese dioxide, oxalyl chloride/dimethyl sulfoxide/triethylamine or chromium trioxide/pyridine. The Oppenauer oxidation also is a suitable process, in which compounds of formula I in which X is -CH(OH)- are reacted with a ketone, preferably cyclohexanone or acetone, in the presence of an aluminium alcoholate, preferably aluminium isopropanolate or aluminium tert.-butanolate.
The oxidation is advantageously carried out in an inert solvent. Suitable solvents are alkanes, such as, for example, hexane, heptane or octane, aromatic hydrocarbons, such as, for example, benzene, toluene or xylenes, or preferably chlorinated hydrocarbons, especially methylene chloride.
The oxidation is advantageously carried out at temperatures of from -80 0
C
to +60 0 C, preferably from -60 0 C to +30 0
C.
i; I i f Xi 0 CH3 A& in which T ‘X is one of the groups or :1296v: i .4A iI 14 By reduction of compounds of formula I in which X is the group in a manner known per se, it is possible to obtain again those compounds in which X is the -CH(OH)- group. The reduction can be effected, for example, in accordance with the Meerwein-Ponndorf-Verley reduction using aluminium isopropanolate in isopropanol.
Compounds of formula I in which X is can be prepared, for example, by reacting compounds of formula I in which X is with hydroxylamine or a salt thereof and, if desired, subsequently introducing the substituent R, R having the meanings given for formula I with the exception of hydrogen, or by carrying out the reaction with a compound of formula NH 2 -OR wherein R has the meanings given for formula I with the exception of hydrogen, or with a salt thereof. Suitable salts are, for example, salts of the above-mentioned amino compounds with sulfuric acid, nitric acid or, especially, hydrochloric acid. The reaction is advantageously carried out in a suitable solvent, for example a lower alkanol, such as methanol, ethanol, propanol; an ethereal compound, such as tetrahydrofuran or dioxane; an aliphatic carboxylic acid, such as acetic acid or propionic acid; water, or in mixtures of these solvents with one another or with other customary inert solvents. The reaction temperatures may vary within wide limits. Advantageously, a temperature in the range of, for example, from +10 0 C to +100 0 C is used. If hydroxylamine is used S in the form of one of its salts, for example in the form of the hydrochloride, it is advantageous, in order to bind the acid, to add one of the bases customarily used for such purposes and, where necessary, to carry out the reaction in the presence of a water-binding agent, for example a molecular sieve. Suitable bases are organic and inorganic bases, e.g. tertiary amines such as trialkylamines (trimethylamine, trit ethylamine, tripropylamine etc.), pyridine and pyridine bases (4-dimethylaminopyridine, 4-pyrrolidylaminopyridine etc.), oxides, hydrides and hydroxides, carbonates and hydrogen carbonates of alkali metals and alkaline earth metals (CaO, BaO, NaOH, KOH, NaH, Ca(OH)2, KHCO3, NaHCO 3 Ca(HCO 3 2
K
2 C0 3 Na 2
CO
3 and alkali metal acetates such as CH 3 COONa or
CH
3 COOK. Also suitable are alkali metal alcoholates such as C 2 HsONa, n-C 3 H70Na etc.. Triethylamine is preferred.
i j 0 ilj a o 9 0 The methyl cellulose is stirred into water and allowed to swell, and the silicic acid is stirred in to give a homogeneous suspension. The active ingredient and the maize starch are mixed, and the aqueous suspension is incorporated into the mixture, which is then kneaded to a paste. This mass is granulated through a sieve (mesh width 12 M) and then dried.
II lactose cryst.
maize starch microcrystalline cellulose magnesium stearate 22.50 17.00 16.50 1.00 All four adjuvants are thoroughly mixed.
d II B j.4 $I i: ;i 40 Phases I and II are mixed and compressed to form tablets or boli.
Injectable composition A. Oily vehicle (slow release) a compound of Examples P1-P12 groundnut oil a compound of Examples P1-P12 sesame oil 0.1-1.0 g ad 100 ml 0.1-1.0 g ad 100 ml I 4 a r( 44
II
Preparation: The active ingredient is dissolved in a portion of the oil while stirring and, if necessary, while heating gently. After cooling, the solution is made up to the prescribed volume and sterile-filtered through a suitable membrane filter having a pore diameter of 0.22 pm.
B. Water-miscible solvent (medium release rate) a compound of Examples P1-P12 0.1-1.0 g 4-hydroxymethyl-1,3-dioxolane (glycerol formal) 40 g 1,2-propanediol ad 100 ml 4T 4 1 a compound of Examples P1-P12 glycerin dimethyl ketal 1,2-propanediol 0.1-1.0 g 40 g ad 100 ml 4j s ~I 4:4rsr (I *41 Preparation: The active ingredient is dissolved in a portion of the solvent while stirring, and the solution is made up to the prescribed volume and sterile-filtered through a suitable membrane filter having a pore diameter of 0.22 pm.
C. Aqueous solubilisate (rapid release) a compound of Examples P1-P12 polyethoxylated castor oil ethylene oxide units)* 0.1-1.0 g 10 g 1,2-propanediol benzyl alcohol aqua ad inject.
*Obtainable comme a compound of Exa polyethoxylated s ethylene oxid 4-hydroxymethyl-1 (glycerol formal) benzyl alcohol J aqua ad inject.
**Obtainable comm i{ i. Preparation: The act surfactant, and the water and then steri 1* 41 20 g 1 g ad 100 ml rcially under the name CREMOPHOR® EL (BASF AG); mples P1-P12 orbitan monooleate e units)** ,3-dioxolane 0.1-1.0 g 8 g 20 g 1 g ad 100 ml ercially under the name TWEEN® 80 (ICI); 4a41 iii 4 4 4 .4 0.22 pm pore diamete The aqueous systems intraruminal adminis Biological Examples ive ingredient is dissolved in the solvents and the solution is made up to the prescribed volume with le-filtered through a suitable membrane filter of r.
may preferably be used also for oral and/or tration.
B-1. Action against L1-larvae of Lucilia sericata h tZ( 1 Ilrrl.
t 1 ml of an aqueous suspension of the test compound is mixed in such a manner with 3 ml of a special larval culture medium at about 50 0 C that a homogeneous composition containing, as desired, 250 ppm or 125 ppm of active ingredient is obtained. About 30 Lucilia larvae (L 1 are put into each of a number of test tubes containing the test compositior. The mortality rate is determined after 4 days. Compounds of formula I, for example those of Examples P1 to P12, achieve complete kill at 250 ppm.
i 42 B-2. Acaricidal action against Boophilus microplus (Biarra strain) Adhesive tape is applied horizontally across a PVC plate in such a manner that 10 female Boophilus microplus ticks (Biarra strain) fully replete with blood can be affixed thereto in the dorsal position side by side in a row. Using an injection needle, each tick is injected with 1 pl of a liquid consisting of a 1:1 mixture of polyethylene glycol and acetone in which a specific amount of active ingredient of 1.0 pg per tick has been dissolved. Control ticks receive an injection that does not contain active ingredient. After treatment, the ticks are kept in an insectarium under normal conditions at about 28 0 C and 80 relative humidity until oviposition has taken place and the larvae have hatched from the eggs of the control ticks.
The activity of a tested compound is determined by the IR 9 o, i.e. that dose of active ingredient is determined at which 9 out of 10 female ticks even after 30 days, lay eggs from which larvae are unable to hatch.
Compounds of formula I, for example of Examples P1-P12, exhibit an IR 90 at a dosage of 5 pg/g.
S B-3. Trial with sheep infested with nematodes (Haemonchus contortus and Trichostrongylus colubriformis) The active ingredient is formulated as a suspension and administered using a stomach probe or by intraruminal injection to sheep that have been artificially infested with Haemonchus contortus and Trichostrongylus colubriformis. 1 to 3 animals are used for each dose. Each sheep is treated once only with a single dose of, as desired, 1 mg or 0.5 mg/kg of a body weight. Evaluation is made by comparing the number of worm eggs excreted in the faeces of the sheep before and after treatment.
Sheep infested simultaneously and in the same manner but untreated are used as controls. In comparison with untreated but infested control groups, sheep that have been treated with compounds of formula I, for example those of Examples P1 to P12 at 1 mg/kg, show no nematode infestation complete reduction of the worm eggs in the faeces).
I i -4i 43 B-4. Larvicidal action against Aedes aegypti A 0.1 solution of the active ingredient in acetone is pipetted onto the surface of 150 ml of water in each of a number of containers in amounts sufficient to give concentrations of, as desired, 10 ppm, 3.3 ppm and 1.6 ppm. After the acetone has evaporated, about 30 to 40 3-day-old 4 edes larvae are put into each container. Mortality counts are made after ij 1, 2 and 5 days.
In this test, compounds of formula I, such as, for example, those of Examples PI to P12, achieve complete kill of all larvae at low concentration after only one day.
tl B-5. Miticidal action against Dermanyssus gallinae 2 to 3 ml of a test solution containing 100 ppm of active ingredient are put into a glass container which is open at the top, and about 200 mites in different stages of development are put into this container. The glass container is sealed with a wad of cotton wool and is uniformly shaken for minutes until the mites have been completely wetted. The container is then inverted until excess test solution has been absorbed by the cotton 4 wool. The container is then stood upright again and the treated mites are I .kept :ider observation for three days under laboratory conditions in i order to evaluate the effectiveness of the test compounds. Mortality is the criterion for effectiveness.
Compounds of Preparation Examples P1 to P12 achieve a kill of the mites at the stated concentration.

Claims (12)

1. Compounds of formula I YH 3 .23 H Ph 1 22/\ Ph Ij 0I 0*OHR 2 H3 GC 0\ Pf~x \CH 3 p 4,to t p p. in which X is one of the groups -CH(0R 1 or C=OR- R, 1 is hydrogen or an OH-protecting group; R is hydrogen, an OH-protecting group, or an alkyl or cycloalkyl group; R. 2 is methyl, ethyl, isopropyl or sec.-butyl; and Ph is a phenyl ring that is substituted by R, 0 R c and R d’ wherein each of RPa, Rb, R c and R d, independently of the others, is hydrogen, Cl-Cloalkyl, C2-Cloalkoxyalkyl, C 2 -Cloalkenyl, C 1 -Cloalkoxy, C 2 -Cloalk- oxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group CI-G 3 alkyl and Gl-C3alkoxy.

2. Compounds of formula I according to claim 1, wherein X is -GH(0R 1 )-and RI is hydrogen or a protecting group, R.2 is methyl, ethyl, isopropyl or sec.-butyl; and Ph is a phenyl ring that is substituted by R a, Rb, Rc and R )wherein each of RPa, Rb, RP. and RPd independently of the others, is hydrogen, CI-Cloalkyl, Cz-Cloalkoxyalkyl, C 2 -Cloalkenyl, Cl-Cloalkoxy, C2-Cloalkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group Cl-C3al’kyl and Cl-C3alkoxy. 4 14 ii i i i r i r s r D e a F I I L I ra i I r~ .r rr r ritr i 45

3. Compounds of formula I according to claim 1, wherein X is -CH(ORi)-and RI is hydrogen, Rz is methyl, ethyl, isopropyl or sec.-butyl; and Ph is a phenyl ring that is substituted by R, R b Rc and R d wherein each of R R b Rc and R d independently of the others, is hydrogen, Ci-Cioalkyl, Cz-Cioalkoxyalkyl, C2-Cioalkenyl, C 1 -Cioalkoxy, C2-Cioalkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group Ci-C3alkyl and Ci-C 3 alkoxy.

4. Compounds of formula I according to claim 1, wherein X is -CH(ORi)-and RI is hydrogen, R 2 is methyl or ethyl; and Ph is a phenyl ring that is substituted by Ra, Rb, Rc and Rd, wherein each of Ra, Rb, Rc and Rd’ independently of the others, is hydrogen, C 1 -Cioaikyl, C 2 -Cioalkoxyalkyl, Cz-Cioalkenyl, C 1 -Cioalkoxy, Cz-Cioalkoxyalkoxy, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one sub- stituent from the group C 1 -C 3 alkyl and Ci-C 3 alkoxy.

5. Compounds of formula I according to claim 1, wherein X is -CH(ORi)-and RI is hydrogen, R 2 is methyl or ethyl; and Ph is a phenyl ring that is substituted by Ra, Rb, R and Rd, wherein each of R Rb, Rc and Rd, independently of the others, is hydrogen, Ci-Cioalkyl, Cz-Cioalkoxyalkyl, Cz-Cioalkenyl, C 1 -Cioalkoxy or Cz-Cioalkoxyalkoxy.

6. Compounds of formula I according to claim 1, wherein X is -CH(ORi)-and RI is hydrogen, R 2 is methyl or ethyl; and Ph is a phenyl ring that is substituted by Ra, Rb, Rc and Rd, wherein each of R a Rb, Rc and Rd’ independently of the others, is hydrogen, or a phenyl or phenoxy radical that is unsubstituted or is substituted by at least one substituent from the group Ci-C 3 alkyl and Ci-C 3 alkoxy.

7. Compounds of formula I according to claim 1, wherein X is -CH(ORi)-and RI is hydrogen, R 2 is methyl or ethyl; and Ph is a phenyl ring that is substituted by Ra, Rb, Rc and Rd, wherein each of R a R b Rc and Rd, independently of the others, is hydrogen, Ci-C3alkyl or C1-C3alkoxy, with the proviso that not more than two of the substituents Ra, Rb, Rc and R d have a meaning other than hydrogen. 4 46

8. Compounds of formula I according to claim 1, wherein X is -CH(ORI)-and R 1 is hydrogen, R 2 is methyl or ethyl; and Ph is a phenyl ring that is substituted by Ra, Rb, Rc and Rd, wherein each of Ra, Rb, Rc and Rd independently of the others, is hydrogen, phenyl or phenoxy, with the proviso that not more than two of the substituents Ra, Rb, Rc and Rd have a meaning other than hydrogen.

9. Compounds of formula I according to claim 1, wherein X is -CH(OR 1 )-and R 1 is hydrogen, Rz is methyl or ethyl; and Ph is phenyl that is unsub- stituted or monosubstituted by methyl, methoxy, phenyl or phenoxy, or disubstituted by methyl or methoxy, or trisubstituted by methyl. Compounds of formula I according to claim 1, wherein X is -CH(OR 1 and R 1 is hydrogen, R 2 is ethyl; and Ph is phenyl that is unsubstituted or monosubstituted by methyl, methoxy, phenyl or phenoxy, or disubsti- tuted by methyl or methoxy, or trisubstituted by methyl.

11. Compounds of formula I according to claim 1, wherein X is -CH(OR 1 and RI is hydrogen, R2 is methyl or, especially, ethyl; and Ph is phenyl that is unsubstituted or monosubstituted by methyl, methoxy, phenyl or phenoxy, or disubstituted by methoxy.

12. A compound of formula I selected from the group:

138-phenyl-milbemycin A4, 132-(2-methoxyphenyl)-milbemycin A4, 13a-(3-methoxyphenyl)-milbemycin A4, 132-(4-methoxyphenyl)-milbemycin A4, 133-(2-methylphenyl)-milbemycin A4, 133-(4-biphenylyl)-milbemycin A4, 138-(4-phenoxyphenyl)-milbemycin A 4 and 13f-(3,4-dimethoxyphenyl)-milbemycin A. 13. A compound of formula I selected from the group: 132-phenyl-milbemycin A 3 13B-(2-methylphenyl)-milbemycin A4 and 13Q-(4-methylphenyl)-milbemycin As. 47 14. A process for the preparation of compounds of formula I, which process comprises reacting a compound of formula II 16 .CH 3 *1 17 1z: IOR 2 H 3 C (II) I I )II CH3 IRI wherein G is one of the groups a or b IH3 CH3 Ei CH/ or H 14,15 1 3 1 4 13B-halogen-A 15-chloro-A R 1 is hydrogen or an OH-protecting group, Rz is as defined for formula I, and E is chlorine, bromine or iodine, with a diaryl zinc compound of formula III Ph-Zn-Ph (III), wherein Ph is as defined for formula I, in the presence of a transition metal salt, and, if desired, when RI is an OH-protecting group, removing that protecting group by hydrolysis. 15. A process according to claim 14, which comprises carrying out the reaction in the presence of a transition metal salt that contains, as the metal component, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd or Pt. 16. A process according to claim 15, which comprises carrying out the reaction in the presence of a transition metal salt that contains, as the metal component, Co, Ni or Pd. -48- 17. A process according to claim 14, which comprises using as the transition metal salt Nil 2′ CoCl 2 E(phenyl) 3 PI 2 NiCl 2 [(phenyl) 3 PI 2 Pd- Cl 2 [(phenyl) 2 PCH 2 1 2 NiCl 2 [(phenyl) 2 PCH 2 2CoBr 2 [(phenyl) 2 PCH 2 CH 2 CH 2 P(phenyl) 2 1iCl 2 [(phenyl) 2 PCH 2 CH 2 1 2 NiCl 2 or [(cyclohexyl) 3 P 2 NiCl 2 18. A process for the preparation of compounds of formula TIb 2 3 YH 3 2 0~ 1 HR (IMb), H RiCH 3 in which Ris hydrogen or an OH-protecting group; and R 2 is methyl, ethyl, isopropyl or- sec.-butyl, which comprises reacting a milbemycin of formula M” 29 1 13 1 H 3 CH wherein Ris methyl, ethyl, isopropyl or sec.-butyl with a chlorinating agent that brings about the formation of the corresponding 15chIooA3,4derivative. 19. A process according to claim 18, which comprises using tert.-butyl hypochlorite as the chlorinating agent. 296v 49 Compounds of formula lib H3 22 3 CH3 H 2 I 0 SCII (lib), II II SCH3 Rj 3 in which R is hydrogen or an OH-protecting group; and R 2 is methyl, ethyl, isopropyl or sec.-butyl. 21. Compositions for controlling pests, which contain at least one compound of formula I according to claim 1 as active ingredient, together with carriers, distributing agents or carriers and distributing agents. 22. A method of controlling pests, which comprises applying or admini- stering a pesticidally effective amount of a compound of formula I according to claim 1 to the host animals, host plants or other loci of the pests. 23. A method according to claim 22, wherein the pests to be controlled are endo- or ecto-parasites of animal-. 24. A method according to claim 22, wherein the pests to be controlled are plant-destructive parasites. A method according to claim 22, wherein the pests are parasitic nematodes. FO i .’j 3.39 C3H7-iso 4 -phenoxyphenyl 3.40 CuHg-sek 4 -phenoxyphenyl 3.41 CH 3 4 -methylphenyl 3.42 C 2 H 5 4 -methylphenyl 3.43 C3H7-iso 4 -methylphenyl 3.44 C4H9-sek 4 -methylphenyl 1 ii 50 26. 13-phenyl-milbemycin derivatives substantially as herein described with reference to any one of the Examples. 27. A process for preparing 13-phenyl-milbemycin derivatives which process is substantially as herein described with reference to any one of the Examples. 28. The product of the process of any one of claims 14 to 19 or 27. 29. A composition for controlling pests, which contains at least one compound according to claim 26 or 28 together with a carrier, distributing agent or a carrier and a distributing agent. 30. A composition for controlling pests substantially as herein described with reference to any one of the Formulation Examples. 31. A method of controlling pests, comprising applying or administering to the locus pesticidally effective amount of a compound as defined in claim 26 or 28 and/or a composition as defined in claim 29 or 32. A method of controlling pests which method is substantially as S” herein described with reference to any one of the Biological Examples B-1 i to 44i4 DATED this NINTH day of JANUARY 1992 j Ciba-Geigy AG Patent Attorneys for the Applicant 4, SPRUSON FERGUSON I ,i KXW:1296v i i_;

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1986-05-07
Ciba-Geigy Ag
13-Halo- and 13-hydroxymilbemycin

US4696922A
(en)

1984-11-26
1987-09-29
Ciba-Geigy Corporation
5-azolylacetoxymilbemycins as ecto- and endoparasites

FI860233A
(en)

1985-01-22
1986-07-23
Ciba Geigy Ag

13 -ALKYL-MILBEMYCINDERIVAT FOER BEKAEMPNING AV PARASITER HOS DJUR OCH VAEXTER.

JPS6289685A
(en)

1985-05-31
1987-04-24
Sankyo Co Ltd
13-halogenomilbemycin derivative

IE67373B1
(en)

1985-09-13
1996-03-20
American Cyanamid Co
Macrolide antibiotics and their preparation

DE3631387A1
(en)

1985-09-18
1987-03-26
Ciba Geigy Ag
Agents for combating parasitic pests

GB8606105D0
(en)

1986-03-12
1986-04-16
Glaxo Group Ltd
Chemical compounds

GB8606116D0
(en)

1986-03-12
1986-04-16
Glaxo Group Ltd
Process

EP0253378A3
(en)

1986-07-18
1988-03-23
Ciba-Geigy Ag
13-beta-alkyl derivatives of s541-antibiotics for combating parasites in domestic animals and plants

EP0262384B1
(en)

1986-09-12
1992-11-04
American Cyanamid Company
23-deoxy derivatives of ll-f28249 compounds

US4831016A
(en)

1986-10-31
1989-05-16
Merck & Co., Inc.
Reduced avermectin derivatives

EP0282456A3
(en)

1987-03-13
1989-10-11
Ciba-Geigy Ag
Mylbemycin derivatives to combat parasites on animals

US4806527A
(en)

1987-03-16
1989-02-21
Merck & Co., Inc.
Avermectin derivatives

US4918097A
(en)

1988-03-11
1990-04-17
Ciba-Geigy Corporation
Insecticides and parasiticides

1989

1989-03-01
US
US07/317,387
patent/US4918097A/en
not_active
Expired – Fee Related

1989-03-02
AT
AT89810161T
patent/ATE112776T1/en
active

1989-03-02
DE
DE58908482T
patent/DE58908482D1/en
not_active
Expired – Fee Related

1989-03-02
ES
ES89810161T
patent/ES2062087T3/en
not_active
Expired – Lifetime

1989-03-02
EP
EP89810161A
patent/EP0332580B1/en
not_active
Expired – Lifetime

1989-03-07
PH
PH38296A
patent/PH25406A/en
unknown

1989-03-09
PT
PT89957A
patent/PT89957B/en
not_active
IP Right Cessation

1989-03-09
IL
IL89550A
patent/IL89550A/en
not_active
IP Right Cessation

1989-03-09
NZ
NZ228280A
patent/NZ228280A/en
unknown

1989-03-09
CA
CA000593194A
patent/CA1325207C/en
not_active
Expired – Fee Related

1989-03-10
HU
HU891196A
patent/HU200775B/en
not_active
IP Right Cessation

1989-03-10
ZA
ZA891834A
patent/ZA891834B/en
unknown

1989-03-10
IE
IE77789A
patent/IE64228B1/en
not_active
IP Right Cessation

1989-03-10
JP
JP1056511A
patent/JP2846333B2/en
not_active
Expired – Lifetime

1989-03-10
AU
AU31195/89A
patent/AU621593B2/en
not_active
Ceased

1989-03-10
ZW
ZW34/89A
patent/ZW3489A1/en
unknown

1989-03-11
KR
KR1019890003062A
patent/KR0126132B1/en
not_active
IP Right Cessation

1990

1990-10-17
US
US07/600,037
patent/US5122618A/en
not_active
Expired – Fee Related

Patent Citations (2)

* Cited by examiner, † Cited by third party

Publication number
Priority date
Publication date
Assignee
Title

AU5071985A
(en)

1984-12-04
1986-06-12
Sankyo Company Limited
13“ -milbemycin derivatives for controlling ecto-and endoparasites of plants and animals

AU574566B2
(en)

1985-02-25
1988-07-07
Merck & Co., Inc.
13-akoxymethoxy avermectin aglycone derivatives

Also Published As

Publication number
Publication date

DE58908482D1
(en)

1994-11-17

PT89957A
(en)

1989-11-10

HU200775B
(en)

1990-08-28

NZ228280A
(en)

1991-09-25

ZW3489A1
(en)

1989-10-04

ES2062087T3
(en)

1994-12-16

PH25406A
(en)

1991-07-01

KR890014550A
(en)

1989-10-24

ATE112776T1
(en)

1994-10-15

IE890777L
(en)

1989-09-11

EP0332580A3
(en)

1991-01-16

CA1325207C
(en)

1993-12-14

IL89550A
(en)

1992-06-21

JP2846333B2
(en)

1999-01-13

EP0332580B1
(en)

1994-10-12

US5122618A
(en)

1992-06-16

IE64228B1
(en)

1995-07-26

EP0332580A2
(en)

1989-09-13

AU3119589A
(en)

1989-09-14

JPH01275584A
(en)

1989-11-06

ZA891834B
(en)

1989-11-29

US4918097A
(en)

1990-04-17

HUT49794A
(en)

1989-11-28

PT89957B
(en)

1994-05-31

KR0126132B1
(en)

1997-12-24

IL89550A0
(en)

1989-09-10

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