Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Reexamination Certificate
2000-12-14
2003-10-07
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C530S328000, C514S011400, C514S016700
Reexamination Certificate
active
06630569
ABSTRACT:
The present invention relates to the use of cyclic depsipeptides, in particular 24-membered cyclodepsipeptides, for controlling ectoparasites, and to ectoparasiticidal compositions which comprise the depsipeptides.
Cyclic depsipeptides, and their preparation and use as parasiticides against helminths, nematodes and trematodes in animals (endoparasiticides) have already been the subject of numerous publications.
Known is, for example, a cyclodepsipeptide with the name PF 1022A and its action against endoparasites (EP-A 382 173 and EP-A 503 538). Further cyclic depsipeptides (cyclooctadepsipeptides: WO 98/55 469; WO 98/43 965; WO 93/19 053; EP-A 634 408; WO 94/19 334; WO 95/07 272; EP-A 626 375; EP-A 626 376; EP-A 664 297; EP 634 408; EP-A 718 298; WO 97/09 331; cyclohexadepsipeptides: WO 93/25 543; WO 95/27 498; EP-A 658 551; cyclotetradepsipeptides: EP-A 664 297; dioxomorpholines: WO 96/38 165: JP 08 225 552) and open-chain depsipeptides (EP-A 657 171; EP-A 657 172; EP-A 657 173; WO 97/07 093) and their endoparasiticidal action have been described.
Furthermore, it is already known that certain 24-membered cyclodepsipeptides, for example bassianolide and PF1022A, have insecticidal activity against silkworms (cf. M. Kanaoka et al., Agric. Biol. Chem. 43 (5), 1979, pp. 1079-83; JP 05 271 013).
However, the insecticidal activity of the prior-art compounds is, in particular at low application rates and concentrations, not entirely satisfactory in all areas of use. Futhermore, their use against ectoparasites, for example ticks, fleas and mites, has hitherto not been disclosed.
The present application provides:
Method of use of cyclooctadepsipeptides of the formula (I)
in which
R
1
represents hydrogen, C
1-4
-alkyl, in particular methyl, hydroxyl, halogen, in particular fluorine, C
1-4
-alkoxy, in particular methoxy or tert-butyloxy, C
1-4
-alkoxy-C
1-4
-alkyl, in particular methoxymethyl, ethoxyethyl, heterocyclylmethyl, in particular pyridylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, furylmethyl, thienylmethyl, heteroaryl-C
1-2
-alkoxy, in particular pyridyl-methoxy, tetrahydrofuryl-methoxy, pyrrolidinyl-methoxy and furyl-methoxy, nitro, —NR
3
R
4
, —SO
2
—NR
3
R
4
,
R
2
represents hydrogen, C
1-4
-alkyl, in particular methyl, hydroxyl, halogen, in particular fluorine, C
1-4
-alkoxy, in particular methoxy or tert-butyloxy, C
1-4
-alkoxy-C
1-4
-alkyl, in particular methoxymethyl, ethoxyethyl, heterocyclylmethyl, in particular pyridylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, furylmethyl, thienylmethyl, heteroaryl-C
1-2
-alkoxy, in particular pyridyl-methoxy, tetrahydrofuranyl-methoxy, pyrrolidinyl-methoxy and furyl-methoxy, nitro, —NR
3
R
4
, —SO
2
—NR
3
R
4
,
R
3
and R
4
independently of one another each represent hydrogen, optionally substituted C
1-4
-alkyl, formyl, C
1-4
-alkoxycarbonyl, optionally substituted arylmethyl, in particular benzyl, or heterocyclylmethyl, in particular pyridylmethyl, tetrahydrofuranylmethyl, pyrrolidinylmethyl, furylmethyl, thienylmethyl,
R
3
and R
4
together with the nitrogen atom to which they are attached represent an optionally substituted mono- or polycyclic, optionally bridged and/or spirocyclic, saturated or unsaturated heterocycle which may contain one to three further heteroatoms from the group consisting of nitrogen, oxygen and sulphur,
X
1
, X
2
, X
3
and X
4
independently of one another represent oxygen or sulphur,
where, if R
1
and R
2
simultaneously represent hydrogen, at least one of the radicals X
1
, X
2
, X
3
and X
4
represents sulphur.
Depending on the nature of the substituents, the compounds of the general formula (I) can be present as geometrical and/or optical isomer mixtures of varying compositions. The invention relates both to the pure isomers and to the isomer mixtures.
The formula (I) provides a general definition of the cyclooctadepsipeptides which can be used according to the invention.
The substituents R
1
and R
2
are preferably in the para- or ortho-position. Particular preference is given to the para-position.
The substituents X
1
, X
2
and X
3
preferably represent oxygen, the substituent X4 preferably represents oxygen or sulphur.
Compounds of the general formula (I) which can be used according to the invention and which may be mentioned are, in particular, the compounds of the formula (II) below known from the PCT applications WO 93/19 053, WO 97/11 064 and EP-A 634 408 A1:
in which
R
1
and R
2
represent identical or different radicals from the group consisting of hydrogen, N-morpholino, nitro, amino, mono- and dimethylamino, furylmethoxy, tetrahydrofurylmethoxy, pyrrolidinylmethoxy or pyridylmethoxy, but do not simultaneously represent hydrogen.
Furthermore, mention may be made of the compounds known from the PCT application WO 94/19 334.
Particular mention may be made of the compounds, known from the PCT applications WO 94/19 334 and WO 97/11 064, of the formula (III) below
in which
R
2
represents hydroxy, methoxy or tert-butoxy and furylmethoxy.
Finally, mention may be made of the prior-art compounds known from the PCT application WO 95/07 272.
The generic formulae and definitions described in these publications, and the individual compounds described therein, are explicitely incorporated herein by way of reference.
Furthermore and in particular, as compounds of the general formula (I) which can be used according to the invention and in which at least one of the substituents X
1
, X
2
and X
3
and/or X
4
represents sulphur, mention may be made of the cyclic depsipeptides of the general formula (IV) and (V):
in which
R
1
and R
2
represent identical or different radicals from the group consisting of hydrogen. N-morpholino, nitro, amino, mono- and dimethylamino, furylmethoxy, tetrahydrofurylmethoxy, pyrrolidinomethoxy or pyridylmethoxy.
The cyclic depsipeptides of the general formula (IV) and (V) form part of the subject-matter of a patent application of the applicant, which is a prior publication (cf. WO 98/43 965). These compounds are prepared by thionating compounds of the formula (I) in which X
1
, X
2
and X
3
and X
4
represent oxygen with a suitable sulphurizing agent in the presence of diluent. Reference is made here to the corresponding Preparation Examples further below.
The cyclic depsipeptides which can be used according to the invention are suitable for controlling animal pests, such as arthropods, preferably insects, arachnids, encountered in animal husbandry and livestock breeding, in productive livestock, breeding stock, zoo animals, laboratory animals, animals used in experiments and pets, and have low toxicity toward warm-blooded animals. They are active against all or some stages of development of the pests and against resistant and normally sensitive species of the pests.
By controlling the animal pests, it is intended to prevent diseases and their transmission, mortality and decreasing performance (for example in the production of meat, milk, wool, hides, eggs), so that more economical and simpler animal keeping is possible, or so that in certain areas animal keeping is possible at all, by using the active compounds.
The pests include:
from the order of the Anoplura, for example, Haematopinus spp., Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.;
from the order of the Mallophaga, for example, Trimenopon spp., Menopon spp., Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicola spp., Damalinea spp., Bovicola spp.;
from the order of the Diptera, for example, Chrysops spp., Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematobosca spp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp., Lucilia spp., Calliphora spp., Auchmeromyia spp., Cardylobia spp., Cochiomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfartia spp., Gasterophilus spp., Oesteromyia spp., Oedemagena sp., Hypoderma spp., Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.
from the order of the Siphonaptera, for example, Ctenocephalides spp., Echidnophaga spp., Ceratophyllus spp.
from the order of the Metastigmata, for example
Hansen Olaf
Jeschke Peter
Mencke Norbert
Turberg Andreas
Bayer Aktiengesellschaft
Low Christopher S. F.
Lukton David
Pellegrino Susan M.
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