HK1117041B - Prevention of vertical endoparasite infections - Google Patents
Prevention of vertical endoparasite infections Download PDFInfo
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- HK1117041B HK1117041B HK08107354.7A HK08107354A HK1117041B HK 1117041 B HK1117041 B HK 1117041B HK 08107354 A HK08107354 A HK 08107354A HK 1117041 B HK1117041 B HK 1117041B
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Description
The invention relates to the use of endoparasiticidal depsipeptides for the production of a medicament for preventing vertical infection by endoparasites.
The cyclic depsipeptide PF1022, and its action against endoparasites, has been disclosed in EP-A382173. Patent application EP-A626376; EP-A626375 and EP-A644883 relate to other cyclic depsipeptides and their endoparasiticidal action,
endoparasiticidal compositions comprising praziquantel or epsiprantel and a cyclic depsipeptide are described in EP 662326.
It is well known that these compositions have an effect against endoparasites in the animals involved after oral, parenteral or transdermal administration. However, it was not previously known that these active compounds are also capable of preventing vertical infections in the offspring of animals.
The invention thus relates to:
use of an endoparasiticidal depsipeptide for the manufacture of a medicament for use in preventing vertical infection by an endoparasite.
Depsipeptides are similar to peptides but differ from the latter in that one or more alpha-amino acid building blocks are replaced by alpha-hydroxycarboxylic acid building blocks. According to the invention, it is preferred to use cyclic depsipeptides having 18 to 24 ring atoms, in particular having 24 ring atoms.
Depsipeptides having 18 ring atoms include compounds of the general formula (I);
wherein
R1、R3And R5Independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, mercaptoalkyl, alkylThioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, guanidinoalkyl which can optionally be substituted by one or two benzyl-oxycarbonyl groups or by one, two, three or four alkyl groups, alkoxycarbonylaminoalkyl, 9-fluorenylmethoxycarbonyl (Fmoc) aminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted arylalkyl, where substituents which may be mentioned are halogen, hydroxy, alkyl and alkoxy,
R2，R4and R6Independently of one another, hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, hydroxyalkyl, mercaptoalkyl, alkanoyloxyalkyl, alkoxyalkyl, aryloxyalkyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, carboxyalkyl, alkoxycarbonylalkyl, arylalkoxycarbonylalkyl, carbamoylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonylaminoalkyl, alkenyl, cycloalkyl, cycloalkylalkyl and optionally substituted aryl or arylalkyl, where substituents which may be mentioned are halogen, hydroxyl, alkyl and alkoxy,
and their optical isomers and racemates.
Preferred are compounds of the formula (I)
Wherein
R1、R3And R5Independently of one another, straight-chain or branched C1-C8Alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, especially hydroxymethyl, 1-hydroxyethyl, C1-C4alkanoyloxy-C1-C6Alkyl, especially acetoxymethyl, 1-acetoxyethyl, C1-C4-alkoxy-C1-C6Alkyl, especially methoxymethyl, 1-methoxyethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl, especially benzyloxymethyl, 1-benzyloxyethyl, mercapto C1-C6Alkyl, especially mercaptomethyl, C1-C4-alkylthio-C1-C6Alkyl radicals, especially methylthioethyl, C1-C4-alkylsulfinyl-C1-C6Alkyl, especially methyl-sulfinylethyl, C1-C4-alkylsulfonyl-C1-C6Alkyl, especially methylsulfonylethyl, carboxy-C1-C4Alkyl, especially carboxymethyl, carboxyethyl, C1-C4-alkoxycarbonyl-C1-C6Alkyl, especially methoxycarbonylmethyl, ethoxycarbonylethyl, C1-C4Aryl alkoxycarbonyl-C1-C6Alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C1-C6Alkyl, especially carbamoylmethyl, carbamoylethyl, amino-C1-C6Alkyl, especially aminopropyl, aminobutyl, C1-C4-alkylamino-C1-C6Alkyl, especially methylaminopropyl, methylaminobutyl, C1-C4-dialkylamino-C1-C6Alkyl, especially dimethylaminopropyl, dimethylaminobutyl, guanidino C1-C6Alkyl, especially guanidinopropyl, C1-C4-alkoxycarbonylamino-C1-C6Alkyl, especially tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, 9-fluorenyl-methoxycarbonyl (Fmoc) amino-C1-C6Alkyl, especially 9-fluorenyl-methoxycarbonyl (Fmoc) aminopropyl, 9-fluorenylmethoxycarbonylRadical (Fmoc) -aminobutyl, C2-C8Alkenyl radicals, in particular vinyl, allyl, butenyl, C3-C7Cycloalkyl, especially cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl, especially cyclopentylmethyl, cyclohexylmethyl, cycloheptyl-methyl, phenyl-C1-C4Alkyl, in particular phenylmethyl, which can optionally be chosen from halogen (in particular fluorine, chlorine, bromine or iodine), hydroxy, C1-C4Alkoxy (especially methoxy or ethoxy) and C1-C4-substitution of groups in alkyl (especially methyl),
R2、R4and R6Independently of one another, straight-chain or branched C1-C8Alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, especially hydroxymethyl, 1-hydroxyethyl, C1-C4alkanoyloxy-C1-C6Alkyl, especially acetoxymethyl, 1-acetoxyethyl, C1-C4-alkoxy-C1-C6Alkyl, especially methoxymethyl, 1-methoxyethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl, especially benzyloxymethyl, 1-benzyloxyethyl, mercapto-C1-C6Alkyl, especially mercaptomethyl, C1-C4-alkylthio-C1-C6Alkyl, especially methylthioethyl, C1-C4-alkylsulfinyl-C1-C6Alkyl, especially methylsulfinylethyl, C1-C4-alkylsulfonyl-C1-C6Alkyl, especially methylsulfonylethyl, carboxy-C1-C6Alkyl, especially carboxymethyl, carboxyethyl, C1-C4-alkoxycarbonyl-C1-C6Alkyl, especially methoxycarbonylMethyl, ethoxycarbonylethyl, C1-C4Aryl alkoxycarbonyl-C1-C6Alkyl, especially benzyloxycarbonylmethyl, carbamoyl-C1-C6Alkyl, especially carbamoylmethyl, carbamoylethyl, amino-C1-C6Alkyl, especially aminopropyl, aminobutyl, C1-C4-alkylamino-C1-C6Alkyl, especially methylaminopropyl, methyl-aminobutyl, C1-C4-dialkylamino-C1-C6Alkyl, especially dimethylaminopropyl, dimethylaminobutyl, C2-C8Alkenyl, especially vinyl, allyl, butenyl, C3-C7Cycloalkyl, especially cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl, especially cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C1-C4Alkyl, in particular phenylmethyl, which can optionally be chosen from halogen (in particular fluorine, chlorine, bromine or iodine), hydroxy, C1-C4Alkoxy (especially methoxy or ethoxy) and C1-C4-alkyl (especially methyl) substituted by a substituent,
and their optical isomers and racemates.
Particularly preferred are compounds of the formula (I), in which
R1、R3And R5Independently of one another, straight-chain or branched C1-C8Alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, especially hydroxymethyl, 1-hydroxyethyl, C1-C4alkanoyloxy-C1-C6Alkyl, especially acetoxymethyl, 1-acetoxyethyl, C1-C4-alkoxy-C1-C6Alkyl, especially methoxymethyl, 1-methoxyethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl, especially benzyloxymethyl, 1-benzyloxyethyl, C1-C4-alkoxycarbonylamino-C1-C6Alkyl, especially tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, C2-C8Alkenyl, especially vinyl, allyl, C3-C7Cycloalkyl, especially cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl, especially cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C1-C4Alkyl, in particular phenylmethyl, which can be optionally substituted by one or more identical or different radicals selected from those specified above,
R2，R4and R6Independently of one another, straight-chain or branched C1-C8Alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C1-C6Alkyl, especially hydroxymethyl, aryl-C1-C4-alkoxy-C1-C6Alkyl, especially benzyloxymethyl, 1-benzyloxyethyl, carboxy-C1-C6Alkyl, especially carboxymethyl, carboxyethyl, C1-C4-alkoxycarbonyl-C1-C6Alkyl, especially methoxycarbonylmethyl, ethoxycarbonylethyl, C1-C4-aryl-alkoxycarbonyl-C1-C6Alkyl, especially benzyloxycarbonylmethyl, C1-C4-alkylamino-C1-C6Alkyl, especially methylaminopropyl, methylaminobutyl, C1-C4-dialkylamino-C1-C6Alkyl, especially dimethylaminopropyl, dimethylaminobutyl, C2-C8Alkenyl, especiallyVinyl, allyl, butenyl, C3-C7Cycloalkyl, especially cyclopentyl, cyclohexyl, cycloheptyl, C3-C7-cycloalkyl-C1-C4Alkyl radicals, in particular cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, phenyl-C1-C4Alkyl, in particular phenylmethyl, which can be optionally substituted by one or more identical or different radicals selected from those specified above,
and their optical isomers and racemates.
Very particular preference is given to compounds of the formula (I) in which
R1、R3And R5Independently of one another, straight-chain or branched C1-C8Alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C2-C8Alkenyl, especially allyl, C3-C7-cycloalkyl-C1-C4Alkyl, especially cyclohexylmethyl, phenyl-C1-C4Alkyl groups, in particular phenylmethyl groups,
R2、R4and R6Independently of one another, straight-chain or branched C1-C8Alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, C2-C8Alkenyl, especially vinyl, allyl, C3-C7-cycloalkyl-C1-C4Alkyl, especially cyclohexylmethyl, phenyl-C1-C4Alkyl, in particular phenylmethyl, which can optionally be substituted by one or more identical or different radicals selected from those specified above,
and their optical isomers and racemates.
In detail, the following compounds of general formula (I) may be mentioned, in which the radical R1To R6Has the following meanings:
| R1 | R2 | R3 | R4 | R5 | R6 |
| -CHMeCH2Me | -cyclohexyl radical | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMeCH2Me | -cyclohexyl radical | -CHMeCH2Me | -Me | -CHMeCH2Me | -cyclohexyl radical |
| -CHMeCH2Me | -CH2-Phe | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMeCH2Me | -CH2-Phe | -CHMeCH2Me | -Me | -CHMeCH2Me | -CH2-Phe |
| -CHMeCH2Me | -(CH2)3-Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMeCH2Me | -(CH2)3-Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -(CH2)3-Me |
| -CHMe2 | -CH2-Phe | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CH2-Phe | -CHMe2 | -CH2-Phe | -CHMe2 | -CHMeCH2Me | -CHMe2 |
| -CH2CHMe2 | -CH2-Phe | -CH2CHMe2 | -Me | -CH2CHMe2 | ·CH2-Phe |
| -(CH2)3-Me | -Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -Me |
| -CHMe2 | -Me | -CHMe2 | -Me | -CHMe2 | -Me |
| -CH2-Me | -Me | -CH2-Me | -Me | -CH2-Me | -Me |
| -(CH2)2-Me | -Me | -(CH2)2-Me | -Me | -(CH2)2-Me | -Me |
| -(CH2)3-Me | -Me | -(CH2)3-Me | -Me | -(CH2)3-Me | -Me |
| -CH2-CH＝CH2 | -Me | -CH2-CH＝CH2 | -Me | -(CH2)-CH＝CH2 | -Me |
| -CHMeCH2Me | -Me | ·CHMeCH2Me | -Me | -CHMeCH2Me | -CH2-Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -(CH2)2-Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -CHMeCH2Me | -(CH2)3-Me |
| -CHMeCH2Me | -Me | -CHMeCH2Me | -Me | -CH2Me | -Me |
| -CHMeCH2Me | -Me | ·CHMeCH2Me | -Me | -(CH2)2-Me | -Me |
| -cyclohexyl radical | -Me | -cyclohexyl radical | -Me | Cyclohexyl radical | -Me |
| -CH2CHMe2 | Cyclohexyl radical | -CH2CHMe2 | -Me | -CHzCHMe2 | Cyclohexyl radical |
| -CH2CHMe2 | -cyclohexyl radical | -CH2CHMe2 | -Me | -CH2CHMe2 | -Me |
| -CHMeCH2Me | -CHMe2 | -CHMeCH2Me | -CHMe2 | -CHMeCH2Me | -Me |
| -CH2-Phe | -Me | -CH2-Phe | -Me | -CH2-Phe | -Me |
| -cyclohexyl radical | -Me | -cyclohexyl radical | -Me | -cyclohexyl radical | -Me |
| -CHMe2 | -CHMe2 | -CHMe | -Me | -CHMe3 | -Me |
| -CHMe2 | -CHMe2 | -CHMe2 | -CHMe2 | -CHMe2 | -Me |
| -CH2-Me | -CHMe2 | -CH2Me | -Me | -CH2-Me | -Me |
| -CH2-Me | -CHMe2 | -CHMe2 | -CHMe2 | -CH2-Me | -Me |
| -(CH2)2-Me | -CHMe2 | -(CH2)2-Me | -Me | -(CH2)2-Me | -Me |
| -(CH2)2-Me | -CHMe2 | -(CH2)2-Me | -CHMe2 | -(CH2)3-Me | -Me |
| -(CH2)3-Me | -CHMe2 | ·(CH2)3-Me | -Me | -(CH2)3-Me | -Me |
| -(CH2)3-Me | -CHMe2 | -(CH2)3-Me | -CHMe2 | -(CH2)3-Me | -Me |
| -CH2-CH＝CH2 | -CHMe2 | -CH2-CH＝CH2 | -Me | -CH2-CH＝CH2 | -Me |
| -CH2-CH＝CH2 | -CHMe2 | -CH2-CH＝CH2 | -CHMe2 | -CH2-CH＝CH2 | -Me |
| -Me | -Me | -CHMeCH2Me | -Me | -CH2-Me | -Me |
| -Me | -Me | -CHMeCH2Me | -Me | -(CH2)3-Me | -Me |
Me ═ methyl; phe ═ phenyl group
Other depsipeptides which may be mentioned are the compound PF1022 which is disclosed in EP-OS382173 and which has the following general formula (IIa):
in addition, depsipeptides which may be mentioned are the compounds disclosed in PCT patent application WO 93/19053.
Mention may in particular be made of the compounds disclosed in WO93/19053 and having the following general formula (IIb):
wherein
Z is N-morpholinyl, amino, mono-or dimethylamino.
Mention may also be made of compounds having the following general formula (IIc):
wherein
R1，R2，R3And R4 independently of one another are hydrogen, C1-C１0Alkyl or aryl, especially phenyl, optionally substituted by hydroxy, C1-C10-alkoxy or halogen substitution.
The compounds of the formulｃA (I) are known and can be obtained by using the processes described in EP-A-382173, DE-A4317432, DE-A4317457, DE-A4317458, EP-A-634408, EP-A-718293, EP-A-872481, EP-A-685469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787141, EP-A-865498 and EP-A-903347.
Cyclic depsipeptides having 24 ring atoms also include compounds of the general formula (IId)
Wherein
R1a，R2a，R11aAnd R12aIndependently of one another is C1-8-alkyl radical, C1-8-halogenoalkyl, C3-6-cycloalkyl, aralkyl, aryl,
R3a，R5a，R7a，R9aindependently of one another, hydrogen or straight-chain or branched C1-8Alkyl, the latter being optionally substituted by hydroxy, C1-4-an alkoxy group, a carboxyl group,the carboxylic acid amide is a carboxylic acid amide,imidazolyl, indolyl, guanidino, -SH or C1-4Alkylthio, and can additionally be substituted by halogen, hydroxy, C1-4-alkyl radical, C1-4-an alkoxy-substituted aryl or aralkyl group,
R4a，R6a，R8aand R10aIndependently of one another, hydrogen, straight chain C1-5-alkyl radical, C2-6-alkenyl radical, C3-7Cycloalkyl radicals, which can be substituted by hydroxy, C1-4Alkoxy, carboxyl, carboxamide, imidazolyl, indolyl, guanidino, SH or C1-4Alkylthio, and may also be substituted by halogen, hydroxy, C1-4-alkyl radical, C1-4-an alkoxy-substituted aryl or aralkyl group,
and their optical isomers and racemates.
Preference is given to using compounds of the formula (IId) in which
R1a，R2a，R11aAnd R12aIndependently of one another, methyl, ethyl, propyl, isopropyl, n-, sec-, tert-butyl or phenyl, which are optionally substituted by halogen, C1-4Alkyl, OH, C1 -4-alkoxy substituted and also benzyl or phenylethyl which can optionally be substituted by the groups mentioned for phenyl; and
R3a-R10ahaving the above-mentionedThe meaning of (a).
Particular preference is given to using compounds of the formula (IId), in which
R1a，R2a，R11aAnd R12aIndependently of one another, methyl, ethyl, propyl, isopropyl or n-, sec-, tert-butyl,
R3a，R5a，R7a，R9ais hydrogen, straight-chain or branched C1-8Alkyl, especially methyl, ethyl, propyl, isopropyl, n-, sec-, tert-butyl, which radicals can optionally be substituted by C1-4Alkoxy (especially methoxy or ethoxy), imidazolyl, indolyl or C1-4Alkylthio (especially methylthio or ethylthio) and is also phenyl, benzyl or phenethyl which can optionally be substituted by halogen (especially chlorine).
R4a，R6a，R8a，R10aIndependently of one another, hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, which can optionally be substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio, and also isopropyl, sec-butyl and additionally phenyl, benzyl or phenylethyl, which are optionally substituted by halogen.
The compounds of the formulｃA (IId) can also be obtained by using the processes described in EP-A-382173, DE-A4317432, DE-A4317457, DE-A4317458, EP-A-634408, EP-A-718293, EP-A-872481, EP-A-685469, EP-A-626375, EP-A-664297, EP-A-669343, EP-A-787141, EP-A-865498 and EP-A-903347,
very particularly preferred depsipeptides according to the invention are PF1022A (see formula (IIa)) and emodepside (PF1022-221, compounds of formula (IIb) in which both Z groups are morpholinyl). INN emodepside is a compound with the following name: cyclo [ (R) -lactyl-N-methyl-L-leucyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucyl.
Depending on their structure, the active compounds can be present in stereoisomeric form or as a mixture of stereoisomers, for example as enantiomers or racemates. Both mixtures of stereoisomers and pure stereoisomers can be used according to the invention.
The following substances may also be used, if appropriate: salts of the active compounds with pharmaceutically acceptable acids or bases, and solvates (especially hydrates) of the active compounds or their salts,
according to the invention, the active compounds can be used for controlling pathogenic endoparasites, which are customary in humans and in animal husbandry and animal breeding, for productive animals, breeding animals, zoo animals, laboratory animals and pet animals. In this regard, the compounds of the present invention are effective against all or various stages of development of the pest as well as against normally susceptible drug-resistant biological species. The control of pathogenic endoparasites is intended to reduce the diseases in production, mortality and yield losses (for example in the production of meat, milk, wool, hides, eggs, etc.), making it possible to achieve simpler and more economical animal husbandry with the active compounds. In a general manner, pathogenic endoparasites include cestodes, trematodes, nematodes, echinococci. Preferably, depsipeptides are used to control nematode infections; the following endoparasites may be mentioned individually:
selected from the order of the mouth pricks, for example: trichuris, capillaris, trichomonas and trichoderma.
Selected from the order of the small rods, for example: micronema and strongyloides.
From the order of the round nematodes, for example strongyloides, tridentate, nodorusus, trichinella, hexadentate-like, Cylindropharynx, Poteriostomum, Cyclocercusspp, Cylicostephanus, nodorusus, Cupressus spp, Cochloesophagus,
heterodera globosa, Heterodera bigemina, Cyathostoma, Stroidogyne spp, Dictyocaulus muller, Heterodera backing-Strongopus, Neostrodia spp, Cystocaulus spp, strongyloides, Spicocculus spp, Elaphstrongylous spp, Parelaphestrongylous spp, Heterodera annulata, Pararenosoma spp, angiostrongyloides, Aellustrongyloides, Filaroides spp, Parafiaroides spp, Trichostrongylus spp, Haemonchus spp, Ostertagia spp, Microbotylenchus spp, Ostertagia spp, Obellischus spp, Eutertagia spp and Ollunulenus spp.
Selected from the order of the Ostertagia, e.g., Ostertagia, Enterobius, Trichosanthes, Ostertagia, Aspiciluris, and Isochrysis.
Selected from the order of the avian ascaridae, e.g., ascaridoides, toxocara, ascaridoides, coleoptera, avian ascaridae and Baylisascaris.
Selected from the order of the Convolvulus, for example, Bacteroides spp, Ostertagia spp, Heterodera spp, Parabernema spp, Draschia spp and Dracaena spp.
Selected from the order filariales, for example, the genera Cytospora, Paraserina, Abelmoschus, Roamidia, Dirofilaria, Photofilaria, Brugia, Wuchereria and Trichosanthes.
Selected from the order Dactylophilus, for example, the genera Filiollis, Candida, Gentiana and Prosthenorchis.
According to the present invention, it is preferred to use the active compounds against infection by worms selected from the order of the rodorma (e.g. strongyloides) and from the order of the strongyloides (e.g. ancyloides) and against infection by worms mentioned above in relation to the order of the ascariasis avium. It is particularly preferred to use the active compounds against toxocara (e.g. canine ascaris).
Production and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, buffalos, donkeys, rabbits, deer horns, reindeer, and fur animals such as mink, chinchilla, and raccoons.
Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
The pet animals include dogs and cats.
The active compounds can be used for prophylactic or therapeutic purposes. Very particular preference is given to using the active compounds in dogs.
When used in accordance with the invention, the depsipeptides proved to be well tolerated by both the dam and the offspring,
vertical infection refers to the transfer from dam to offspring, which occurs especially prenatally (i.e., in the mother) and/or during the lactation period (i.e., through milk). Prevention of prenatal infection is particularly important.
"prevention of prenatal and lactation infection" refers not only to complete prevention of infection; also refers to incomplete prevention, wherein the risk of infection is only reduced and/or the infection is attenuated. At least 90% efficacy is desired.
The active compounds can be used as such or in the form of suitable preparations, the administration preferably being effected to the dam by the small intestinal route, by the parenteral route or by the transdermal route (transdermal).
The active compound is administered via the small intestinal route, for example, orally in the following form: powder, suppository, tablet, capsule, syrup, potion, microgranule, drench, bolus (boli) or medicated feed or drinking water. They can be used in transdermal routes, for example, by dipping, spraying, bathing, washing, pouring and spotting and dusting. They can be used parenterally, for example in the form of injections (intramuscular, subcutaneous, intravenous or intraperitoneal) or with the aid of implants.
Suitable formulations are:
solutions such as injection solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, formulations for pouring and gels;
emulsions and suspensions for oral or dermal use and injection; a semi-solid formulation;
formulations for inserting the active compounds into ointment bases or into oil-in-water or water-in-oil emulsion base preparations;
solid preparations such as powders, premixes or concentrates, microgranules, granules, tablets, boluses, capsules; aerosols and inhalants, and moldings containing active compounds.
Injection solutions are used by intravenous, intramuscular and subcutaneous routes.
Injectable solutions are prepared by dissolving the active compound in a suitable solvent and, if appropriate, adding, for example, solubilizers, acids, bases, buffer salts, antioxidants and preservatives. The solution was sterilized by filtration and divided into aliquots.
Solvents which may be mentioned are: physiologically tolerable solvents, such as water, alcohols, such as ethanol, butanol, benzyl alcohol and glycerol, hydrocarbons, propylene glycol, polyethylene glycol and N-methylpyrrolidone and mixtures thereof.
The active compounds can, if appropriate, also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.
Solubilizers which may be mentioned are: solvents which promote dissolution of the active compound in the main solvent or prevent its precipitation out. Examples are polyvinylpyrrolidone, polyethoxylated castor oil and polyethoxylated sorbitan esters.
The preservative is: benzyl alcohol, chlorobutanol, p-hydroxybenzoate and n-butanol.
The oral solution is used directly. The concentrate is administered orally after pre-dilution to the use concentration. Oral solutions and concentrates are prepared as described above in connection with injectable solutions, possibly without the need for handling under sterile conditions.
The solutions for application to the skin are dropped, spread, rubbed in with force, sprayed or misted on the skin or applied by dipping (soaking, bathing or washing). These solutions were prepared as described for the injection solutions.
It is desirable to add a thickener during the preparation process.
The thickening agent is: inorganic thickeners, such as bentonite, colloidal silicic acid and aluminum monostearate, and organic thickeners, such as cellulose derivatives, polyvinyl alcohol and copolymers thereof, acrylates and methacrylates.
Gels are applied to the skin or applied or introduced into body holes. Gels are prepared by treating those solutions (prepared as described for the injectable solutions) with sufficient thickening agent to form a clear mass having an ointment-like consistency. The thickeners used are those mentioned above.
Pour-on formulations are poured or sprayed onto the skin to the specified extent, wherein the active compound penetrates the skin and acts systemically or is dispersed on the body surface.
Pour-on formulations are prepared by dissolving, suspending or emulsifying the active compound in a suitable, skin-compatible solvent or solvent mixture. If appropriate, further auxiliaries, such as colorants, absorption promoters, antioxidants, light stabilizers, binders, are added.
Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenylethanol and phenoxyethanol, esters such as ethyl acetate, butyl acetate and benzyl benzoate, ethers such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl ether and diethylene glycol monobutyl ether, ketones such as acetone and methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone and 2-dimethyl-4-oxymethylene-1, 3-dioxolane.
Colorants are all colorants recommended for animals and they can be dissolved or suspended.
Examples of absorption enhancers are DMSO, spreading oils, such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides and fatty alcohols.
The antioxidant is sulfite or metabisulfite, such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole and tocopherol.
Examples of light stabilizers are substances from the class of benzophenones or novantisolidicacids,
examples of binders are cellulose derivatives, starch derivatives, polyacrylates and natural polymers such as alginates and gelatin.
The emulsion can be administered orally, transdermally or as an injection.
The emulsion is of the water-in-oil or oil-in-water type.
They are prepared by dissolving the active compound in the hydrophobic phase or in the hydrophilic phase and then homogenizing the latter, together with the solvents of the other phases, by using suitable emulsifiers and, if appropriate, further auxiliaries (such as colorants, absorption promoters, preservatives, antioxidants, light stabilizers and viscosity-increasing substances).
Hydrophobic phases (oils) which may be mentioned are: paraffinic oils, silicone oils, natural vegetable oils, such as sesame oil, almond oil and castor oil, synthetic triglycerides, such as caprylic/capric acid diglyceride, containing C8-12Triglyceride mixtures of vegetable fatty acids of chain length or other specifically selected natural fatty acids, partial glyceride mixtures of saturated and unsaturated (if appropriate also hydroxyl) fatty acids, and C8/C10Monoglycerides and diglycerides of fatty acidsEsters
Fatty acid esters such as ethyl stearate, di-n-butyl adipate, hexyl laurate and dipropylene glycol pelargonate, branched fatty acids of medium chain length with C16-C18Esters of saturated fatty alcohols of chain length, isopropyl myristate, isopropyl palmitate, C12-C18Caprylic/capric acid esters of saturated fatty alcohols of chain length, isopropyl stearate, oleyl oleate, decyl oleate, ethyl lactate, waxy fatty acid esters, such as artificial duck tail gland fat, dibutyl phthalate, diisopropyl adipate, ester mixtures related to the latter, and others,
fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetyl/stearyl alcohol and oleyl alcohol.
Fatty acids such as oleic acid and mixtures thereof.
Hydrophilic phases which may be mentioned are:
water, alcohols such as propylene glycol, glycerol, sorbitol and mixtures thereof.
Emulsifiers which may be mentioned are: nonionic surfactants such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glyceryl monostearate, polyoxyethylstearate and alkylphenol polyglycol ether;
amphoteric surfactants such as di-Na-N-lauryl-beta-iminodipropionate or lecithin;
anionic surfactants such as Na lauryl sulfate, fatty alcohol ether sulfates, mono/dialkyl polyglycol ether orthophosphate monoethanol amine salts;
cationic surfactants such as cetyltrimethylammonium chloride.
Other auxiliary substances which may be mentioned are: viscosity-increasing agents and emulsion-stabilizing substances, such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, food gums, polyvinylpyrrolidone, polyvinyl alcohol, copolymers composed of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes and colloidal silicic acid, or mixtures of the substances listed,
the suspension can be administered orally, transdermally or as an injection. They are prepared by suspending the active compounds in a suspending liquid, if appropriate in the presence of further auxiliaries, such as wetting agents, colorants, absorption promoters, preservatives, antioxidants and photostabilizers.
The suspending liquids which may be mentioned are all homogeneous solvents and solvent mixtures.
Wetting agents (dispersants) which may be mentioned are the surfactants specified above.
Other auxiliaries which may be mentioned are those specified above.
The semi-solid formulation can be administered orally or transdermally. They differ from the above-mentioned suspensions and emulsions only by having a higher viscosity,
to produce solid preparations, the active compounds are mixed with suitable excipients, if appropriate in the presence of auxiliaries, and then adjusted to the desired form.
Excipients which may be mentioned are all physiologically tolerable solid inert substances. Inorganic and organic substances are used for this purpose. Examples of inorganic substances are sodium chloride, carbonates, such as calcium carbonate and bicarbonate, aluminum oxide, silicic acid, clay-containing clays, precipitated or colloidal silica and phosphates.
Examples of organic substances are sugars, cellulose, and also food and feed products such as milk powder, animal food, flour and roughage food, and starch.
Auxiliaries are preservatives, antioxidants and colorants which have already been listed above.
Other suitable auxiliaries are lubricants and glidants, such as magnesium stearate, stearic acid, talc, bentonite, disintegration-promoting agents, such as starch or crosslinked polyvinylpyrrolidone, binders, such as starch, gelatin or linear polyvinylpyrrolidone, and dry binders, such as microcrystalline cellulose,
preferred administration forms are oral, for example by means of suitable tablets, or transdermal, for example by means of suitable spot-on formulations.
The compositions according to the invention additionally comprise synergists or other active compounds, for example those against pathogenic endoparasites. Examples of such active compounds are L-2, 3, 5, 6-tetrahydro-6-phenylimidazole-thiazole, benzimidazole carbamates, such as febantel, and, in addition, pyrantel, epsiprantel or macrolides, such as abamectin, abamectin or selamectin. Particularly preferred is praziquantel as a combination partner, especially with emodepside.
Praziquantel has long been known for use as a compound against endoparasites (see, e.g., US 4001411). Ideal conjugates of depsipeptides with praziquantel or epsiprantel are described in EP- ｃA-662326, which is hereby incorporated by reference.
Conjugates of depsipeptides with piperazine are described in EP-A-1189615, which is hereby expressly incorporated herein by reference,
compositions capable of transdermal administration and comprising cyclic depsipeptides for controlling endoparasites are described in our German patent application No. 10358525.7, which is likewise pending.
In general, ready-to-use preparations comprise the active compound in a concentration of in each case from 0.01 to 25% by weight, preferably from 0.1 to 20% by weight.
The cyclic depsipeptides are generally used in amounts of from 0.1 to 8% by weight, preferably from 1 to 6% by weight.
Praziquantel is generally used in an amount of 1 to 25% by weight, preferably 5 to 15% by weight, particularly preferably 6 to 14% by weight.
The compositions are prepared by mixing the appropriate amounts of the components in suitable equipment. The procedure should preferably be such that the liquid components are mixed, after which the solid components are added and a homogeneous solution is prepared.
In general, in order to achieve effective results, it has proven desirable to administer an amount of the mixture of the invention of from about 0.1 to about 20mg of active compound per kg of body weight per day. From 0.5 to 10mg of active compound per kg of body weight are preferred.
The following examples are intended to illustrate the invention without limiting it.
Biological examples
A study was conducted on eighteen beagle puppies that had been experimentally infected with the ascaris canis (Toxocara canis). Six of these animals were used as untreated controls. Two different treatment regimens were used. In treatment group 1(T1), six bitches were treated daily, starting on day 42 of pregnancy and until the birth of the puppies, with 1mg emodepside per kg body weight orally in each case as a tablet formulation; six bitches in treatment group 2(T2) were treated identically except that treatment was only given every third day instead of daily. The efficacy of the treatment was evaluated by determining three target numbers in puppies: the number of somatic dog toxocara larvae in the liver, lung, kidney and gastrointestinal tract (including contents) and samples of muscle tissue (euthanasia of puppies directly after birth), the number of excretory worm eggs per gram of feces and the number of intestinal dog toxocara stages after washout from the intestine (euthanasia of puppies on day 35 of life).
The percent efficacy of emodepside in T1 was 99.9% for the target number of excreted worm eggs per gram of faeces, 96.4% for the target number of somatic larvae in the digestive organs and 99.9% for the target number of intestinal stage parasites in the intestine. In T2, the target number of eggs per gram of feces of the excreting parasite also reached 99.9% efficacy. Treatment regimen 2 achieved a percentage efficacy of 93.8% emodepside treatment for the target number of somatic larvae and 98.7% for the target number of intestinal stage parasites in the intestine. In both treatment regimens, the percent efficacy of emodepside for each target amount, and the mean values obtained from these target amounts in each treatment group (T1 ═ 98.7%; T2 ═ 97.5%) were significantly higher than the minimum percent efficacy of 90%, which minimum efficacy of 90% was required for the anthelmintic substance by Guideline 7 of the International Cooperation on Harmonisation of Technical requisitions for registration of the Veterinary medical Products (VICH). Both treatment regimens achieved a significant reduction in prenatal infection of the dog ascaris lumbricoides in puppies.
No incompatibility phenomena were observed in either the dam or in puppies.
Claims (1)
1. Use of an endoparasiticidal depsipeptide for the manufacture of a medicament for preventing vertical infection of a dog by an endoparasite, wherein the endoparasiticidal depsipeptide is emodepside.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102004055316.5 | 2004-11-16 | ||
| DE102004055316A DE102004055316A1 (en) | 2004-11-16 | 2004-11-16 | Prevention of vertical endoparasite infections |
| PCT/EP2005/011748 WO2006053641A1 (en) | 2004-11-16 | 2005-11-03 | Prevention of vertical endoparasite infections |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1117041A1 HK1117041A1 (en) | 2009-01-09 |
| HK1117041B true HK1117041B (en) | 2012-03-09 |
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