HK1102915B - Endoparasiticidal agents for topical application - Google Patents

Description

endoparasiticidal compositions for topical application

The invention relates to transdermally administrable compositions containing cyclic depsipeptides and/or praziquantel, to the production thereof and to the use thereof for controlling endoparasites.

Anthelmintically active compounds praziquantel (U.S. Pat. No. 4001411) are usually administered orally, see for example DE-A-19941024, WO98/03157, US2002/0081292A1 and WO 97/25976. In the case of topical application of endoparasiticides, the active compound must pass through the skin into the bloodstream in order to reach the endoparasite. Since praziquantel is not particularly suitable for transdermal administration, topical transdermal administration forms of this compound are rare, particularly for dogs, due to the difficulties to be expected. EP-A-267404 describes ｃA composition for the dermal treatment of helminthiasis using praziquantel. However, the administration of this composition is restricted to cats, in which case it is significantly easier to obtain an effective transdermal administration than for example in the case of dogs.

WO01/60380(Phoenix Scientific, Inc.) discloses parasiticidal formulations for injection or pour-on applications which may contain a pyrrolidone solvent, another solvent and a parasiticidally active compound. Among the large number of active compounds listed, praziquantel is mentioned.

EP-A-1308163(Wyeth) discloses endoparasiticidal compositions in the form of ｃA gel comprising moxidectin, praziquantel, benzyl alcohol, ethanol, silicｃA gel, ｃA surfactant and an oil.

WO95/23950(Bomac Laboratories) discloses a complex method for preparing dermally applied anthelmintic compositions. The composition comprises a carrier, an emulsifier, an oil and a diluent. Suitable active compounds are preferably benzimidazoles, but macrolides and praziquantel are also mentioned.

WO02/094288 describes a veterinary drug which contains an avermectin oxime derivative, in particular selamectin, in combination with praziquantel. Suggested routes of administration include topical administration; the corresponding formulation contains di (C)_2-4Diol) mono (C)_1-4-alkyl) ethers and, if desired, skin-friendly solvents.

The cyclic depsipeptide PF1022 and its action on endoparasites is known from EP-A382173.

Other cyclic depsipeptides and their endoparasiticidal action are those of German patent application EP-A626376; EP-A626375; subject matter of EP-A644883.

EP662326 describes endoparasiticidal compositions containing praziquantel or epsiprantel and a cyclic depsipeptide.

The endoparasiticidal compositions provided in WO96/38165 contain avermectins, ivermectin, milbemycins in combination with cyclic depsipeptides and, where appropriate, praziquantel or epsiprantel.

WO01/62268 describes transdermally administrable compositions containing cyclic depsipeptides for controlling endoparasites.

Penetration or penetration enhancers which improve transdermal administration of drugs are generally known in the art, see, e.g., Sinha et al in Drug Development and Industrial Pharmact, 26(11), 1131-1140 (2000); clarys et al, chapters six in European Journal of pharmaceuticals and BioPharmaceutics 46(1998), 279-283 and Dermatopharma zie (Wissenschaftliche Verlagsgesellschaft mbH Stuttgart 2001).

However, the activity and/or duration of action of the compositions of the prior art are not entirely satisfactory in all fields of application, in particular in the case of certain hosts, for certain organisms and/or at low application concentrations.

Since modern medicaments are subject to a variety of requirements, for example with regard to the level of activity (for example the plasma concentration of the active compound), the duration of action, the spectrum of activity, the range of application, the toxicity, the combination with other active compounds, the combination with formulation auxiliaries, and since resistances may be present, the development of new medicaments is never complete, and there is an increasing and extensive need for new compositions which have advantages over the known compositions at least in some respects.

In order to be able to administer endoparasiticidally active compounds in as simple a manner as possible for the pet owner, it is desirable to provide a composition which can be applied transdermally.

As is known from the literature, molecules with a molecular weight of more than 1000u are extremely difficult to penetrate the skin when applied topically. Peptides or proteins with a larger molecular weight are particularly impermeable (Cevc et al, Advanced Drug Delivery Reviews 18(1996) 349-. However, penetration is a prerequisite for endoparasiticidally active compounds, since these active compounds are intended to act on endoparasites, for example in the gastrointestinal tract.

Although some publications of the prior art propose topical application of praziquantel and/or cyclic depsipeptides, the person skilled in the art knows that these active compounds are not particularly suitable for this purpose, and therefore the known formulations are not entirely satisfactory, in particular for, for example, the so-called dose-boosting (dosstreibenden) helminths, such as the Trichuris foxtail (trichouri) and/or the tapeworm Taenia canis.

It is therefore an object of the present invention to provide topically applicable endoparasiticidal compositions having the following properties:

● has good transdermal activity on various hosts, especially dogs, and on dose-propelling worms (e.g. caenorhabditis foxi, Taenia canis),

● good skin compatibility

● long term stability

● user friendliness

The present invention provides:

a composition comprising:

● Cyclic depsipeptides and/or Praziquantel as active compounds

● pyrrolidone solvent

● terpene penetration enhancers and/or aliphatic fatty acids and/or aliphatic fatty alcohols as penetration enhancers.

The invention also provides the preparation of the composition and the application of the composition in preventing and treating endoparasites.

Depsipeptides are similar to peptides, differing from the latter in that one or more alpha-amino acid building blocks are replaced by alpha-hydroxycarboxylic acid building blocks. Preferred cyclic depsipeptides are those having 18 to 24 ring atoms, in particular 24 ring atoms.

Depsipeptides having 18 ring atoms include compounds of the general formula (I) and optical isomers and racemates thereof:

wherein

R¹、R³And R⁵Independently of one another, represent 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 may optionally be substituted by one or two benzyloxycarbonyl 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, hydroxyl, alkyl and alkoxy,

R²、R⁴and R⁶Independently of one another, represent 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, optionally substituted aryl or arylalkyl, where substituents which may be mentioned are halogen, hydroxyl, alkyl, alkoxy.

Preferred compounds of formula (I) are:

wherein

R¹、R³And R⁵Independently of one another, represents straight-chain or branched C₁-C₈Alkyl, especially methylAlkyl, 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-C₄-alkanoyloxy-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, methylaminobutyl, C₁-C₄-dialkylamino-C₁-C₆Alkyl, especially dimethylaminopropyl, dimethylaminobutyl, guanidino-C₁-C₆Alkyl, especially guanidinopropyl, C₁-C₄-alkoxycarbonylamino-C₁-C₆-alkyl radicals, especiallyIs tert-butoxycarbonylaminopropyl, tert-butoxycarbonylaminobutyl, 9-fluorenylmethoxycarbonyl (Fmoc) amino-C₁-C₆Alkyl, in particular 9-fluorenylmethoxycarbonyl (Fmoc) aminopropyl, 9-fluorenylmethoxycarbonyl (Fmoc) aminobutyl, 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, said radical optionally being substituted by halogen, in particular fluorine, chlorine, bromine or iodine, hydroxy, C₁-C₄Alkoxy, especially methoxy or ethoxy, C₁-C₄Alkyl, in particular methyl,

R²、R⁴and R⁶Independently of one another, represents 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-C₄-alkanoyloxy-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-alkyl sulfonic acidAcyl radical-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, methylaminobutyl, 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, said radical optionally being substituted by halogen, in particular fluorine, chlorine, bromine or iodine, hydroxy, C₁-C₄Alkoxy, especially methoxy or ethoxy, C₁-C₄Alkyl, in particular methyl,

and optical isomers and racemates thereof.

Particularly preferred compounds of the formula (I) are,

wherein

R¹、R³And R⁵Independently of one another, represents straight-chain or branched C₁-C₈Alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl,Heptyl, isoheptyl, sec-heptyl, octyl, isooctyl, sec-octyl, hydroxy-C₁-C₆Alkyl, especially hydroxymethyl, 1-hydroxyethyl, C₁-C₄-alkanoyloxy-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 may optionally be substituted by one or more of those radicals which are identical or different,

R²、R⁴and R⁶Independently of one another, represents 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-C₄Aryl alkoxycarbonyl-C₁-C₆Alkyl, especially benzyloxycarbonylmethyl, C₁-C₄-alkylamino-C₁-C₆Alkyl, especially methylaminopropyl, methylaminobutyl, 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 may optionally be substituted by one or more of those radicals which are identical or different,

and optical isomers and racemates thereof.

The most particularly preferred compounds of the formula (I) are

Wherein

R¹、R³And R⁵Independently of one another, represents 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-C₄-an alkyl group, in particular a phenylmethyl group,

R²、R⁴and R⁶Independently of one another, represents 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 may optionally be substituted by one or more of those radicals which are identical or different,

and optical isomers and racemates thereof.

In the sense of the above invention, all compounds of the general formula (I) can be used, which can be present in optically active stereoisomeric forms or as racemic mixtures. However, the present invention preferably uses optically active stereoisomeric forms of the compounds of formula (I).

In particular, mention may be made of the compounds of the following general formula (I) in which the radical R is¹-R⁶As defined below:

R	R	R	R	R	R
						-CHMeCHMe	-cyclohexyl radical	-CHMeCHMe	-Me	-CHMeCHMe	-Me
-CHMeCHMe	-cyclohexyl radical	-CHMeCHMe	-Me	-CHMeCHMe	-cyclohexyl radical
						-CHMeCHMe	-CH-Phe	-CHMeCHMe	-Me	-CHMeCHMe	-Me
-CHMeCHMe	-CH-Phe	-CHMeCHMe	-Me	-CHMeCHMe	-CH-Phe
						-CHMeCHMe	-(CH)-Me	-CHMeCHMe	-Me	-CHMeCHMe	-Me
-CHMeCHMe	-(CH)-Me	-CHMeCHMe	-Me	-CHMeCHMe	-(CH)-Me
						-CHMe	-CH-Phe	-CHMeCHMe	-Me	-CHMeCHMe	-Me
-CH-Phe	-CHMe	-CH-Phe	-CHMe	-CHMeCHMe	-CHMe
						-CHCHMe	-CH-Phe	-CHCHMe	-Me	-CHCHMe	-CH-Phe
-(CH)-Me	-Me	-CHMeCHMe	-Me	-CHMeCHMe	-Me
						-CHMe	-Me	-CHMe	-Me	-CHMe	-Me
-CH-Me	-Me	-CH-Me	-Me	-CH-Me	-Me
						-(CH)-Me	-Me	-(CH)-Me	-Me	-(CH)-Me	-Me
-(CH)-Me	-Me	-(CH)-Me	-Me	-(CH)-Me	-Me
						-CH-CH＝CH	-Me	-CH-CH＝CH	-Me	-(CH)-CH＝CH	-Me
-CHMeCHMe	-Me	-CHMeCHMe	-Me	-CHMeCHMe	-CH-Me
						-CHMeCHMe	-Me	-CHMeCHMe	-Me	-CHMeCHMe	-(CH)-Me
-CHMeCHMe	-Me	-CHMeCHMe	-Me	-CHMeCHMe	-(CH)-Me
						-CHMeCHMe	-Me	-CHMeCHMe	-Me	-CHMe	-Me

R	R	R	R	R	R
						-CHMeCHMe	-Me	-CHMeCHMe	-Me	-(CH)-Me	-Me
-cyclohexyl radical	-Me	-cyclohexyl radical	-Me	-cyclohexyl radical	-Me
						-CHCHMe	-cyclohexyl radical	-CHCHMe	-Me	-CHCHMe	-cyclohexyl radical
-CHCHMe	-cyclohexyl radical	-CHCHMe	-Me	-CHCHMe	-Me
						-CHMeCHMe	-CHMe	-CHMeCHMe	-CHMe	-CHMeCHMe	-Me
-CH-Phe	-Me	-CH-Phe	-Me	-CH-Phe	-Me
						-cyclohexyl radical	-Me	-cyclohexyl radical	-Me	-cyclohexyl radical	-Me
-CHMe	-CHMe	-CHMe	-Me	-CHMe	-Me
						-CHMe	-CHMe	-CHMe	-CHMe	-CHMe	-Me
-CH-Me	-CHMe	-CHMe	-Me	-CH-Me	-Me
						-CH-Me	-CHMe	-CHMe	-CHMe	-CH-Me	-Me
-(CH)-Me	-CHMe	-(CH)-Me	-Me	-(CH)-Me	-Me
						-(CH)-Me	-CHMe	-(CH)-Me	-CHMe	-(CH)-Me	-Me
-(CH)-Me	-CHMe	-(CH)-Me	-Me	-(CH)-Me	-Me
						-(CH)-Me	-CHMe	-(CH)-Me	-CHMe	-(CH)-Me	-Me
-CH-CH＝CH	-CHMe	-CH-CH＝CH	-Me	-CH-CH＝CH	-Me
						-CH-CH＝CH	-CHMe	-CH-CH＝CH	-CHMe	-CH-CH＝CH	-Me
-Me	-Me	-CHMeCHMe	-Me	-CH-Me	-Me
						-Me	-Me	-CHMeCHMe	-Me	-(CH)-Me	-Me

Me ═ methyl; phe ═ phenyl group

Another depsipeptide which may be mentioned is the compound PF1022 of the formula (IIa) known from EP-A382173:

depsipeptides which may also be mentioned are the compounds known from PCT application WO 93/19053.

Mention may in particular be made, in WO93/19053, of the compounds of formula (IIb):

wherein

Z represents N-morpholinyl, amino, mono-or dimethylamino.

Furthermore, mention may be made of compounds of formula (IIc):

wherein

R¹、R²、R³、R⁴Independently of one another, represents 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 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, EP-A-903347.

Cyclic depsipeptides having 24 ring atoms also include compounds of the general formula (IId)

Wherein

R^1a、R^2a、R^11aAnd R^12aIndependently of one another represent C_1-8-alkyl radical, C_1-8-haloalkyl radical, C_3-6-cycloalkyl, aralkyl, aryl,

R^3a、R^5a、R^7a、R^9aindependently of one another, represents hydrogen or straight-chain or branched C_1-8Alkyl, which may optionally be substituted by hydroxy, C_1-4-alkoxy, carboxyl,A carbamoyl group,Imidazolyl, indolyl, guanidino, -SH or C_1-4-alkylthio which is substituted and represents optionally halogenHydroxy, C_1-4Alkyl radical, C_1-4-an alkoxy-substituted aryl or aralkyl group,

R^4a、R^6a、R^8a、R^10aindependently of one another, represents hydrogen, straight chain C_1-5-alkyl radical, C_2-6-alkenyl, C_3-7Cycloalkyl, which may optionally be substituted by hydroxy, C_1-4Alkoxy, carboxyl, carbamoyl, imidazolyl, indolyl, guanidino, SH or C_1-4Alkylthio, which is optionally substituted by halogen, hydroxy, C_1-4Alkyl radical, C_1-4-an alkoxy-substituted aryl or aralkyl group,

and optical isomers and racemates thereof.

The compounds of the formula (IId) which are preferably used are those in which

R^1a、R^2a、R^11aAnd R^12aIndependently of one another, represents methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or phenyl, which may optionally be substituted by halogen, C_1-4Alkyl, OH, C_1-4-alkoxy substituted and also represents benzyl or phenethyl, which groups may be optionally substituted by the groups mentioned with respect to phenyl;

R^3ato R^10aAs defined above.

Particularly preferred compounds of the formula (IId) are those in which

R^1a、R^2a、R^11aAnd R^12aIndependently of one another, represents methyl, ethyl, propyl, isopropyl or n-, sec-, tert-butyl,

R^3a、R^5a、R^7a、R^9arepresents hydrogen, straight or branched C_1-8Alkyl, in particular methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, which may optionally be substituted by C_1-4Alkoxy, especially methoxy, ethoxy, imidazolyl, indolyl or C_1-4Alkylthio, especially methylthio, ethylThio is substituted, and also represents phenyl, benzyl or phenethyl, which may optionally be substituted by halogen, in particular chlorine.

R^4a、R^6a、R^8a、R^10aIndependently of one another, represents hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, cyclohexyl, which is optionally substituted by methoxy, ethoxy, imidazolyl, indolyl, methylthio, ethylthio, also represents isopropyl, sec-butyl, and furthermore represents optionally halogenated phenyl, benzyl or phenethyl.

The compounds of the formulｃA (IId) can also be obtained by 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, EP-A-903347.

The depsipeptides most particularly preferred according to the invention are PF1022A (see formula (IIa)) and emodepside (PF1022-221, formula (IIb)) compounds in which both radicals Z represent morpholinyl. INN emodepside represents a compound having the following system name: cyclo [ (R) -lactyl-N-methyl-L-leucinyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucinyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucinyl.

Praziquantel is a compound known for a long time to be effective against endoparasites (see e.g. US 4001411); corresponding products are commercially available, for example under the name DroncitThe product of (1).

The compositions of the invention may contain one or more of the above cyclic depsipeptides or praziquantel as active compounds. However, a combination comprising both cyclic depsipeptides and praziquantel, particularly emodepside and praziquantel, is preferred.

The unique advantages of the compositions of the present invention are greatly amplified by the particular choice of permeation enhancer for this purpose. Penetration enhancers are compounds that improve the topical transdermal administration of a pharmaceutically active compound. A number of different compounds and classes of compounds have been described in the literature as penetration enhancers. However, it has been found that these substances produce very different results, depending on the active compound and other auxiliary compounds used. Sometimes, delivery through the skin is not sufficient, or there is a problem in skin compatibility.

Tests with praziquantel and/or cyclic depsipeptides show that no results suitable for practical application can be obtained with many penetration enhancers described in the literature, whereas the compositions of the invention, in particular due to the particular choice of penetration enhancer, give excellent results.

Terpene penetration enhancers are described in chapter six of "Dermatopharmazie" (Wissenschaftlichegsgesellschaft Stuttgart 2001), which publication is expressly incorporated herein by reference. A typical classification of terpene penetration enhancers is terpene hydrocarbons such as limonene, alpha-pinene or beta-carene; terpene alcohols, such as alpha-terpineol, terpin-4-ol or carveol; terpenoids, such as carvone, pulegone, menthone (Piperiton) or menthone (menthone), and terpene oxides, such as limonene oxide, alpha-pinene oxide, 1, 8-cineole and related compounds cyclohexene oxide or cyclopentene oxide. Among these, terpene hydrocarbons, in particular limonene, are preferred. Useful terpene penetration enhancers typically have a 10 carbon backbone.

Terpene penetration enhancers are generally used in amounts of up to 25 wt%, preferably 2-20 wt%, especially 5-15 wt%.

Suitable penetration enhancers are also aliphatic fatty acids; these substances are described in chapter six of "Dermatopharmazie" (Wissenschaftliche Verlagsgesellschaft mbHStuttgart 2001), which publication is expressly incorporated herein by reference. These compounds generally have from 5 to 18 carbon atoms. Liquid fatty acids, for example those having one or two double bonds, are particularly advantageous. Saturated fatty acids which may be mentioned are, for example, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, stearic acid, pelargonic acid, isovaleric acid, pivalic acid, neoheptanoic acid, neononanoic acid, neodecanoic acid and isostearic acid. Unsaturated fatty acids which may be mentioned are oleic acid, linoleic acid and linolenic acid. Linoleic acid, especially oleic acid, is particularly preferred.

Penetration enhancers suitable for use in the compositions of the invention, in addition to the aliphatic fatty acid, are aliphatic fatty alcohols; these substances are also described, for example, in chapter six of "Dermatopharmazie" (Wissenschaftlichegsgesellschaft Stuttgart 2001), which publication is expressly incorporated herein by reference. Suitable aliphatic fatty alcohols preferably have from 8 to 18 carbon atoms. Examples which may be mentioned are octanol, decanol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleoyl alcohol (oleylolekohol), linolyl alcohol and linolenyl alcohol. Isostearyl alcohol is particularly preferred.

The aliphatic fatty acids and aliphatic fatty alcohols are generally used in amounts of up to 25% by weight, preferably from 1 to 20% by weight, particularly preferably from 2 to 15% by weight.

Terpene penetration enhancers or aliphatic fatty acids that act as penetration enhancers or aliphatic fatty alcohols that act as penetration enhancers may be employed as penetration enhancers in the compositions of the present invention. Combinations of these types of penetration enhancers may also be administered.

It is preferred to use a terpene penetration enhancer in combination with an aliphatic fatty acid or aliphatic fatty alcohol, which can result in an unexpected synergistic enhancement of activity. Most particularly preferred is a combination of limonene and oleic acid.

Unless otherwise indicated, the stated percentage amounts of the ingredients in the compositions of the present invention are weight percentages based on the total weight of the finished composition.

In the compositions of the invention, the active compound should be present in relatively high concentrations, firstly to improve transdermal activity-for example in the case of dose-promoting helminths, such as pratylenchus foxi-, and secondly to maintain the volume for small applications. However, with such highly concentrated compositions, there is a risk of crystallization of the active compound on the coat or skin in the case of topical application (e.g. spot-coating), which is generally harmful and generally leads to poor skin penetration. Surprisingly, it has now been found that by the addition of aliphatic fatty acids, crystallization of the active compound can be prevented and the preparations thus formed can be used for a long time for percutaneous absorption.

The compositions of the present invention have advantageous warm-blooded animal toxicity and are suitable for use in the control of pathogenic endoparasites encountered in humans and animal husbandry, productive livestock, breeding stock, zoo animals, laboratory animals, animals used in testing and pets. They are active against resistant and often sensitive species and against all or some stages of development of the pest. By controlling pathogenic endoparasites, it is intended to reduce diseases, mortality and reduction in productivity (for example in the production of meat, milk, wool, hides, eggs, honey and the like), so that more economical and simpler animal breeding is possible by using the active compounds. Pathogenic endoparasites include cestodes, trematodes, nematodes and echinocandis (acanthopeles):

praziquantel is particularly effective against the following endoparasites:

from the order of the Ruscus aculeatus, for example: the genus Schistostostosoma, Echinococcus, Schistocephalus spp, genus Tolyxopsis, genus Diphyllum, and genus Diphyllophonoporus.

From the order of the orbicularis, for example: the genus Meadowrum, the genus Paragymnocyst, the genus Mennitz taenia, the genus chalepenia, the genus Trigonella, the genus Oenothera, the genus Stelstenia, the genus Taenia, the genus Andriella, the genus Borter taenia, the genus Taenia, the genus Echinococcus, the genus Nephalospermum, the genus Daphnia, the genus Thymptonema, the genus Echinodermata, the genus Birdonella, the genus Molonaea, the genus Ojotaenia, and the genus Binaea.

Monozoideae, for example, Triplophora, Dactylogyrus, Polyschistosoma.

Subclass of the subclass.

Cyclic depsipeptides particularly prevent the following endoparasites:

from the order of the Siberidactylorum, for example, Trichogasoides, Trichosporus, Trichogasoides, Trichogaster.

Rod-shaped orders, such as, for example, the genus Micronematoda, Strongyloides.

Round mesh, for example: strongyloides, trichinella, oesophagostomus, trichinella, cuproids, columbina, bowlexoides, cyclecerus, cuprochaeformis, oesophagostertan, caberbet nematoda, caudada, ancyloides, gondoides, balladella, biwinged, strongyloides, dictyoides, dictyodosphaera, dictyodera, mullerodera, mellonella, strongyloides, neologyloides, capsulatus, pulmonologyloides, strongyloides, necator strongyloides, paraboroides, odontophilus, Paracrenosoma, angiostrongyloides, catorodera, nematoda, paraprofilaria, strongyloides, haemonchyloides, oesophagostomus, strongyloides, and cephalorachidoides.

From the order of the Ostertagia species, for example Ostertagia species, Ostertagia species.

From the order of the avian ascaridae, for example, ascaridae, toxocara, ascaridae, anisakis, and aviascaridae.

The order of the gyrodacty, for example: orthoenchus, Ostertagia, Acidovorax, Strongyloides, Lithodias, Paralewisia, Derashi, Dracocephala.

From the order of the filariales, for example, the genera Cytopira, Parafilaria, Abies, Luomaria, Dirofilaria, Gomphrena, Brucella, Wuchereria, Spilaria.

From the order of Juglans, for example, the genus Echinoderma, the genus Candida, the genus Echinoderma, the genus epididymis.

The use of suitable active compound combinations makes it possible to cover all the in vivo parasite spectra listed above.

Domestic and domestic animals include mammals, such as cattle, horses, sheep, pigs, goats, camels, buffalos, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, such as minks, chinchillas or racoons, birds, such as chickens, geese, turkeys, ducks, ostriches.

Laboratory and test animals include rats, mice, guinea pigs, hamsters, dogs, and cats.

Pets include dogs and cats.

Administration can be prophylactic or therapeutic. Most particularly preferred is administration to dogs.

Pyrrolidone solvents are pharmaceutically acceptable solvents derived from pyrrolidone. Pyrrolidones having one or more alkyl substituents up to 4 carbon atoms are preferred. A particularly preferred pyrrolidone solvent is 2-pyrrolidone optionally having alkyl substituents of 1 to 4 carbon atoms on the ring nitrogen and optionally further alkyl substituents of 1 to 4 carbon atoms on other ring positions. Examples are 1, 5-diethyl-2-pyrrolidone, N-ethyl-2-pyrrolidone. Particularly preferred are 2-pyrrolidones, such as 2-pyrrolidones, especially N-methylpyrrolidone, optionally having only one alkyl substituent on the nitrogen atom.

The compositions according to the invention contain a pyrrolidone solvent or mixtures thereof, generally in an amount of 99 to 20% by weight, preferably 96 to 35% by weight, particularly preferably 90 to 65% by weight.

In particular for compositions containing cyclic depsipeptides, it is advantageous to use conventional antioxidants such as BHA, BHT or propyl gallate.

The compositions of the invention may additionally contain synergists or other active compounds, for example active compounds active against pathogenic endoparasites. The active compounds are, for example, L-2, 3, 5, 6-tetrahydro-6-phenylimidazothiazole, benzimidazole carbamates, such as febantel, and furthermore pyrantel, epsilon prantel, or macrolides, such as abamectin, ivermectin or selamectin.

The preparations ready for mixing usually contain the active compounds in concentrations of from 0.01 to 25% by weight, preferably from 0.1 to 20% by weight, in each case.

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 ingredients in a suitable apparatus. Preferably, the liquid components are mixed, followed by the addition of the solid components, and then a homogeneous solution is prepared.

Generally, it has been found advantageous to administer the mixture of the invention in an amount of about 1 to 100mg of active compound per kilogram of body weight per day to achieve effective results. Preferably, 1-10mg of active compound per kg of body weight is used.

The following examples illustrate the invention without limiting it.

Examples

To prepare the following formulations, the liquid ingredients were mixed first, and then the solid ingredients were dissolved in the mixture under stirring. All percentages are weight percentages based on the total weight of the finished formulation.

Example 1

4％ PF1022

8% Praziquantel

79.1% N-methylpyrrolidone

4.4% limonene

4.4% oleic acid

0.1％ BHA

Example 2

4％ emodepside

8% Praziquantel

79.1% N-methylpyrrolidone

4.4% limonene

4.4% oleic acid

0.1％ BHA

Example 3

4％ emodepside

14% Praziquantel

68.9% N-methylpyrrolidone

5% limonene

5% oleic acid

0.1％ BHA

Example 4

4％ emodepside

8% Praziquantel

72.9% N-methylpyrrolidone

5% limonene

5% oleic acid

5% isostearyl alcohol

0.1％ BHA

Example 5

4％ emodepside

8% Praziquantel

67.9% N-methylpyrrolidone

5% limonene

5% oleic acid

10% isostearyl alcohol

0.1％ BHA

Example 6

4％ emodepside

8% Praziquantel

77.9% N-methylpyrrolidone

10% isostearyl alcohol

0.1％ BHA

Example 7

4％ emodepside

8% Praziquantel

67.9% N-methylpyrrolidone

20% isostearyl alcohol

0.1％ BHA

Example 8

8% Praziquantel

87% N-methylpyrrolidone

5% oleic acid

Example 9

4％ emodepside

8% Praziquantel

70.9% N-methylpyrrolidone

5% limonene

4.4% oleic acid

6.5% isostearyl alcohol

1.5% Octanoic acid

0.1％ BHA

Example 10

8% Praziquantel

87% N-methylpyrrolidone

5% limonene

Example 11

8% Praziquantel

83% N-methylpyrrolidone

4% limonene

4% oleic acid

Example 12

4％ emodepside

8% Praziquantel

72.9% N-methylpyrrolidone

15% limonene

0.1％ BHA

Example 13

8% Praziquantel

77% N-methylpyrrolidone

15% limonene

Example 14

8% Praziquantel

72% N-methylpyrrolidone

20% limonene

Example 15

4％ emodepside

8% Praziquantel

67.9% N-methylpyrrolidone

20% limonene

0.1％ BHA

Example 16

8% Praziquantel

78% N-methylpyrrolidone

4.4% limonene

4.4% oleic acid

5% isostearyl alcohol

Example 17

4％ emodepside

8% Praziquantel

72.9% N-methylpyrrolidone

5% limonene

5% linoleic acid

5% isostearyl alcohol

0.1％ BHA

Example 18

6％ emodepside

12% Praziquantel

71.9% N-methylpyrrolidone

5% limonene

5% oleic acid

0.1％ BHA

Biological examples

The solutions of examples 2 or 3 were applied to the epidermis on the back of the parasite-infected animal. Details are given in the following table:

Claims (10)

1. A composition for transdermal administration for controlling endoparasites, comprising:

● Cyclic depsipeptides having 24 ring atoms and/or praziquantel as active compounds, wherein the active compound content is from 0.01 to 25% by weight;

● pyrrolidone solvent, said pyrrolidone solvent being pyrrolidone optionally having alkyl substituents containing from 1 to 4 carbon atoms on the ring nitrogen and optionally further alkyl substituents containing from 1 to 4 carbon atoms in other ring positions, and the concentration of pyrrolidone solvent being from 20 to 99% by weight;

● A terpene hydrocarbon penetration enhancer having a 10 carbon atom skeleton, said terpene hydrocarbon being present in an amount of from 2 to 20% by weight,

provided that the total amount of all components in the composition is 100 wt%.

2. The composition of claim 1 containing limonene as a terpene hydrocarbon penetration enhancer.

3. The composition of claim 1, further comprising a fatty acid having 5 to 18 carbon atoms as a penetration enhancer, said fatty acid being present in an amount of 1 to 20 wt%.

4. The composition of claim 3 wherein the terpene hydrocarbon penetration enhancer is limonene and the fatty acid penetration enhancer is oleic or linoleic acid.

5. The composition of claim 4, wherein the fatty acid penetration enhancer is oleic acid.

6. The composition according to claim 1, comprising as active compound cyclo [ (R) -lactyl-N-methyl-L-leucinyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucinyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucinyl.

7. The composition of any one of claims 1-5, comprising a cyclic depsipeptide having 24 ring atoms and praziquantel.

8. The composition of claim 7 comprising cyclo [ (R) -lactyl-N-methyl-L-leucinyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucinyl- (R) -3- (p-morpholinophenyl) lactyl-N-methyl-L-leucinyl and praziquantel.

9. Process for the preparation of a composition according to any one of claims 1 to 8, characterized in that the active compound is mixed with a solvent and optionally further auxiliaries.

10. Use of a composition according to any one of claims 1 to 8 for the preparation of a medicament for controlling endoparasites.