JP5740676B2 - A composition comprising a C-13 alkoxy ether macrolide compound and a phenylpyrazole compound - Google Patents

Description

[Related applications]
This application claims priority to US application No. 11 / 317,932, filed 22 December 2005, and French application 96/11446, filed 19 September 1996, designating the United States. Of US application No. 09 / 271,470 (currently US Pat. No. 6,482,425) filed Mar. 17, 1999, which is a continuation-in-part of international application PCT / FR97 / 01548 filed Sep. 15, 1997. U.S. Application No. 10 / filed May 24, 2002, which is a divisional application of U.S. Patent Application No. 09 / 376,736 (currently U.S. Pat. No. 6,426,333) filed August 17, 1999 Reference is made to US Application No. 10 / 279,356, filed Oct. 24, 2002, which is a continuation-in-part of 155,397 (currently US Pat. No. 6,962,713).
Citation or reference in any of the foregoing applications, and all references cited therein ("application citations") and all references cited or referenced in application citations, and in the specification. All references cited ("citations in this specification") and all references cited or referenced in the references cited herein are hereby incorporated by reference herein or in any reference incorporated herein by reference. Any manufacturer's instructions, instructions, product specifications, and product sheets for any product mentioned are incorporated herein by reference and used in the practice of the invention.
(Field of the Invention)
The present invention relates to a composition comprising N-phenylpyrazole and a novel ivermectin derivative for controlling avian and mammalian parasites. The present invention also provides an improved method for eradicating, controlling and preventing avian and mammalian parasitic infections. The present invention also provides novel ivermectin derivatives.

BACKGROUND OF THE INVENTION
Animals such as birds and mammals are often susceptible to parasitic infections. These parasites may be ectoparasites such as insects, and endoparasites such as filariae and worms.
Domesticated animals such as cats and dogs are often parasitized by one or more of the following ectoparasites:
-Cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp., Etc.),
-Ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyoma sp., Etc.), and-ticks (Demodex sp., Sarcoptes sp., Otodectes sp., Etc.),
-Lice (Trichodectes sp., Cheyletiella sp., Lignonathus sp., Etc.),
-Mosquitoes (Aedes sp., Culex sp., Anopheles sp., Etc.) and flies (Hematobia sp., Musca sp., Stomoxys sp., Dermatobia sp., Coclyomia sp., Etc.).
Fleas are particularly problematic because they not only have a detrimental effect on animal or human health, but also cause significant psychological stress. In addition, fleas are vectors of animal virulence factors such as Dipylidium caninum, and human virulence factors.
Similarly, ticks are detrimental to the physical and psychological health of animals or humans. However, the most serious problem associated with ticks is that ticks are vectors of pathogenic agents that cause disease in both humans and animals. Major diseases caused by ticks include borreliosis (Lyme disease caused by Borrelia burgdorferi), Babesiosis (or piroplasmosis caused by Babesia sp.) And rickettsiosis (also known as Rocky Mountain spotted fever) It is done. Ticks also release toxins that cause inflammation or paralysis in the host. Sometimes these toxins are involved in the life of the host.
Furthermore, mites and lice are particularly difficult to suppress because they have few active substances that act on these parasites and need to be treated frequently.

Similarly, livestock are susceptible to parasitic infections. For example, cattle are attacked by numerous parasites. Parasites that are highly prevalent among livestock are the genus Boophilus, especially the species microplus (bovine tick), decoloratus and anulatus. Ticks such as Boophilus microplus are particularly difficult to control because they live in farms where livestock graze. Other important parasites of cattle and sheep are listed below in order of decreasing importance.
-Fly larvae, eg Dermatobia hominis (known as Berne in Brazil) and Cochlyomia hominivorax (greenbottle); ). These are flies whose larvae constitute animal parasites.
-Flies themselves, ie flies whose adults constitute parasites such as Haematobia irritans (horn fly);
Lice, such as Linognathus vitulorum, etc .; and ticks, such as Sarcoptes scabiei and Psoroptes ovis.
The above list is not exclusive and it is well known in the art that other ectoparasites are harmful to animals and humans. This includes, for example, migratory dipterous larvae.

Animals and humans also suffer from endoparasite infections. For example, helminthiasis most frequently caused by a group of parasitic helminths described as nematodes or roundworms. These parasites not only attack livestock and poultry, but also cause severe economic losses in pigs, sheep, horses and cattle. Other parasites present in the gastrointestinal tract of animals and humans include Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Toxocara, Toxacaris, Trichiris, Enterobius and parasites found in blood or other tissues and organs, such as Examples include the iliac worms and the extraintestinal stages of Strogyloides, Toxocara and Trichinella.
There are many insecticides in the art for treating parasites. These pesticides vary in their effectiveness against specific parasites and their costs. However, the results of these insecticides are not always satisfactory, for example due to the development of resistance to the therapeutic agent by parasites, as is the case for example with carbamates, organophosphorus compounds and pyrethrin analogues. In addition, there are currently no truly effective methods for controlling both ticks and intestinal parasites, and there are still few effective means of controlling the series of parasites described above. Accordingly, there is a need in the art for the treatment and protection of animals, such as mammals, fish and birds, with a more effective antiparasitic formulation against a wide range of parasites. Furthermore, the art describes an antiparasitic formulation that is easy to use for any type of livestock, regardless of its size and the nature of its jacket, and that does not need to be sprinkled throughout the body of a mammal, fish or bird. There is a request for.

A new family of insecticides based on 1-N-phenylpyrazole is described in patents EP-A-295,217 and EP-A-352,944. The family of compounds defined in these patents is extremely active and one of these compounds is 1- [2,6-Cl ₂ -4-CF ₃ phenyl] -3-CN-4- [SO -CF ₃ ] -5-NH ₂ pyrazole, ie fipronil, is particularly effective not only against crop parasites, but also against mammalian and avian ectoparasites. Fipronil is not exclusive, but is particularly effective against fleas and ticks.
Endectocidal compounds that are active against a wide range of endoparasites are known in the art. These compounds possess a macrocyclic lactone ring, and ectoparasites such as lice, blowfly, flies, mosquitoes, ticks, migratory dipterous larvae and ticks, and endoparasites such as nematodes and roundworms It has been found in the art to be particularly effective against. This group of compounds includes avermectins, milbemycins, and derivatives of these compounds, such as ivermectin or emamectin. Such materials are described, for example, in US Pat. Nos. 3,950,360, 4,199,569, 4,879,749, and 5,268,710.
Although it is known in the art that, in some cases, various parasiticides can be used in combination to broaden the scope of antiparasites, it is not possible to a priori predict which combination will work for a particular animal or disease state. Can not. For this reason, the results of various combinations are not always successful, and there is a need in the art for more effective formulations that can be easily administered to animals. The effectiveness of formulations containing 1-N-phenylpyrazole derivatives and macrolide lactone anthelmintics or antiparasitic agents such as evermectin, ivermectin and milbemycin against the endoparasites or ectoparasites of a unique host is numerous and complex hosts -Especially difficult to predict due to parasite interactions.
Patent application AU-A-16 427/95 is a very widely substituted 1-N-pyrazole derivative and evermectin in the discussion involving a very large number of different types of insecticides or parasiticides such as fipronil. Describes the combination of ivermectin or moxidectin. However, this patent application provides specific teachings on how to prepare 1-N-pyrazole derivatives with compounds of the avermectin or milbemycin type, and also spot-on compositions containing these compounds. No specific teaching on how to prepare is provided to those skilled in the art. Furthermore, the application does not indicate what specific combination the particular parasite is sensitive to.

Various methods for preparing antiparasitic formulations are well known in the art. These include oral formulations, poison baits, dietary supplements, powders, shampoos, pastes, concentrated solutions, suspensions, microemulsions, emulsions and the like. Formulations for localized topical application of antiparasitic formulations are also well known in the art.
Ready to use solutions containing 1-N-phenylpyrazole, such as fipronil, are well known in the art and are described in US Pat. No. 6,395,765, the contents of which are hereby incorporated by reference. .
Pour-on solutions containing 1-N-phenylpyrazole, such as fipronil, are well known in the art and are described in US Pat. No. 6,010,710, the contents of which are hereby incorporated by reference. .
Spot-on formulations are a well-known technique for local delivery of antiparasitic agents to a limited area of the host. A spot-on formulation comprising 1-N-phenylpyrazole and a macrocyclic lactone is described in US Pat. No. 6,426,333.
Paste formulations are also an effective means of delivering antiparasitic agents to certain areas on the host. Paste formulations are described in US Pat. No. 6,787,342.
Although compositions comprising 1-N-phenylpyrazole and macrocyclic lactones are generally known in the art, the ivermectin derivatives described for use herein are novel compounds. Furthermore, it would be advantageous if the composition for controlling the parasite had a rapid action and a long lasting effect and could reduce the number of applications required to control the parasite. Furthermore, it is well known that parasites tend to develop resistance to known therapeutic agents, and it would be beneficial to develop new compositions for controlling parasites.

For the purposes of this application, the following terms have the following definitions unless otherwise indicated herein.
(1) Alkyl represents both straight and branched carbon chains; references to individual alkyl groups are specific to straight chains (eg, butyl = n-butyl). In one embodiment of alkyl, the number of carbon atoms is 1-20, in another embodiment of alkyl, the number of carbon atoms is 1-8, and in still another embodiment, the number of carbon atoms. Is 1 to 4 carbon atoms. Other ranges of carbon numbers are contemplated and depend on the position of the alkyl moiety on the molecule.
(2) Alkenyl represents both straight and branched carbon chains having at least one carbon-carbon double bond. In one embodiment of alkenyl, the number of double bonds is 1-3, and in another embodiment of alkenyl, the number of double bonds is 1. In one embodiment of alkenyl, the number of carbon atoms is 2-20, in another embodiment of alkenyl, the number of carbon atoms is 2-8, and in another embodiment of alkenyl, the number of carbon atoms is 2-2. 4. Other ranges of carbon-carbon double bonds and carbon numbers are also contemplated and depend on the position of the alkenyl moiety on the molecule.
(3) Alkynyl represents both straight and branched carbon chains having at least one carbon-carbon triple bond. In one embodiment of alkynyl, the number of triple bonds is 1-3, and in another embodiment of alkynyl, the number of triple bonds is 1. In one embodiment of alkynyl, the number of carbon atoms is 2-20, in another embodiment of alkynyl, the number of carbon atoms is 2-8, and in another embodiment of alkynyl, the number of carbon atoms is 2-2. 4. Other ranges of carbon-carbon triple bonds and carbon numbers are possible and depend on the position of the alkynyl moiety on the molecule.
(4) Aryl represents a C ₆ -C ₁₀ aromatic ring structure. In one embodiment of aryl, the moiety is phenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl, and in another embodiment of aryl, the moiety is phenyl.
(5) Alkoxy represents -O-alkyl, alkyl is as defined in (1); alkylalkoxy represents -alkyl-O-alkyl, and alkyl is as defined in (1).
(6) Alkanoyl or acyl represents formyl (—C (═O) H) and —C (═O) -alkyl, where alkyl is as defined in (1).
(7) Alkanoyloxy represents —OC (═O) -alkyl, and alkanoyl is as defined in (6).
(8) Alkanoylamino represents —NH ₂ —C (═O) -alkyl, alkanoyl is as defined in (6), and the amino (NH ₂ ) moiety is substituted with alkyl as defined in (1). It may be.
(9) Aminocarbonyl represents —NH ₂ —C (═O), and the amino (NH ₂ ) moiety may be substituted with alkyl as defined in (1).
(10) Alkoxycarbonyl represents —C (═O) —O-alkyl, and alkoxy is as defined in (5).
(11) Alkenoyl represents —C (═O) -alkenyl, and alkenyl is as defined in (2).
(12) Alkynoyl is —C (═O) -alkynyl, where alkynyl is as defined in (3).
(13) Aroyl is —C (═O) -aryl, where aryl is as defined above.
(14) Cyclo (for example, cycloalkyl, cycloalkenyl, cycloalkynyl) as a prefix represents a saturated or unsaturated cyclic ring structure having 3 to 8 carbon atoms in the ring, and this range falls within the definition of aryl above. The intention is to separate and distinguish from. In one embodiment of cyclo, the ring size range is 4-7 carbon atoms, and in another embodiment of cyclo, the ring size range is 3-4. Other ranges of carbon numbers are possible and depend on the position of the cyclo moiety on the molecule.
(15) Halogen means atomic fluorine, chlorine, bromine and iodine. “Halo” (eg as exemplified by the term haloalkyl) refers to all degrees of substitution from mono to perhalo substitution (eg, chloromethyl (—CH ₂ Cl), dichloromethyl (—CHCl ₂ ), trichloromethyl ( -CCl ₃ ) as exemplified by methyl)).
(16) Heterocycle, heterocyclic or heterocyclo is an unsaturated cyclic, including fully saturated or aromatic (ie, “heteroaryl”) having at least one heteroatom in the ring containing at least one carbon atom Represents a group, for example a 4-7 membered monocyclic, 7-11 membered bicyclic, or 10-15 membered tricyclic ring system. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen, oxygen and / or sulfur atoms. Here, the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system.

Typical monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolidinyl, isothiazolynyl, isothiazolyl , Furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl , Pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dio SORUN and tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.
Typical bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, Coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (eg furo [2,3-c] pyridinyl, furo [3,2-b] pyridinyl] or furo [2,3-b] pyridinyl), dihydroisoin A drill, dihydroquinazolinyl (eg 3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl and the like.
Typical tricyclic heterocyclic groups include carbazolyl, benzoindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
Unless otherwise noted or apparent by context, an “active agent” or “active ingredient” or “therapeutic agent” as used herein refers to a C-13 alkoxy ether macrolide compound or phenylpyrazole compound of the present invention. means.
In this disclosure and in the claims and / or paragraphs, the C-13 alkoxy ether macrolide compound of the present invention and the term “phenylpyrazole compound” used to describe the present invention refer to all stereoisomers and crystalline forms thereof ( It should also be noted that it is intended to encompass hydrated forms, polymorphs and amorphous forms having a crystal structure of up to 15% by weight.
In this disclosure and in the claims, the terms “comprises”, “includes”, “includes”, and the like can have the meanings ascribed to them in US Patent Law, for example, they “include” , "Includes", "includes", etc .; and terms such as "consisting essentially of" and "consisting essentially of" belong to the United States Patent Law Note that they have meanings that are considered to be, and they exclude elements not explicitly listed, but exclude elements that are found in the prior art or that affect the basic or novel features of the present invention. I want to be.
In addition, the present invention provides any previously disclosed product, product manufacturing method or product that meets the written specification and enablement requirements of USPTO (35 USC 112, paragraph 1) or EPO (Article 83 of EPC). Is not intended to be within the scope of the present invention, and Applicant reserves the right to reserve any rights to any previously described product, method of manufacture of the product, or method of use of the product. Note that disclaimer is disclosed.

  The present invention provides a composition for treating or preventing parasites in mammals and birds, particularly cats, dogs, horses, chickens, sheep and cows, and in these parasites commonly encountered by mammals and birds. Provided for the purpose of liberating the host. The present invention relates to the effectiveness of ectoparasites such as fleas, ticks, ticks, such as mites, mosquitoes, flies and lice, as well as endoparasites, nematodes, such as filariae, helminths, beetles and roundworms in the digestive tract of animals and humans. It also provides long-lasting extermination.

In particular, this invention is a novel composition for the treatment or prevention of parasitic infections in mammals or birds,
(A) an effective amount of 1-N-phenylpyrazole derivative,
(B) an effective amount of an ivermectin derivative, and
(C) A composition comprising a pharmaceutically effective carrier is provided.
The present invention is a simple method for treating or preventing parasitic infections in mammals or birds, wherein an effective amount of the formulation of the present invention is topically applied to said mammals or birds. A method comprising the steps is also provided.
The invention also provides a composition comprising a combination of 1-N-phenylpyrazole derivatives and ivermectin derivatives that exhibit synergistic activity against parasites when compared to formulations containing only one class of therapeutic agents. .
The present invention also provides a novel ivermectin derivative compound, the compound and a method for producing a composition containing the compound.
The very high effectiveness of the methods and compositions / formulations of the present invention results in not only high immediate effectiveness after treatment of mammals or birds, but also very long duration effectiveness. The composition / formulation is a combination of other commercial antiparasitic formulations (parasites resistant to these formulations) such as FRONTLINE® (fipronil) and K-9 ADVANTIX® (imidacloprid / permethrin) Provide an alternative to
For the purposes of this invention, the term “pharmaceutical” / “pharmaceutically” is intended to encompass the treatment of animals, humans and birds.
These and other embodiments are disclosed by, or are apparent from, the following detailed description, and are encompassed by the following detailed description. As will be apparent, the preferred features and characteristics of one aspect of the invention can be applied to many other aspects of the invention.
In this disclosure, “including”, “including”, “containing”, “having”, and the like can have the meaning that they are considered to belong to in US patent law, and “include”, “ Such as “consisting essentially of” or “consisting essentially of” has the meaning considered to belong to the United States patent law, and this The term is an unlimited term that allows for the presence of anything other than those listed unless the fundamental or novel properties of those listed are changed by the presence of those other than those listed, but prior art embodiments are Exclude.

In the following, various preferred features and embodiments of the present invention will be described in more detail by way of non-limiting examples with reference to the accompanying drawings.
It is a figure which compares the efficacy with respect to a tick of a dog after administering a fipronil containing composition and a composition containing a fipronil and ivermectin derivative. It is a figure which compares the number of dogs without a tick after administering a fipronil containing composition and a fipronil and ivermectin derivative containing composition. It is a figure which compares the efficacy with respect to a dog's flea after administering a fipronil containing composition and a fipronil and ivermectin derivative containing composition. It is a figure which compares the number of dogs without a flea after administering a fipronil containing composition and a composition containing a fipronil and ivermectin derivative. It is a figure which compares the efficacy with respect to a flea of a cat after administering a fipronil containing composition and a fipronil and ivermectin derivative containing composition. It is a figure which compares the number of the cat without a flea after administering a fipronil containing composition and a fipronil and ivermectin derivative containing composition.

[Detailed explanation]
The present invention relates to a composition for treating or preventing avian or mammalian parasitic infections,
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or alkyl;
R ₂ is S (O) _n R ₃ , 4,5-dicyanoimidazol-2-yl or haloalkyl;
R ₃ is alkyl or haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , alkyl, haloalkyl, OR ₈ group or -N = C (R ₉ ) (R ₁₀ ) group;
R ₅ and R ₆ independently represent hydrogen, alkyl, haloalkyl, C (O) alkyl, S (O) _r CF ₃ , alkoxycarbonyl; or
R ₅ and R ₆ may together form a divalent alkylene group (optionally interrupted by 1 or 2 divalent heteroatoms);
R ₇ represents alkyl or haloalkyl;
R ₈ represents alkyl, haloalkyl or hydrogen;
R ₉ represents alkyl or hydrogen;
R ₁₀ represents an optionally substituted aryl or an optionally substituted heteroaryl group;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, haloalkyl, haloalkoxy, S (O) _q CF ₃ or SF ₅ ;
m, n, q and r each independently represents an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (II)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl);
(C) A composition comprising a pharmaceutically acceptable carrier is provided.

In another embodiment of the invention for the compound of formula (II), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or C ₁ -C ₈ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₈ haloalkyl;
R ₃ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, OR Represents ₈ groups;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₈ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₈ represents C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (II)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for the compound of formula (II), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or C ₁ -C ₄ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₄ haloalkyl;
R ₃ is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₄ is hydrogen, fluorine, chlorine, bromine, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₄ alkyl, C ₁ -C ₄ represents a haloalkyl, OR ₈ group;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₄ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₈ represents C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (II)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for the compound of formula (II), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1;
X represents CR ₁₂ (this compound is also known as fipronil));
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (II)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for Formula (IIa), the composition for treating or preventing avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or alkyl;
R ₂ is S (O) _n R ₃ , 4,5-dicyanoimidazol-2-yl or haloalkyl;
R ₃ is alkyl or haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , alkyl, haloalkyl, OR ₈ group or -N = C (R ₉ ) (R ₁₀ ) group;
R ₅ and R ₆ independently represent hydrogen, alkyl, haloalkyl, C (O) alkyl, S (O) _r CF ₃ , alkoxycarbonyl; or
R ₅ and R ₆ may together form a divalent alkylene group (optionally interrupted by 1 or 2 divalent heteroatoms);
R ₇ represents alkyl or haloalkyl;
R ₈ represents alkyl, haloalkyl or hydrogen;
R ₉ represents alkyl or hydrogen;
R ₁₀ represents an optionally substituted aryl or an optionally substituted heteroaryl group;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, haloalkyl, haloalkoxy, S (O) _q CF ₃ or SF ₅ ;
m, n, q and r each independently represents an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIa)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, C ₁ -C ₄ alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl); and
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for Formula (IIa), the composition for treating or preventing avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or C ₁ -C ₈ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₈ haloalkyl;
R ₃ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, OR Represents ₈ groups;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₈ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₈ represents C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIa)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy)
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for Formula (IIa), the composition for treating or preventing avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or C ₁ -C ₄ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₄ haloalkyl;
R ₃ is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₄ is hydrogen, fluorine, chlorine, bromine, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₄ alkyl, C ₁ -C ₄ represents a haloalkyl, OR ₈ group;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₄ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₈ represents C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIa)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In an embodiment of the invention for formula (IIa), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1;
X represents CR ₁₂ (this compound is also known as fipronil));
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIa)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In an embodiment of the invention for formula (III), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1;
X represents CR ₁₂ (this compound is also known as fipronil));
(B) A pharmaceutically effective amount of the ivermectin derivative of the following formula (III)

(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ); and
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for formula (IIb), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or alkyl;
R ₂ is S (O) _n R ₃ , 4,5-dicyanoimidazol-2-yl or haloalkyl;
R ₃ is alkyl or haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , alkyl, haloalkyl, OR ₈ group or -N = C (R ₉ ) (R ₁₀ ) group;
R ₅ and R ₆ independently represent hydrogen, alkyl, haloalkyl, C (O) alkyl, S (O) _r CF ₃ , alkoxycarbonyl; or
R ₅ and R ₆ may together form a divalent alkylene group (optionally interrupted by 1 or 2 divalent heteroatoms);
R ₇ represents alkyl or haloalkyl;
R ₈ represents alkyl, haloalkyl or hydrogen;
R ₉ represents alkyl or hydrogen;
R ₁₀ represents an optionally substituted aryl or an optionally substituted heteroaryl group;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, haloalkyl, haloalkoxy, S (O) _q CF ₃ or SF ₅ ;
m, n, q and r each independently represents an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIb)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, C ₁ -C ₄ alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl); and
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for formula (IIb), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or C ₁ -C ₈ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₈ haloalkyl;
R ₃ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, OR Represents ₈ groups;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₈ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₈ represents C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIb)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for formula (IIb), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is halogen, CN or C ₁ -C ₄ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₄ haloalkyl;
R ₃ is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₄ is hydrogen, fluorine, chlorine, bromine, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₄ alkyl, C ₁ -C ₄ represents a haloalkyl, OR ₈ group;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₄ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₈ represents C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring);
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIb)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In another embodiment of the invention for the compound of formula (IIb), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1;
X represents CR ₁₂ (this compound is also known as fipronil));
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IIb)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy);
(C) includes a pharmaceutically acceptable carrier.

In an embodiment of the invention for formula (IV), the composition for the treatment or prevention of avian or mammalian parasitic infections comprises:
(A) a pharmaceutically effective amount of at least one compound of formula (I)

(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1;
X represents CR ₁₂ (this compound is also known as fipronil));
(B) A pharmaceutically effective amount of an ivermectin derivative of the following formula (IV)

(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ); and
(C) includes a pharmaceutically acceptable carrier.

In each of the above embodiments, a pharmaceutically acceptable carrier is selected based on the form of the composition, which includes oral formulations, baits, dietary supplements, powders, shampoos, pastes, concentrated solutions, Suspensions, microemulsions and emulsions can be mentioned. Compositions intended for pharmaceutical use can be prepared by any method known in the art of pharmaceutical composition manufacture (Remington-The Science and Practice of Pharmacy (21st edition) (2005), Goodman &Gilman's The Pharmacological Basis of Therapeutics (11th edition) (2005) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (8th edition), Allen et al., Lippincott Williams & Wilkins, (2005)).
Organic solvents for pharmaceutically acceptable carriers include generally acceptable organic solvents known in the formulation art unless otherwise specified. These solvents are found, for example, in Remington Pharmaceutical Science, 16th edition (1986). Examples of these solvents include acetone, ethyl acetate, methanol, ethanol, isopropanol, dimethylformamide, dichloromethane, or diethylene glycol monoethyl ether (Transcutol). These solvents can be supplemented with various excipients according to the nature of the desired phase, eg C ₈ -C ₁₀ caprylic / capric triglycerides (Estasan or Miglyol 812), oleic acid or propylene glycol.

The pharmaceutical carrier may comprise a microemulsion. Microemulsions are also suitable as liquid carrier vehicles. Microemulsions are quaternary systems that include an aqueous phase, an oil phase, a surfactant and a cosurfactant. Microemulsions are translucent isotropic liquids.
A microemulsion is composed of a stable dispersion of water phase microdroplets in an oil phase or vice versa. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of alternating surface active (SA) molecules and co-surface active (Co-SA) molecules, and microemulsions are spontaneously formed by lowering the interfacial tension.
The oily phase may in particular be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides or from mixtures of the compounds. The oil phase preferably comprises triglycerides, more preferably medium chain triglycerides such as C ₈ -C ₁₀ caprylic / capric triglycerides. The oil phase will correspond in particular to about 2 to about 15% of the microemulsion, more particularly about 7 to about 10%, preferably about 8 to 9% V / V.
Examples of the aqueous phase include water or glycol derivatives such as propylene glycol, glycol ether, polyethylene glycol or glycerol. Propylene glycol, diethylene glycol monoethyl ether and dipropylene glycol monoethyl ether are particularly preferred. In general, the aqueous phase will correspond to a rate of about 1 to about 4% V / V of the microemulsion.
Surfactants for microemulsions include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycosylated C ₈ -C ₁₀ glycerides or polyglyceryl-6 diolates. In addition to these surfactants, cosurfactants include short chain alcohols such as ethanol and propanol.

Some compounds are common to the three components described above, namely the aqueous phase, surfactant and cosurfactant. However, the use of different compounds for each component of the same formulation is well within expert skill levels. The ratio of cosurfactant to surfactant is preferably from about 1/7 to about 1/2. Preferably from about 25 to about 75% V / V surfactant and from about 10 to about 55% V / V co-surfactant will be present in the microemulsion.
In one embodiment of the present invention, the composition may be in the form of a prepared solution as described in US Pat. No. 6,395,765. In addition to the compounds of formula (I) and formula (II), the prepared solution may contain a crystallization inhibitor, an organic solvent and an organic co-solvent.
In another embodiment of the prepared solution, the crystallization inhibitor is present in particular in a proportion of 1-20% (W / V), preferably 5-15%, and this inhibitor is tested according to the following: Satisfy: 0.3 ml of solution A containing 10% (W / V) of the compound of formula (I) and 10% of this inhibitor in an organic solvent as described below was placed on a glass slide at 20 ° C. for 24 hours. Later, little or no crystals are seen on the slide glass with the naked eye, in particular only less than 10 crystals are seen, preferably 0 crystals; the organic solvent is 10 to 35, preferably 20 Having a dielectric constant of ˜30, the content of this organic solvent in the total composition preferably corresponds to an amount that complements 100% of the composition; the organic cosolvent is less than 100 ° C., preferably less than 80 ° C. Having a boiling point and a dielectric constant of 10 to 40, preferably 20 to 30; this cosolvent advantageously has an organic cosolvent / organic solvent mass / mass (W / W) ratio of 1/15 to 1/2 Present in the composition. This solvent is particularly volatile to act as a drying accelerator and is miscible with water and / or organic solvents.
The crystallization inhibitor may be present in particular in a proportion of about 1 to about 20% (W / V), preferably about 5 to about 15%. This inhibitor is preferably placed on a glass slide at 20 ° C. with 0.3 ml of a solution containing 10% (W / V) of the compound of formula (I) and 10% of the inhibitor in a liquid carrier and left for 24 hours. Corresponds to the test. Next, the glass slide is observed with the naked eye. An acceptable inhibitor provides little or no crystals, especially less than 10 crystals, preferably 0 crystals.
The formulation can include an antioxidant intended to inhibit oxidation in the air, which agent is particularly about 0.005 to about 1% (W / V), preferably about 0.01 to about 0.05%. Present in proportion.
Examples of the crystallization inhibitor that can be used in the present invention include the following.
Polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives such as methacrylate Other-anionic surfactants such as alkaline stearates, especially sodium stearate, potassium stearate or ammonium stearate; calcium stearate or triethanolamine stearate; sodium abietic acid; alkyl sulfates, especially sodium lauryl sulfate and cetyl sulfate Sodium; sodium dodecylbenzenesulfonate or disulfosuccinate Sodium chill; or fatty acids, in particular fatty acids derived from coconut oil, - cationic surfactants, such as those of the formula ^{N + R'R''R '"R""} Y - in the water-soluble quaternary ammonium salt (wherein, R groups Is the same or different optionally hydroxylated hydrocarbon group, Y ⁻ is an anion of a strong acid, such as halide, sulfate and sulfonate anions; one of the cationic surfactants for which cetyltrimethylammonium bromide can be used One)
-Amine salt of formula N ⁺ R'R "R '", where R groups are the same or different optionally hydroxylated hydrocarbon groups; a cationic interface where octadecylamine hydrochloride can be used One of the active agents),
Non-ionic surfactants, for example, optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, ie polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, Polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and propylene oxide,
An amphoteric surfactant, for example a substituted lauryl compound of betaine,
-Or preferably a mixture of at least two of the above compounds.

In a particularly preferred embodiment, a crystallization inhibitor pair is used. Examples of such a pair include a combination of a polymer type film forming agent and a surfactant. These agents are in particular selected from the compounds mentioned above as crystallization inhibitors.
Particularly preferable polymer type film forming agents include the following.
-Various grades of polyvinylpyrrolidone,
-Polyvinyl alcohol, and-copolymers of vinyl acetate and vinyl pyrrolidone.
Particularly preferred surfactants include nonionic surfactants, preferably polyoxyethylenated esters of sorbitan, especially various grades of polysorbates such as those made by Polysorbate 80.
Film formers and surfactants can be incorporated in particular or in the same amounts, especially within the limits of the total amount of crystallization inhibitors mentioned elsewhere.
The pair thus constructed ensures in a noticeable manner the purpose of not crystallizing on the jacket and of maintaining the cosmetic appearance of the fur. That is, there is no tendency to become sticky or sticky appearance despite the high concentration of active substance.
Particularly preferred antioxidants are those conventional in the art, such as butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium pyrosulfite, propyl gallate, sodium thiosulfate or up to two of them. A mixture is mentioned.
The formulation adjuvants described above are well known to those skilled in the art and can be obtained commercially or via known techniques. These concentrated compositions are generally prepared by simple mixing of the above components; advantageously, the starting point is to mix the active materials in the main solvent, followed by the addition of other components or adjuvants.
The volume to be applied may be about 0.3 to about 1 ml, preferably about 0.5 ml for cats, about 0.3 to about 3 ml for dogs, and depends on the body weight of the animal.

In another embodiment of the present invention, the composition may be in pour-on form, as described in US Pat. No. 6,010,710. The pour-on formulation is advantageously oily and generally comprises a diluent or vehicle and, if the compound of formula (I) is insoluble in the diluent, also a solvent (organic solvent) for the compound.
Examples of organic solvents that can be used in the present invention include: acetyl tributyl citrate, fatty acid esters such as dimethyl ester, diisobutyl adipate, acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide , Dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propylene glycol, 2-pyrrolidone, especially N- Methyl pyrrolidone, diethylene glycol monoethyl ether, ethylene glycol and diethyl phthalate, or A mixture of at least two of al of the solvent.
Vehicles or diluents include vegetable oils such as soybean oil, peanut oil, castor oil, corn oil, cottonseed oil, olive oil, grape seed oil, sunflower oil, etc .; mineral oils such as petroleum, paraffin, silicone, etc .; aliphatic or cyclic Examples include hydrocarbons or medium chain (particularly C8 to C12) triglycerides.
Preferably, a softening agent and / or a spreading agent and / or a film forming agent are added. This drug is selected in particular from:
(a) polyvinyl pyrrolidone, polyvinyl alcohol, copolymer of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan ester; lecithin, sodium carboxymethyl cellulose, silicone oil, polydiorganosiloxane oil, In particular polydimethylsiloxane (PDMS) oils, such as those containing silanol functional groups, ie 45V2 oils,
(b) Anionic surfactants such as alkaline stearates, especially sodium stearate, potassium or ammonium; calcium stearate, triethanolamine stearate; sodium abietic acid; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; dodecylbenzene Sodium sulfonate, dioctyl sodium sulfosuccinate; fatty acids, especially those derived from coconut oil,
(c) cationic surfactants, such as those of the formula ^{N + R'R''R '"R""} Y - water-soluble quaternary ammonium salts (wherein the groups R are optionally substituted hydrocarbon which be hydroxylated Y ⁻ is a strong acid anion, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the available cationic surfactants),
(d) amine salt of formula N ⁺ R′R ″ R ′ ”(wherein the group R is an optionally hydroxylated hydrocarbon group; a cationic surfactant that can be used with octadecylamine hydrochloride) One of the agents),
(e) nonionic surfactants, such as sorbitan esters optionally polyoxyethylenated, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene -Styrol ether: Polyethylene glycol stearate, polyoxyethylenated derivative of castor oil, polyglycerol ester, polyoxyethylenated fatty alcohol, polyoxyethylenated fatty acid, copolymer of ethylene oxide and propylene oxide,
(f) amphoteric surfactants, such as substituted lauryl compounds of betaine, or
(g) A mixture of at least two of the above compounds.
The solvent is used in proportion to the concentration of Compound I and the solubility of Compound I in this solvent. For example, the solubility of fipronil in acetyltributyl citrate is 4.3% m / V. You will pursue the lowest volume possible. The vehicle fills the gap to 100%.
Preferably, the softening agent is used in a proportion of 0.1-10% by volume, especially 0.25-5%.

In another embodiment of the invention, the composition may be in spot-on form. For spot-on formulations, the carrier may be a liquid carrier vehicle as described in US Pat. No. 6,426,333. This liquid carrier vehicle contains a solvent and a co-solvent, and the solvent is acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, Ethylene glycol monomethyl ether, monomethyl acetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycol, propylene glycol, 2-pyrrolidone, especially N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate fatty acid ester such as diethyl ester Or the group consisting of diisobutyl adipate and a mixture of at least two of these solvents And the co-solvent is selected from the group consisting of absolute ethanol, isopropanol or methanol.
The liquid carrier vehicle is optionally an anionic surfactant, cationic surfactant, nonionic surfactant, amine salt, amphoteric surfactant or polyvinylpyrrolidone, polyvinyl alcohol, vinyl acetate and vinylpyrrolidone copolymer, polyethylene glycol, benzyl A crystallization inhibitor selected from the group consisting of alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan ester; lecithin, sodium carboxymethylcellulose, and acrylic derivatives, or a mixture of these crystallization inhibitors may be included.
Spot-on formulations can be prepared by dissolving the active ingredient in a pharmaceutically or veterinary acceptable vehicle. Alternatively, spot-on formulations can be prepared by encapsulation of the active ingredient to leave the therapeutic agent on the surface of the animal. These formulations vary with respect to the mass of therapeutic agent in the combination, which will depend on the species of host animal to be treated, the severity and type of infection and the weight of the host.
In another embodiment of the invention, the composition may be in paste form. One embodiment of a paste form is described in US Pat. No. 6,787,342, the contents of which are hereby incorporated by reference. In addition to the 1-N-phenylpyrazole and ivermectin derivative compounds described above, the paste comprises fumed silica; viscosity modifier; carrier; absorption promoter if necessary; and optionally colorants, stabilizers, surfactants. An agent or a preservative is also contained.
The method for preparing a paste preparation includes the following steps.
(a) a step of dissolving or dispersing 1-N-phenylpyrazole and an ivermectin derivative compound in a carrier by mixing;
(b) adding fumed silica to a carrier containing this dissolved 1-N-phenylpyrazole and ivermectin derivative compound, and mixing until the silica is dispersed in the carrier;
(c) precipitating the intermediate formed in step (b) for a time sufficient to escape the air entrained in step (b); and
(d) A step of adding a viscosity modifier while mixing with this intermediate to produce a homogeneous paste.
These steps are exemplary and not limiting. For example, step (a) may be moved last.
Another embodiment of the paste of the present invention is 1-N-phenylpyrazole and ivermectin derivative compound, fumed silica, viscosity modifier, absorption enhancer, colorant; and hydrophilic which is triacetin, monoglyceride, diglyceride or triglyceride Including a carrier.
Further embodiments of the paste include, but are not limited to, the viscosity modifier is PEG200, PEG300, PEG400, PEG600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan monooleate (Polysorbate 80 or Tween 80) and a polyoxamer (eg Pluronic L 81); the absorption enhancer is selected from the group consisting of magnesium carbonate, calcium carbonate, starch, and cellulose and derivatives thereof; and And pastes wherein the colorant is selected from the group consisting of titanium dioxide, iron oxide and FD & C Blue # 1 aluminum lake.

Certain classes of phenylpyrazoles are well known in the art, for example, U.S. Patent No. 5,885,607, U.S. Patent No. 6,010,710, U.S. Patent No. 6,083,519, U.S. Patent No. 6,096,329, U.S. Patent No. 6,395,765 and U.S. Patent No. 6,867,229 ( All of which belong to Merial, Ltd.) and U.S. Pat. No. 5,576,429, U.S. Pat. No. 5,122,530, and EP295177. These disclosures, as well as the references cited herein, are incorporated by reference. This class of insecticides has been found to have excellent activity against insects such as ticks and fleas.
Ivermectin is recognized as part of a broader class of compounds known as macrocyclic lactones. In each of the above embodiments of the present invention, an additional macrocyclic lactone can be added to the composition. Examples of such macrocyclic lactones include, but are not limited to, avermectins such as avermectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin ) And milbemycin, such as milbemectin, milbemycin D and moxidectin. Also included are the 5-oxo and 5-oxime derivatives of the avermectin and milbemycin.
These known macrocyclic lactone compounds are readily obtained commercially or via techniques well known in the art. Browse widely available technology and commercial catalogs. For evermectin, ivermectin and avermectin, for example, a study by MH Fischer and H. Mrozik “Ivermectin and avermectin” (1989, William C. Campbell, Springer Verlag. Published), or Albers-Schonberg et al. (1981) “Evermectin structure determination”. (J. Am. Chem. Soc., 103, 4216-4221). For doramectin, “Veterinary Parasitology” (vol. 49, No. 1, June 1993, 5-15) can be particularly referred to. Milbemycin includes, among others, Davies HG et al. (1986), “Evermectin and Milbemycin” (Nat. Prod. Rep., 3, 87-121, Mrozik H. et al. (1983), “Synthesis of Milbemycin from Evermectin” (Tetrahedron Lett. 24, 5333-5336), U.S. Pat. No. 4,134,973 and EP 677,054.

Macrocyclic lactones are natural products or semi-synthetic derivatives thereof. The structures of evermectin and milbemycin are very related, for example, sharing a complex 16-membered macrocyclic lactone ring; milbemycin lacks the glycoside portion of evermectin. The natural product evermectin is disclosed in US Pat. No. 4,310,519 to Albers-Schonberg et al., And the 22,23-dihydrovermectin compound is disclosed in US Pat. No. 4,199,569 to Chabala et al. In particular, Kitano US Pat. No. 4,468,390, Beuvry et al. US Pat. No. 5,824,653, European Patent Application 0007812A1 (published June 2, 1980), British Patent Specification 1390336 (published April 9, 1975), European Patent Reference may also be made to application 0002916A2 and Ancare New Zealand Patent No. 237086. Naturally occurring milbemycin is cited in Aoki et al. US Pat. No. 3,950,360 and “The Merck Index” (12th edition, edited by S. Budavari, Merck & Co., Inc. Whitehouse Station, New Jersey (1996)). Described in various references. Latidectin is described in "International Nonproprietary Names for Pharmaceutical Substances (INN)" (WHO Drug Information, vol. 17, no. 4, pp. 263-286, (2003)). Semi-synthetic derivatives of these classes of compounds are well known in the art, e.g., U.S. Pat.No. 5,077,308, U.S. Pat.No. 4,859,657, U.S. Pat. No. 4,874,749, U.S. Pat.No. 4,427,663, U.S. Pat.No. 4,310,519, U.S. Pat.No. 4,199,569, U.S. Pat.No. 5,055,596, U.S. Pat.No. 4,973,711, U.S. Pat.No. 4,978,677, U.S. Pat. Have been described.
In each of the above embodiments, a cestodal agent may be added, including but not limited to, praziquantel, pyrantel, espirantel, niclosamide, mebendazole ), Albendazole, triclabendazole, metrifonate, oxamniquine and morantel. In one embodiment of the invention, at least one additional macrocyclic lactone and / or tapeworm control agent is added to the composition, the macrocyclic lactone is eprinomectin and the tapeworm control agent is praziquantel.
In each of the above embodiments, nitroguanidine or pyridylmethylamine insecticide may be added. These insecticides include but are not limited to clothiandin, dinotefuran, imidacloprid, thiamethoxam, acetamiprid, nitepyram, and thiacloprid. It is done.

Where applicable, it is also envisioned that pharmaceutically acceptable acid or base salts of 1-N-phenylpyrazole and macrolide lactone are provided herein. The term “acid” contemplates all pharmaceutically acceptable inorganic or organic acids. Inorganic acids include mineral acids such as hydrochloric acid, hydrohalic acids such as hydrobromic acid and hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Organic acids include all pharmaceutically acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids, tricarboxylic acids and fatty acids. Preferred acids are linear or branched saturated or unsaturated C ₁ -C ₂₀ aliphatic carboxylic acids, or C ₆ -C ₁₂ aromatic carboxylic acids, optionally substituted with halogen or hydroxyl groups. Examples of such acids are carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, α-hydroxy acids such as glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methanesulfonic acid, and salicylic acid. . Examples of dicarboxylic acids include oxalic acid, malic acid, succinic acid, tartaric acid and maleic acid. An example of a tricarboxylic acid is citric acid. Fatty acids include all pharmaceutically or veterinary acceptable saturated or unsaturated aliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms. Examples include butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and phenylsteric acid. Other acids include gluconic acid, glycoheptonic acid and lactobionic acid.
The term “base” contemplates all pharmaceutically or veterinary acceptable inorganic or organic bases. Examples of the base include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, or calcium salts. Organic bases include common hydrocarbyl and heterocyclic amine salts, such as morpholine and piperidine salts.

The subject of the present invention is also a method for eliminating parasites of mammals and birds, in particular dogs and cats, using the compositions of the present invention.
In one embodiment of the present invention, the direct pour-on skin formulation of the present invention may obtain sustained and widespread efficacy when the solution is applied along the back of the animal, preferably along the back line at one or more points. it can.
According to a first embodiment for direct administration of pour-on formulations, the method consists in applying the solution to the animals in the ranch and / or to the animals before the animals arrive on the ranch, preferably monthly, The application is preferably repeated every two months.
According to a second embodiment for direct administration of the pour-on formulation, the method consists in applying the solution to the livestock before the livestock arrives at the “rearing site”, before this application is before the animal is sacrificed. It can be the last one.
Obviously, the method may consist in using these two embodiments together, i.e. performing the second embodiment after the first embodiment.
The solution of the present invention may be applied using any means known per se, but preferably an applicator gun or a measuring flask is used.
This method helps clean the animal's skin and hair by eliminating not only the parasites on the animal, but also their residues and feces. The result is that animals no longer feel sterle by parasites and their bites, which has positive consequences for example in the growth of the animals themselves and in food supply applications.

In another embodiment of the present invention, application of the spot-on formulation of the present invention can also provide sustained and widespread efficacy when the solution is applied to mammals or birds.
Administration of the spot-on formulation may be intermittent in time and may be administered daily, weekly, biweekly, monthly, bimonthly, every three months, or even longer duration. The time between treatments depends on factors such as the parasite being treated, the degree of infection, the type of mammal or bird, and the environment in which the mammal or bird lives. It is well within the skill level of the practitioner to determine the period of administration specific to a particular situation. The present invention contemplates a method for permanently combating parasites in an environment where the animal is subjected to strong parasite pressure, where administration is less frequent than daily administration. For example, for dogs and cats, the treatment of the present invention is preferably performed monthly.
Administration of spot-on formulations also provides a way to clean animal jackets and skin by removing existing parasites and parasite excretion and feces. Animals treated in this way exhibit an envelope that is entertaining and comfortable to touch.
While not wishing to be bound by any theory, it is believed that the spot-on formulations of the present invention work with doses that are dissolved in the natural oils of the host's skin, fur or feathers. From there, the therapeutic agent is distributed throughout the host body through the sebaceous glands of the skin. Therapeutic drugs remain in the sebaceous glands. In this way, the sebaceous glands provide a natural reservoir of therapeutic agent that allows the therapeutic agent to flow slowly into the follicle and reapply the therapeutic agent itself to the skin and hair. This not only eliminates the need to administer the dose again after the host has become moist due to rain, bathing, etc., but also provides a long application interval. Furthermore, the formulations of the present invention are further advantageous in letting animals groom, since they do not deposit directly on the skin or fur. When deposited directly on the skin or fur, an animal may become sick or interact with other therapeutic agents that are orally administered by ingesting the therapeutic agent.

Other routes of administration include paste formulations, oral liquid formulations, chewable formulations, transdermal or transmucosal patches or liquids, gels or pastes, solutions for inhalation and injectable formulations.
In another preferred embodiment, the present invention is a composition for combating small mammals, particularly dog and cat fleas, in a vehicle that is tolerated by said animals, in a parasite effective amount for fleas and worms, and Providing, in proportion, at least one compound (A) of formula (I) as defined above and at least one endectocidal compound (B).
Particularly for prevention, the compounds (A) and (B) can be continuously administered by a known method. In general, it is sufficient to administer a dose of about 0.001 to about 10 mg / kg body weight as a single dose or in divided doses for 1 to 5 days, but of course if a higher or lower dose range is indicated This is within the scope of the present invention. Determining specific dosage regimes for specific hosts and parasites is well within the routine skills of the practitioner.
Preferably, a single formulation comprising compounds (A) and (B) in a substantially liquid carrier, in a form that allows for a single application or a small number of repeated applications, very topically in an animal, The animal is preferably administered over the area between the two shoulders. Remarkably, the formulation has been found to be very effective against both targeted ectoparasites and targeted endoparasites.
Preferably, particularly when directly administered topically, on a single occasion to the host, about 0.001 to about 100 mg / kg of the derivative (A) and about 0.1 to about 2000 μg / kg, more preferably 1000 μg / kg of type (B ) Is administered to administer a dose containing the compound.
The amount of compound (A) for birds and small animals is preferably greater than about 0.01 mg, and in a particularly preferred manner is about 1 to about 50 mg / kg.
The effective amount in the dose is preferably about 0.001, preferentially about 0.1 to about 100 mg for compound (A), and about 1 to about 50 mg / kg (animal body weight) in a particularly preferred manner. Is increased for a very long time in and on the animal body.
The effective amount of compound (B) in the dose is preferably about 0.1 μg, preferentially about 1 μg to about 10 mg, and in a particularly preferred manner about 5 to about 200 μg / kg (animal body weight). Particularly preferred is a dose of about 0.1 to about 10 mg / kg (animal body weight), with about 0.5 to 6 mg / kg most particularly preferred.
The mass ratio of compound (A) to compound (B) is preferably about 5/1 to about 10,000 / 1.
In another embodiment of the present invention, a novel ivermectin derivative compound of the following formula (II) is provided.

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl. )
In another embodiment of the present invention, a compound of the following formula (II) is provided.

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy. )
In another embodiment of the present invention, a compound of the following formula (II) is provided.

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkylalkoxy. )
In another embodiment of the present invention, a compound of the following formula (II) is provided.

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkylalkoxy. )
In another embodiment of the present invention, there is provided a compound of formula (IIa)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, C ₁ -C ₄ alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl. )
In another embodiment of the present invention, there is provided a compound of formula (IIa)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy),
(C) A pharmaceutically acceptable carrier.
In another embodiment of the present invention, there is provided a compound of formula (IIa)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy)
(C) A pharmaceutically acceptable carrier.
Another embodiment of the invention for a compound of formula (IIa) provides a compound having the following formula (III):

(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ . )
In another embodiment of the present invention, there is provided a compound of formula (IIb)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, C ₁ -C ₄ alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl. )
In another embodiment of the present invention, there is provided a compound of formula (IIb)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy. )
In another embodiment of the present invention, there is provided a compound of formula (IIb)

(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkylalkoxy. )
Another embodiment of the invention for a compound of formula (IIb) provides a compound having the following formula (IV):

(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ . )

  Another embodiment of the present invention is a method for producing the novel ivermectin derivatives of the present invention. Ivermectin is a mixture of the following formulas B1a and B1b forms, which are two homologous compounds.

(B _1a = Z = CH ₂ CH ₃
B _1b = Z = CH ₃ )

The method for producing a novel ivermectin derivative compound of the present invention includes the following steps.
(a) cleaving a disaccharide at the C-13 position of ivermectin to give -OH to C-13;
(b) protecting the —OH group of C-5, C-7 and C-13;
(c) selectively deprotecting the protected —OH group of C-13;
(d) alkylating this deprotected —OH to produce the component — (CH ₂ ) _s (OCH ₂ ) _t O-alkyl or — (CH ₂ ) _s (OCH ₂ CH ₂ ) _u O-alkyl, where , S, t and u are as defined above;
(e) purifying the product formed in step (d);
(f) deprotecting the protected —OH groups of C-7 and C-13 and purifying the resulting compound; and
(g) If necessary, performing one of the following additional steps (i) to (iii):
(i) alkylating C-5 —OH;
(ii) oxidizing 5-OH of C-5 to form a 5-oxo compound;
(iii) oxidizing the -OH of C-5 to form a 5-oxo compound, and optionally further reacting the 5-oxo compound with hydroxylamine to form a 5-oxime compound; Accordingly, alkylating the —OH of the oxime moiety.

In another embodiment of the present invention for the method for producing the novel ivermectin derivative of the present invention, the method comprises the following steps.
(a) cleaving a disaccharide at the C-13 position of ivermectin by acid-catalyzed hydrolysis to yield -OH to C-13;
(b) After the first protection step in which the —OH groups of C-5, C-7, and C-13 are reacted with t-butyldimethylsilyl chloride (TBDMS), the TBDMS-protected hydroxyl group Is protected by a second protection step in which it is reacted with trimethylsilyl chloride (TMS) to obtain C-7 and C-13 TMS protected hydroxyl and C-5 TBDMS protected hydroxyl;
(c) selectively deprotecting the TMS-protected hydroxyl group of C-13 by reaction with dichloroacetic acid;
(d) alkylating the deprotected —OH with 2-methoxyethoxymethyl chloride (MEM chloride) to form the component —CH ₂ —OCH ₂ CH ₂ —O—CH ₃ ;
(e) purifying the product formed from step (d) by crystallization; and
(f) deprotecting the protected —OH groups of C-7 and C-13 and purifying the resulting compound by crystallization.

Disaccharide cleavage can be caused by any means well known to those skilled in the art, for example by acid or base catalyzed hydrolysis / solvolysis. The selection of suitable protecting groups for the selective protection of hydroxyl groups is well known in the art (eg, Protective Groups in Organic Synthesis, 3rd edition, Chapter 2-including "1,2- and 1,3-diols"). (See Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols), Green and Wuts, John Wiley and Sons, pages 17-245 (1999)). Is possible. Purification can be achieved by any means known in the art such as HPLC, crystallization and the like. Arbitrary steps (i) to (iii) can be performed using the technique described in US Pat. No. 5,015,630, the contents of which are incorporated herein by reference.
Upon reading the following description given as a non-limiting example, other advantages and features of the present invention will become apparent.

Example 1 Synthetic Procedure for Producing Ivermectin MEM Derivative

(In the formula, R ₁₆ = -CH ₂ CH _{3 for} type B1a and R ₁₅ = -CH _{3 for type} B1b)
Have
To synthesize the MEM derivative of ivermectin, the disaccharide moiety is cleaved at the C-13 position of ivermectin by acid solvolysis using a 1% acid solution to achieve cleavage to ivermectin aglycone. Next, the —OH group of C-5, C-7, and C-13 is protected with t-butyldimethylsilyl chloride (TBDMS), and then protected with trimethylsilyl chloride (TMS) to produce 7,13-bis-O—. TMS-5-O-TBDMS ivermectin aglycone is obtained.
This 7,13-bis-O-TMS-5-O-TBDMS ivermectin aglycone is then selectively deprotected using dichloroacetic acid to give 7-O-TMS-5-O-TBDMS ivermectin aglycone. This aglycone is then alkylated with 2-methoxyethoxymethyl chloride (MEM chloride) and subsequently purified by crystallization to give 13-MEM-7-O-TMS-5-O-TBDMS ivermectin aglycone.
This 13-MEM-7-O-TMS-5-O-TBDMS ivermectin aglycone was deprotected to remove residual silyl groups and purified by crystallization from isopropanol to obtain an isopropanol solvate of the MEM derivative of ivermectin. Generate. The result is an ivermectin MEM derivative with an overall yield of about 65%.
Synthetic procedures for producing ivermectin MEM derivatives are well known to those skilled in the art. See, for example, Cvetovich et al, J. Org. Chem. 62: 3989-3993 (1997), the entire contents of which are incorporated herein by reference.

Example 2: Efficacy of ivermectin MEM derivative against fleas
Two ivermectin derivatives (formula (III) and formula (IV)) were tested for their efficacy against fleas on male dogs. The efficacy of the compounds of formula (III) and formula (IV) against fleas was demonstrated using different pedigrees and 20 female dogs and 16 male dogs weighing 9.3-21.6 kg. Dogs were assigned to treatment with constrained randomization based on the number of fleas before treatment (day 0). Treatment is vehicle control, compound of formula (III) in 1.5% or 2.5% solution topically applied at 1 ml / kg to give a dose of 15 or 25 mg / kg, 1 ml to give a dose of 10 or 15 mg / kg The compound of formula (IV) in a 1% or 1.5% solution applied topically at / kg. Dogs were individually housed in cages or indoor enclosures. Each dog was infected with 100 fleas (Ctenocephalides felis) on days -1, 13, 20 and 27. Count the number of live fleas observed by dividing dog hair by hand on days 0, 1, 2, 3, 14, 15, 16, 21, 22, 23, 28, 29, 30 and 31 The flea count was performed (so-called “thumb count”). After thumb counting on day 31, each dog's hair was thoroughly combed and the number of live fleas picked up by the comb was recorded ("comb count").
Flea counts in dogs treated with 15 mg / kg of the compound of formula (III) or the compound of formula (IV) were significantly lower (p <0.05) than the control counts on all post-treatment count days except day 1. There was no significant difference between 25 mg / kg of the compound of formula (III) and 15 mg / kg of the compound of formula (IV). The group treated with 15 mg / kg of the compound of formula (III) was significantly more significant than the group treated with the compound of formula (IV) having a flea count (comb count) of 10 mg / kg on days 1, 22, 23 and 31 ( p <0.05) higher and the flea count (thumb count) on days 30 and 31 was significantly (p <0.05) higher than the group treated with 15 mg / kg of the compound of formula (IV). The percentage reduction from the control based on day 31 comb counts ranged from 46.9% of the compound of formula (III) at 15 mg / kg to 89.1% of the compound of formula (IV) at 10 mg / kg.

Example 3: Efficacy of ivermectin MEM derivative against scabies
Two ivermectin derivatives (formula (III) and formula (IV)) were tested for their efficacy against scabies in male dogs. Twenty-three hybrid dogs with an estimated age of 3 to 7 years and naturally infected with Sarcoptes scabiei var canis (Sarcoptes scabiei var canis) and 1 Heeler (Australian cattle) The efficacy of compounds of formula (III) and formula (IV) applied topically according to a multi-point application system using dogs was compared. There were 12 male dogs and 12 female dogs.
Dogs were kept individually in the kennel. Based on animal availability and tick counts, 4 dogs were replicated; within the replicates, dogs were randomized in the vehicle-treated (L-930,870) group or at a dose volume of 1 ml / kg (III) Of 15 mg / kg (body weight) or the compound of formula IV assigned to receive 10 mg / kg or 15 mg / kg. The investigator did not see the processing code. All treatments were applied topically on day 0. The number of ticks was evaluated on day-1 or 0, 7, 14, 28, 42, and 56.
During the study, ticks were collected from 4 of 6 animals in the vehicle-treated group. No mites were found on day 28 and thereafter in any of the 6 dogs treated with the compound of formula (III) at 15 mg / kg. Dogs treated with the compound of formula (III) or the compound of formula (IV) had significantly fewer (p <0.05) live mites than control dogs at the observation time after each treatment.

Example 4: Efficacy of ivermectin MEM derivatives against helminths and roundworms 15 mg of compound of formula (III) / kg (body weight) and 10 mg and 15 mg of formula (IV) for topical use against dog worms and roundworm infections A study was conducted to compare the activity of / kg (body weight). 13 male and 11 female beagle pups by orally administering 800 larvated eggs of Toxocara canis and 150 larvae of Ancylostoma caninum on day-47 The dog was infected. The puppies were 15-16 weeks old and weighed 4.1-5.8 kg. After both parasite infections became patency, puppies were assigned to 6 replicates of 4 puppies based on the number of fecal eggs / g of roundworm each day-1. Within replicate experiments, puppies were randomly assigned to one of the four coded treatment groups (1-4). The processing was as follows:
1) Vehicle control, 1 ml / kg (body weight);
2) Compound of formula (III), 1.5% solution, 1 ml / kg, 15 mg / kg (body weight);
3) a compound of formula (IV), 1.0% solution, 1 ml / kg, 10 mg / kg body weight; and
4) Compound of formula (IV), 1.5% solution, 1 ml / kg, 15 mg / kg body weight.
The investigator did not know which formulation was assigned to which code.
On day 0, test compound approximately once a fifth of the total volume of drug solution applied to the skin at each of five spaced spots evenly between the middle of the neck and the base of the tail along the dog's back Was administered topically. At 24 and 48 hours after treatment, each hair was graded and graded. Blood samples for collection of plasma were collected from each dog on days -5, 6, 12, and 24 hours; and 2, 3, 7, and 14 days after treatment. At the time of necropsy (day 14), hair, skin swabs, and skin samples were taken from three sites of each dog.
All six vehicle control pups had mature canine worms (geometric mean = 81.1 worms). The compound of formula (III) at 15 mg / kg removed worms of 3 out of 6 puppies and reduced the helminth burden by 97.5% compared to the helminth burden of the control (p <0.05). The compound of formula (IV) in each dosing regimen (10 and 15 mg / kg) removes worms of 5 out of 6 puppies and is only 99.4% and 99.8% respectively compared to the helminth burden of the control Reduced insect burden (p <0.05).
Five of the six controls had dog roundworms at necropsy (geometric mean = 4.4 worms). No roundworms were recovered from any of the treated puppies. The efficacy of the 3 topical formulations against dog roundworm was 100% compared to the control (p <0.05).

Example 5: Efficacy test of canine combination therapy against ticks and fleas To test the efficacy of the composition of the invention, 5% or 10% of the MEM derivative of ivermectin (compound of formula (III)) with 10% solution of fipronil Spot-on compositions containing% solutions were prepared and administered to groups of 6 dogs per study. Efficacy was measured once a week for ticks (Rhipicephalus sanguineus) and fleas (Ctenocephalides felis) infection and compared to the same test using a composition containing only 10% fipronil.

Table 1-Efficacy data for dog ticks

As can be seen from the table, the activity of the spot-on composition of the present invention against ticks shows much greater initial potency against ticks than only 10% fipronil. Furthermore, this improved activity against ticks of the spot-on composition of the present invention is seen for at least 2 weeks even beyond the 30-day score.
Although there appears to be only a marginal difference in efficacy from day 9 to day 30 based solely on observation of the data in Table 1, these trials notice a significant change in the number of dogs that were completely free of ticks. . In FIG. 2, it can be seen that the spot-on composition of the present invention was much better at maintaining dogs without ticks compared to a composition containing only 10% fipronil from day 16 to day 44. As such, the composition of the present invention is more suitable for a once-monthly dosing regimen than a composition containing only 10% fipronil.
Similarly, although less prominent against ticks, the spot-on formulation of the present invention was particularly potent against fleas in the period after 30 days (see FIG. 3), but the composition of only 10% fipronil It was much more potent to maintain dogs that were completely free of fleas (Figure 4).

Example 6: Efficacy test against fleas in cats To test the efficacy of the composition of the present invention, a 5% or 10% solution of a MEM derivative of ivermectin (compound of formula (III)) is included with a 10% solution of fipronil. Spot-on compositions were prepared and administered to groups of 6 cats per study. Efficacy was measured for flea (Ctenocephalides felis) infection on a weekly basis and compared to the same study using a composition containing only 10% fipronil.

Table 2-Efficacy data for cat fleas

  Similar to the effect seen in dogs, the potency of the spot-on composition of the present invention against cat fleas after 30 days is improved over the composition of only 10% fipronil. Although there is a marginal difference in potency before 30 days, the spot-on composition of the present invention shows greatly improved potency in maintaining cats that are completely free of ticks. Over 29 days, 5 measurements were taken, but the average total number of cats that were completely flea-free when treated with the spot-on composition of the present invention was 5.0 (25 cats / 5 measurements) Data), when treated with only 10% fipronil, the average of the total number of cats without fleas was 3.0 (15 cats / 5 measured data).

  The above description of the invention is intended to be illustrative and not limiting. Those skilled in the art will be aware of various changes or modifications to the embodiments described herein. These changes or modifications can be made without departing from the scope and spirit of the invention.

Next, the aspect of this invention is shown.
1. The following formula (II)
(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl)
Compound.
2. In formula (II),
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy,
2. The compound according to 1 above.
3. In formula (II),
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is a C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy,
2. The compound according to 1 above.
4. In formula (II),
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is a C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy,
2. The compound according to 1 above.
5. The following formula (IIa)
(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, C ₁ -C ₄ alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl)
2. The compound according to 1 above, wherein
6. Formula (IIa)
(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy)
(C) The compound according to 1 above, which has a pharmaceutically acceptable carrier.
7. Formula (IIa)
(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy)
(C) The compound according to 1 above, which has a pharmaceutically acceptable carrier.
8. The following formula (III)
(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ )
2. The compound according to 1 above, wherein
9. The following formula (IIb)
(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen, C ₁ -C ₄ alkyl or phenyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is alkyl, alkenyl, alkynyl, acyl, alkylalkoxy, aryl, alkanoyloxy, alkoxycarbonyl, alkenoyl, alkinoyl, or aroyl)
2. The compound according to 1 above, wherein
10. Formula (IIb)
(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1 or 2);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₈ alkyl, C ₁ -C ₈ acyl, or C ₁ -C ₈ alkyl alkoxy)
2. The compound according to 1 above, wherein
11. Formula (IIb)
(Where
R ₁₄ represents — (CH ₂ ) _s —OZ (where s is 1);
Y represents —CH (OR ₁₅ ) —, —C (═O) — or —C (═NOR ₁₅ );
R ₁₅ represents hydrogen or C ₁ -C ₈ alkyl; and
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ ;
Z is C ₁ -C ₄ alkyl, C ₁ -C ₄ acyl, or C ₁ -C ₄ alkyl alkoxy)
2. The compound according to 1 above, wherein
12. The following formula (IV)
(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ )
2. The compound according to 1 above, wherein
13. A composition for the treatment or prevention of avian or mammalian parasitic infections,
A pharmaceutically effective amount of the compound according to 1 above,
A pharmaceutically effective amount of the following formula (I)
(Where
R ₁ is halogen, CN or alkyl;
R ₂ is S (O) _n R ₃ , 4,5-dicyanoimidazol-2-yl or haloalkyl;
R ₃ is alkyl or haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , alkyl, haloalkyl, OR ₈ group or -N = C (R ₉ ) (R ₁₀ ) group;
R ₅ and R ₆ independently represent hydrogen, alkyl, haloalkyl, C (O) alkyl, S (O) _r CF ₃ , alkoxycarbonyl; or
R ₅ and R ₆ may together form a divalent alkylene group (optionally interrupted by 1 or 2 divalent heteroatoms);
R ₇ represents alkyl or haloalkyl;
R ₈ represents alkyl, haloalkyl or hydrogen;
R ₉ represents alkyl or hydrogen;
R ₁₀ represents an optionally substituted aryl or an optionally substituted heteroaryl group;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, haloalkyl, haloalkoxy, S (O) _q CF ₃ or SF ₅ ;
m, n, q and r each independently represents an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring)
At least one compound of
A composition comprising a pharmaceutically acceptable carrier.
14. In formula (I),
R ₁ is halogen, CN or C ₁ -C ₈ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₈ haloalkyl;
R ₃ is C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₄ is hydrogen, halogen, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, OR Represents ₈ groups;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₈ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₈ alkyl or C ₁ -C ₈ haloalkyl;
R ₈ represents C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₈ haloalkyl, C ₁ -C ₈ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2; and
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring),
14. The composition as described in 13 above.
15. In formula (I),
R ₁ is halogen, CN or C ₁ -C ₄ alkyl;
R ₂ is S (O) _n R ₃ or C ₁ -C ₄ haloalkyl;
R ₃ is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₄ is hydrogen, fluorine, chlorine, bromine, NR ₅ R ₆ , S (O) _m R ₇ , C (O) R ₇ , C (O) OR ₇ , C ₁ -C ₄ alkyl, C ₁ -C ₄ represents a haloalkyl, OR ₈ group;
R ₅ and R ₆ independently represent hydrogen, C ₁ -C ₄ alkyl, C (O) alkyl; or
R ₇ represents C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ₈ represents C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or hydrogen;
R ₁₁ and R ₁₂ each independently represent hydrogen, halogen, CN or NO ₂ ;
R ₁₃ represents halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, S (O) _q CF ₃ or SF ₅ ; m, n, q and r are each independently 0, 1 Or an integer equal to 2; and
X represents a trivalent nitrogen atom or a CR ₁₂ group (three other valences of the carbon atom form part of an aromatic ring),
14. The composition as described in 13 above.
16. In formula (I),
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1, and
X represents CR ₁₂
14. The composition as described in 13 above.
17. A composition for treating or preventing avian or mammalian parasitic infections,
A pharmaceutically effective amount of the compound according to 8 above, and
A pharmaceutically effective amount of at least one compound of formula (I)
(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1; and
X represents CR ₁₂ )
And at least one compound.
18. A composition for the treatment or prevention of avian or mammalian parasitic infections,
A pharmaceutically effective amount of the compound according to 12 above, and
A pharmaceutically effective amount of the following formula (I)
(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1; and
X represents CR ₁₂ )
And at least one compound.
19. The composition of claim 13, further comprising at least one additional macrocyclic lactone compound.
20. The composition according to 19 above, further comprising an insecticide.
21. The composition according to 20 above, wherein the one additional macrocyclic lactone compound is eprinomectin and the tapeworm control agent is praziquantel.
22. The composition according to 13 above, further comprising a nitroguanidine or a pyridylmethylamine insecticide.
23. The composition according to 22 above, wherein the nitroguanidine or pyridylmethylamine insecticide is imidacloprid.
24. A method for treating or preventing avian or mammalian parasitic infections, which comprises the step of administering a pharmaceutically effective amount of the composition according to 13 above.
25. The above-mentioned composition is in a form selected from the group consisting of a prepared preparation, pour-on preparation, spot-on preparation, paste preparation, oral liquid preparation, transdermal or transmucosal preparation, chewable preparation and injection preparation. The method according to 24.
26. The method according to 25 above, wherein the mammal is a dog or a cat.

Claims (10)

A spot-on composition for the treatment or prevention of parasitic infections in birds or mammals (excluding humans),
A pharmaceutically effective amount of the following formula (III)
(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ )
A compound of
A pharmaceutically effective amount of at least one compound of formula (I)
(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1; and
X represents CR ₁₂ )
Spot-on composition comprising at least one compound of the. A spot-on composition for the treatment or prevention of parasitic infections in birds or mammals (excluding humans),
A pharmaceutically effective amount of the following formula (IV)
(Where
R ₁₆ represents —CH ₃ or —CH ₂ CH ₃ )
A compound of
A pharmaceutically effective amount of the following formula (I)
(Where
R ₁ is CN;
R ₂ is S (O) _n R ₃ ;
R ₃ is CF ₃ ;
R ₄ represents NR ₅ R ₆ ;
R ₅ and R ₆ independently represent hydrogen;
R ₁₁ and R ₁₂ represent Cl;
R ₁₃ represents CF ₃ ;
n is 1; and
X represents CR ₁₂ )
Spot-on composition comprising at least one compound of the. The spot-on composition according to claim 1 or 2 , further comprising at least one additional macrocyclic lactone compound. The spot-on composition according to claim 3 , further comprising an insecticide. It said one additional macrocyclic lactone compound Ru eprinomectin der, spot-on composition according to claim 4. The spot-on composition according to claim 4, wherein the tapeworm-controlling agent is praziquantel. The spot-on composition according to claim 1 or 2 , further comprising a nitroguanidine or a pyridylmethylamine insecticide. The spot-on composition of claim 7 , wherein the nitroguanidine or pyridylmethylamine insecticide is imidacloprid. Use of the spot-on composition according to claim 1 or 2 for the treatment or prevention of parasitic infections in birds or mammals (excluding humans). The use according to claim 9 , wherein the mammal (excluding human) is a dog or a cat.