parasiticidal dihydroazole compounds and compositions comprising the same

专利摘要:
ANTIPARASITARY COMPOUNDS DIHIDROAZOLE AND COMPOSITIONS UNDERSTANDING THE SAME The present invention relates to new dihydroazoles of formula (I) and their salts: in which Rl, Al, A2, C, X and Y are as defined in the specification of the present invention, themselves, processes for their preparation and use to prevent or treat parasitic infestations or infections in animals and as pesticides.
公开号:BR112012014921B1
申请号:R112012014921-0
申请日:2010-12-16
公开日:2020-11-03
发明作者:Loic Patrick Le Hir De Fallois；Hyoung Ik Lee；Douglas Edward Wilkinson；Brent Christopher Beck
申请人:Merial, Inc.；
IPC主号:

专利说明:

FIELD OF THE INVENTION.
The present invention relates to new parasiticidal dihydroazole compounds of formula (I):
(I) wherein, Ri, Ai, A2, G, X and Y are as defined below, and compositions comprising at least one compound of formula (I) in combination with a pharmaceutically acceptable or agriculturally acceptable carrier. The invention also relates to uses of the compounds and methods comprising the compounds for the treatment and prevention of infections or parasitic infestations and to control pests in crops, plants, plant propagating material and wood-derived materials. CROSS REFERENCE FOR RELATED ORDERS.
The present patent application claims priority benefit from US provisional application No. 61 / 287,545 filed on December 17, 2009, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION.
Several patent publications have described isoxazoline derivatives having pesticidal properties, compositions comprising these compounds and the use of the compounds in the fields of agriculture and veterinary medicine. International patent documents Nos. W02009 / 072621, WO 2009/001942, WO 2009/024541, WO 2009/035004, W02008 / 108448, WO 2005/085216, WO 2007/075459, WO 2007/079162, WO 2008/150393, WO 2008/154528, WO 2009 / 002809, WO 2009/003075, WO 2009/045999, W02009 / 051956, WO 2009/02451, WO 2008/122375, WO 2007/125984, WO 2008/130651, WO 2009/022746, JP 2008/133273, WO 2008 / 126665, WO 2009/049846 and WO 2008/019760 describe isoxazoline-derived pesticides, compositions comprising the compounds and uses of the compounds against parasites and pests that harm animals and plants.
More recently, international patent documents Nos. WO 2009/141093, W02010 / 027051, WO 2010/005048, WO 2009/049845, WO 2009/04946, WO 2010/020521, WO 2010/020522, WO 2010/070068, WO 2010/084067, WO 2010/086225, WO 2010/108733, WO 2010/070068, WO 2010/079077, WO 2010/072781, WO 2010/112545, WO 2009/025983, WO 2009/126668 and WO 2010/090344, and the Japanese patent documents JP 2010/235590 and JP 2010/168367 also described isoxazoline derivatives having pesticidal activity and compositions comprising these compounds.
WO 2009/097992 describes arylpyrrole compounds with pesticidal activity, and WO 2008/128711 and WO 2010/043315 describe arylpyrrolidines that act against pests. WO 2009/112275 describes condensed aryl ring compounds with pesticidal activity.
Although some of these publications describe compounds that contain a substituted isoxazoline ring having pesticidal and parasiticidal properties, none of the previous publications describes compounds of formula (I) that have parasiticidal and pesticidal activity, particularly for controlling endoparasites or ectoparasites in or in animals.
The previous documents and all documents mentioned in this specification or during the processing of the same ("documents cited in the order") and all documents cited or referenced in the documents cited in the order and all documents cited or mentioned here ("documents here cited ") and all documents cited or referenced in the documents cited herein, together with any manufacturer's instructions, product descriptions and specifications, and product explanatory brochures for any products mentioned in this document or any document incorporated herein by reference, are here incorporated by reference, and can be used in the practice of the invention.
The citation or identification of any document in the present patent application is not an admission that such a document is available as a state of the art with respect to the present invention. SUMMARY OF THE INVENTION.
The present invention provides new and inventive dihydroazole compounds of formula (I) that are biologically active against endoparasites and ectoparasites that infest and cause damage to animals and against pests that damage crops, plants, plant propagating materials and wood-derived materials. Accordingly, the present application provides parasiticidal and pesticidal compositions, comprising the dihydroazole compounds in combination with a pharmaceutically acceptable carrier or an agriculturally acceptable carrier. The present invention also provides methods for treating or preventing parasitic infection or infestation in an animal and for controlling pests that cause damage to plants, plant propagating material and materials derived from wood, which comprise the administration of an effective amount of a compound of the invention to the animal or plants, or the soil on which the infected plant grows, or wood-derived material, with a pesticidally effective amount of a compound of formula (I).
A first object of the invention is to provide new and inventive parasiticidal compounds and pesticides, wherein the compounds of the invention are dihydroazoles of the formula Where:
RI is hydrogen, halogen, -CN or alkyl, haloalkyl, alkenylene, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each being unsubstituted or substituted with one or more of: halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenylene, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2 ~, R7C (O) -, R7R8NC ( O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or 5 N02; X is aryl or heteroaryl, which can be unsubstituted or substituted by one or more of: halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2- / R7C (O) -, R7R8NC (O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8- , -CN or -NO2; Ai and A2 are, independently, oxygen, NR2 or CR7R8; G is Gl or G-2;
B3, B4 and B5 are, independently, N or C-R9; Y is hydrogen, halogen, -CN; or Y is alkyl, alkenylene, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, heterocyclyl or heteroaryl, each of which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di 5 (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2_R7C (O) -, R7R8NC (O), (O) -, R7C (O) O-, R7C (O) NR8-, -CN or - N02; or Y is Yl, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10 10, Y-ll, Y-12 or Y-13;
in Ro they are, independently, hydrogen, alkyl, 1x2 ®. , • „ia, cycloalkyl, RIQS (O) -, Rio (θ) 2- / RioC (O), haloalkim-i-3 'R10C (S) -, RioRnNC (O) -, RioRiiNC (S) -R10OC ( 0) -; R4, R5 and R6 are, independently, hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl; R7 and Rs are, independently, hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; R9 is hydrogen, halogen, -CN or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each, not substituted or substituted by one or more of: halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2-, R7C (O) -, RvRgNCOO -, RvOCÍO) -, R7C (O) O-, R7C (O) NRg-, -CN or - NO2; RIO, R11, R12 and Ri3 are each, independently, hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or R10, together with Rn form = 0, = S or = NR2, * R12, together with Ri3 form = 0, = S or = NR2, 'W is 0, S or NR2; n is 1 to 4; em is 0, 1 or 2.
In addition, the present invention provides antiparasitic compositions for the treatment or prevention of parasitic infections and infestations in animals comprising a parasitically effective amount of the compounds of formula (I) in combination with a pharmaceutically acceptable carrier. The compositions can be formulated for oral, subcutaneous, parenteral and topical administration, including spot-on and pour-on administration.
Another object of the invention is to provide pesticidal compositions that comprise a compound of formula (I) to combat pests that are harmful to plants, plant propagating material or wood-derived material in combination with a pesticidally effective vehicle.
Another object of the invention is to provide veterinary and agricultural compositions for combating pests and parasites that comprise a pesticide or parasitically effective amount of the compounds of the invention or veterinary or agriculturally acceptable salts thereof, in combination with another other active agent and a veterinary vehicle or diluent or agriculturally acceptable.
Another object of the invention is to provide plant propagation material (for example, seed), comprising at least one compound of formula (I) or its agriculturally acceptable salts, and plant propagation material that has been treated with a compound of formula (I) or a composition comprising the compound.
Another object of the present invention is to provide methods of treating and preventing parasitic infections or infestations in or on an animal, which comprise treating the infected animal with a parasitically effective amount of a compound of formula (I).
Another object of the present invention is to provide methods for combating pests in crops, plant propagating material, plant or wood-derived material, which comprises treating the infected plant or the soil on which the infected plant grows or wood-derived material with a pesticidally effective amount of a compound of formula (I).
Another object of the invention is to provide methods for combating or controlling pests at a locus, comprising administering a pesticide or parasitically effective amount of a compound of formula (I) or veterinary or agriculturally acceptable salts to said locus.
Another object of the invention is to provide the use of a compound of formula (I) in the treatment or prevention of a parasitic infection or infestation in or on an animal. Yet another object of the invention is the use of a compound of formula (I) in the preparation of a medicament for the treatment or prevention of parasitic infestation or infection in or on an animal.
Yet another object of the present invention is to provide processes for the preparation of dihydroazole compounds of formula (I).
The present invention is not intended to cover, within the scope of the invention, any previously disclosed compound, product, product manufacturing process or method of using the product, which satisfies the USPTO's written description and qualification requirements (35 USC 112, first paragraph) or EPO (Article 83 of the EPC), so that the applicant reserves the right to hereby release a declaration of waiver of any product described above, of the method of making the product or process of use the product. It is, therefore, an intention of the invention not to explicitly cover compounds, products, product manufacturing processes or compounds or methods of using products or compounds which are explicitly described in the prior art or whose novelty is destroyed by the prior art, including , without limitation, any prior art mentioned herein and the claimant explicitly reserves the right to introduce a reservation in any claim as to any previously disclosed compound, product, product manufacturing process or method of using the product. Specifically, the compounds of the invention are not intended to encompass dihydroazole compounds that have been previously disclosed in the art.
Note that in this disclosure, and particularly in the claims and / or paragraphs, terms such as "comprise", "comprise the compound", "contains" and the like may have the meaning ascribed to them in US patent law; for example, they may mean "includes", "included", "including" and the like, and terms such as "consisting essentially of" and "consisting essentially of" have the meaning ascribed to them in US patent law; for example, they allow elements not explicitly cited to be included, but exclude elements that are found in the prior art or that affect a basic or new feature of the present invention.
These and other modalities are disclosed or will be evident from the detailed description presented below. DETAILED DESCRIPTION OF THE INVENTION.
The new and inventive dihydroazole compounds of the present invention have been determined to have superior activity against pests, including parasites, which cause damage to animals, plants and damaging pests, plant and wood propagating material or wood-containing material. It has surprisingly been found that the dihydroazole compounds of the invention are highly effective against pests and parasites. Accordingly, the compounds of the invention have been found useful for the prevention and treatment of parasitic infestation / infection in an animal and for controlling and eradicating pests that cause damage to plants, plant propagating material and materials derived from wood.
The present invention provides new and inventive compounds of compounds and compositions comprising dihydroazole compounds. In addition, the invention provides methods for the prevention and / or treatment of a parasitic infestation or infection in an animal, as well as the use of the compounds for the treatment of a parasitic infestation or infection in an animal or the use of the compounds in the manufacture of a medicament. for treating an infestation or parasitic infection in an animal. Surprisingly, it has been found that the compounds of the present invention have a potent activity against both ectoparasites and endoparasites that cause damage to animals. In one embodiment, the compounds of the invention can be used for the prevention and / or treatment of endoparasitic infections of animals, including infections caused by nematode parasites. In another embodiment, the compounds of the invention are used for the prevention and / or treatment of animal infections by endoparasites Dirofilaria immitis.
In another embodiment, the present invention provides use of the compounds to control and eradicate pests that cause damage to plants, plant propagating material and materials derived from wood.
A first object of the invention is to provide new and inventive parasiticides and pesticides, which are dihydroazole compounds of formula (I): (I)
Where: RI is hydrogen, halogen, -CN; or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, 5 haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each, being unsubstituted or substituted with one or more of: halogen, hydroxy, amino, alkyl- or di (alkyl) amino , alkyl, cycloalkyl, haloalkyl, alkenyl, 10 haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (0) -, R7S (O) 2- / R7C (O) -, R7R8NC (O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or - NO2; X is aryl or heteroaryl, which can be unsubstituted or substituted by one or more of: halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy , haloalkoxy, alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2-, R7C (O) -, R7R8NC (O) -, pnr (O1-, R7C (O) O-, R7C (O) NR8- , -CN or -N02; A and A2 are, independently, oxygen, NR2 or CR7R8; G is G ~ 1 or G-2; Gl G-2
Bi, B2, 83, β4 and B5 are, independently, N or C-R9; Y is hydrogen, halogen, -CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkylyl, alkylcycloalkynyl, cycloalkylalkynyl, aryl, or heterocyclyl or 10 heteroaryl, each of which may be unsubstituted or substituted with one or more halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2-, R7C (O) -,, R7R8NC (O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or -NO2 or Y is Yl, Y-2, Y-3, Y-4, Y- 5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11 and Y-12 or Y-13;
R2, R3 are, independently, hydrogen, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, haloalkenyl, alkynyl, haloalkyl, thioalkyl, alkylthiohydroalkyl, alkoxyalkyl, alkenyl, haloalkyl; are, independently, hydrogen, alkyl thioalkyl, alkylthioalkyl, hydroxyalkyl alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or R9 is hydrogen, halogen, -CN or alkyl, haloalkyl, alkenyl, haloalkenyl, alkaline, haloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl one, which may be unsubstituted or substituted with one or more of: halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio , R7S (O) -, R7S (O) 2-, R7C (O) -, R7R8NC (O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or - NO2; RIO, Rn, R12 and Ri3 are, independently, hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or Rio, together with Ru form = 0, = S ou = NR2, 'or RÍ2 together with Ri3 form = 0, = S ou = NR2; W is 0, S or NR2; nié from 1 to 4; em is 0, 1 or 2.
In one embodiment, the invention provides compounds of formula (D, in which G ® is another embodiment, the invention provides compounds of formula (I), in which G is G-2.
In yet another embodiment, the invention provides compounds of formula (I), wherein R1 is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl.
In another embodiment, the invention provides compounds of formula (I), wherein Ai ® oxygen and A2 is CR7R8.
In another embodiment of the invention, a compound of formula (I) is provided in which Ai and oxygen and A2 and CR7R8, RI is C1-C4 alkyl or C1-C4 haloalkyl and X and aryl.
In another embodiment of the invention, a compound of formula (I) is provided where Ai is oxygen and A2 is NR2, Ri is C1-4 alkyl or C1-C4 haloalkyl and X and aryl.
In another embodiment of the invention, a compound of formula (I) is provided in which Ax and CR7R8 and A2 and oxygen, R1 is Cx-C4 alkyl or Cx-C4 haloalkyl and X is aryl.
In yet another embodiment, the invention provides a compound of formula (I) in which At is oxygen and A2 is CR7R8, Ri is C1-4 alkyl or C1-C4 haloalkyl and X is heteroaryl.
In another embodiment, a compound of formula (I) is provided in which R10 and Ru, together, form = 0, = S or = NR2.
In yet another embodiment of the invention, a compound of formula (I) in which R12 θ * 13 together form = 0, = S or = NR2.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is aryl; RX is hydrogen, alkyl or haloalkyl; and Y is Y-1, Y-2 or Y-3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G ® G-1; Ai is oxygen; X is aryl; Ri is hydrogen, alkyl or haloalkyl; and Y is Y-4, Y-5 or Y-6.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is aryl; RX is hydrogen, alkyl or haloalkyl; and Y is Y-7, Y-8 or Y-9.
In yet another embodiment, the invention provides a compound of formula (I) in which: G β G-1; Ai is oxygen; X is aryl; Ri is hydrogen, alkyl or haloalkyl; and Y is Y-10, Y-ll, Y-12 or Y-13.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y is Y-1, Y-2 or Y-3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y ® Y-4 'Y-5 or Y "6-
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y is Y-7, Y-8 or Y-9.
In yet another embodiment, the invention provides a compound of formula (I) wherein: G is G-1; it's oxygen; X is heteroaryl; f> x is hydrogen, alkyl or haloalkyl; and Y is Y-10, Y-ll, Y-12 or Y-13.
In another embodiment of the invention, a compound of formula (I) is provided in which: G ® G-2; it's oxygen; X is aryl; Ei is hydrogen, alkyl or haloalkyl; and Y is Y-1, Y-2 or Y-3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; it's oxygen; X is aryl; Ri is hydrogen, alkyl or haloalkyl; and Y is Y-4, Y-5 or Y-6.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; Ai is oxygen; X is aryl; R-L is hydrogen, alkyl or haloalkyl; and Y is Y-7, Y-8 or Y-9. In yet another embodiment, the invention provides a compound of formula (I) in which: G ® G-2; Ai is oxygen; X is aryl; Ei is hydrogen, alkyl or haloalkyl; and Y is Y-10, Y-ll, Y-12 or Y-13.
In another embodiment of the invention, a compound of formula (I) is provided in which: G ® G-2; Ai is oxygen; X is heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y is Y-1, Y-2 or Y-3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G θ G-2; Ai is oxygen; X is heteroaryl; RX is hydrogen, alkyl or haloalkyl; and Y is Y-4, Y-5 or Y-6.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; Ai is oxygen; X is heteroaryl; Ei is hydrogen, alkyl or haloalkyl; and Y is Y-7, Y-8 or Y-9.
In yet another embodiment, the invention provides a compound of formula (I) in which: G is G-2; Ai is oxygen; X is heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y is Y-10, Y-ll, Y-12 or Y-13.
In yet another embodiment, the invention provides a compound of formula (I) wherein: G is G-1; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-1, Y-2 or Y-3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-4, Y-5 or Y-6.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-7, Y-8 or Y-9.
In yet another embodiment, the invention provides a compound of formula (I) wherein: G is G-1; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-10, Y-ll, Y-12 or Y-13.
In yet another embodiment, the invention provides a compound of formula (I) in which: G θ G-2; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-1, Y-2 or Y-3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-4, Y-5 or Y-6.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G θ G-2; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-7, Y-8 or Y-9.
In yet another embodiment, the invention provides a compound of formula (I) in which: G is G-2; Ai is oxygen; X is aryl or heteroaryl; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; and Y is Y-10, Y-ll, Y-12 or Y-13.
In another embodiment of the invention, a compound of formula (I) is provided in which: G © G-1; Ai is oxygen; X is aryl; Ri is hydrogen, alkyl or haloalkyl; and Y is aryl.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; Ai is oxygen; X is aryl; Ri is hydrogen, alkyl or haloalkyl; and Y is aryl.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is aryl; it is hydrogen, alkyl or haloalkyl; and Y is heteroaryl.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; Ai is oxygen; X is aryl; Ei is hydrogen, alkyl or haloalkyl; and Y is heteroaryl. In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y is heteroaryl.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G β G-2; Ai is oxygen; X is heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y is heteroaryl. In another embodiment of the invention, a compound of formula (I) is provided in which: G β G-1; Ai is oxygen; X is aryl; Ri is hydrogen, alkyl or haloalkyl; and Y is pyrazolyl or triazolyl.
In another embodiment of the invention, a compound of formula (I) is provided in which: G and G-2; Ai is oxygen; X is aryl; R1 is hydrogen, alkyl or haloalkyl; and Y is pyrazolyl or triazolyl. In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is Gl; Ai is oxygen; X is aryl or heteroaryl; R! it is hydrogen, alkyl or haloalkyl; and Y is
R2
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; Ai is oxygen; X is aryl or heteroaryl; Ri is hydrogen, alkyl or haloalkyl; and Y is R2.

In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; A2 is oxygen; X is aryl; and Ri is hydrogen, alkyl or haloalkyl.
In another embodiment of the invention, a compound of formula (I) is provided in which: G θ G-2; A2 is oxygen; X is aryl; and Ri is hydrogen, alkyl or haloalkyl. In another embodiment of the invention, a compound of formula (I) is provided in which: G ® G-1; A2 is NR2; X is aryl; and RX is hydrogen, alkyl or haloalkyl.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; A2 is NR2; X is aryl; and Ri is hydrogen, alkyl or haloalkyl.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; Ai is oxygen; X is phenyl, which is unsubstituted or substituted C1-C4 alkyl or C1 "G4 'Ri haloalkyl is hydrogen, alkyl or haloalkyl; and Y is aryl.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G and G-2r Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more of halogen, C1-C4 alkyl or C1-C4 haloalkyl; Ri is hydrogen, alkyl or haloalkyl; and Y is aryl.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G and G-1; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more of halogen, C1-C4 alkyl or C1-C4 haloalkyl; Ri is hydrogen, alkyl or haloalkyl; and Y is hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl.
In yet another embodiment of the invention, a compound of formula (I) is provided in which: G and G-2; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more of halogen, C1-C4 alkyl or C1-C4 haloalkyl; Ri is hydrogen, alkyl or haloalkyl; and Y is hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl.
In various embodiments of the invention, Y is a five membered ring of heteraryl ring having from one to four heteroatoms. In another embodiment, Y is a six-membered heteroaryl ring having one to four heteroatoms. In other embodiments, Y is a heterocyclic ring. In yet other embodiments of the invention, Y is pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, imidazolyl, imidazolinyl, triazolyl, tetrazolyl, thiophene, oxazolyl, oxazolinyl, isothiazolyl, thiadazolyl, pyrazolyl, hydrofuryl or furyl or furyl or hydrophilic. In yet other embodiments, Y is pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzofuranyl, isoindolyl, benzothiophene, quinolyl, isoquinolyl, quinazolinyl or quinazolinyl or quinazoline. In another embodiment, the invention provides compounds of formula (I) in which: G is G-1; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-4 alkyl or C1-4 haloalkyl; and Y is Y-1, Y-2 or Y-3; and Rio and Rn, together, form = 0. In another embodiment, the invention provides compounds of formula (I) in which: G is G-1; is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C1-4 haloalkyl; Y is Y-4, Y-5 or Y-6; Rio and R11 together form = 0; and R12 ® R13 together form = 0. In another embodiment, the invention provides compounds of formula (I) in which: 1 G is G-1; R-L is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C1-4 haloalkyl and Y is Y-7, Y-8 or Y-9; R10 and Rn θm together form = 0; and R12 and R13 θm together form = 0. In another embodiment, the invention provides compounds of formula (I) in which: G and G-1r R1 is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C1-4 haloalkyl; and Y is Y-10, Y-ll, Y-12 or Y-13. In another embodiment, the invention provides compounds of formula (I) in which: G and G-2; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C 1 -C 4 alkyl halo C 1 -C 4 alkyl; Y is Y-1, Y-2 or Y-3; and R10 and Rn, together, form = 0.
In another embodiment, the invention provides compounds of formula (I) in which: G is G-2; R1 is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C-C4 haloalkyl; Y is Y-4, Y-5 or Y-6; Rio and Rn together form = 0; and R12 and R13 ertl together form = 0.
In another embodiment, the invention provides compounds of formula (I) in which: G is G-2; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C-C4 haloalkyl; Y is Y-7, Y-8 or Y-9; R10 θ Rn θm together form = 0; and R12 θ R13 θm together form = 0.
In another embodiment, the invention provides compounds of formula (I) in which: G is G-2; RX is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C-C4 haloalkyl; and Y is Y-10, Y-ll, Y-12 or Y-13.
In another embodiment, the invention provides compounds of formula (I) in which: G and G-1; R1 is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C1-4 haloalkyl; Y is Y-4, Y-5 or Y-6; Rio and Rn are, independently, hydrogen, C1-C4Â ° alkyl or C1-C4 haloalkyl; and R12 and R13 together form = 0.
In another embodiment, the invention provides compounds of formula (I) in which: G is G-1; R-L is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C-C4 haloalkyl; and Y is Y-7, Y-8 or Y-9; Rio θ R11 are, independently, hydrogen, C1-C4 alkyl or C1-C4 haloalkyl; and R12 and Ris together form = 0.
In another embodiment, the invention provides compounds of formula (I) in which: G is G-2; RX is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-4 alkyl or C1-4 haloalkyl; Y is Y — 4, Y-5 or Y-β; R10 and Rn are, independently, hydrogen, C1-C4 alkyl or C1-C4 haloalkyl; and R12 AND R13 together form = 0.
In another embodiment, the invention provides compounds of formula (I) in which: G is G-2; R is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or Cx-c4 haloalkyl; Y is Y-7, Y-8 or Y-9; Rio and Rn are, independently, hydrogen, C1-C4 alkyl or C1-C4 haloalkyl; and R12 θ R13 together form = 0.
In another embodiment, the invention provides compounds of formula (I) in which: G is G-1; is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-4 alkyl or C1-4 haloalkyl; y £ Y-4, Y-5 OR Y-6; RIO and Rn together form = 0; and R12 and R13 are, independently, hydrogen, C1-C4 alkyl or C1-C4 haloalkyl.
In another embodiment, the invention provides compounds of formula (I) in which: G and G-1r is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C1-4 haloalkyl; and Y is Y-7, Y-8 or Y-9; River θ Rn together form = 0; and R12 and R13 are, independently, hydrogen, C1-C4 alkyl or C1-C4 haloalkyl.
In another embodiment, the invention provides compounds of formula (I) θm that: G is G-2; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, Cx-C4 alkyl or C1-4 haloalkyl; Y is Y-4, Y-5 or Y-6; Rio and Rn together form = 0; and R12 and Ria are, independently, hydrogen, C1-C4 alkyl or C1-4 haloalkyl.
In another embodiment, the invention provides compounds of formula (I) in which: G and G-2; Ri is halogen, -CN, alkenyl, haloalkenyl, alkynyl or haloalkynyl; Ai is oxygen; X is phenyl, which is unsubstituted or substituted by one or more halogens, C1-4 alkyl or C1-4 haloalkyl; Y is Y-7, Y-8 or Y-9; Rio and Rn together form = 0; and R12 and R13 are, independently, hydrogen, C1-4 alkyl or C1-C4 haloalkyl.
In another embodiment of the invention, a compound of formula (I) is provided in which: G and G1; R1 is C1-Q alkyl or Ct-C haloalkyl .; phenyl, which may be unsubstituted X ®,, in one OU plus halogens, C1-C4 alkyl substituted by C1-C4 haloalkyl; Ai is oxygen; I A2 is CR7R8 ', .. η V — 4 Y-5 or Y-6; Y is Y-1, x 1 R2 and R4 are, independently, hydrogen, C 1 -C 4 alkyl, OR C 1 -C 4 haloalkyl, C 1 -C 4 -alkyl or C 1 -C alkylthio-C 1 -C 6 alkyl; and ions independently, hydrogen, C1-3 alkyl and R9 sa <->, J-11 and C4 or C1-C4 haloalkyl.
In another embodiment of the invention, a compound is provided in which: of the formula (D and G is G-2; Bi, B2, B3, B4 and B5 are each CR9; R1 is C1-C4 alkyl or C1 haloalkyl -C4> v- unsubstituted or,. 1 -i _ mi »nndp be nat> X is substituted haloalkyl Ai is oxygen; A2 is CR7R8 / Y Yl, Y-4, Y-5 or Y-6, RR are, independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 -alkoxy - C 1 -alkyl or C 1 -C-alkylthio-C 1 'C 4 ~ alkyl' and R and R 9 are independently hydrogen, C 1 C 4 alkyl or C 1 haloalkyl C4. Embodiment of the invention, a compound In another xvu. »Of formula (D is provided where: G is Gl; B1 / B2, B4 and B5 are each C-R9; B3 is N; R1 is alkyl C1-C4 or C1-C4 haloalkyl; X is phenyl, which may be unsubstituted or substituted by one or more halogens, C1-C4 alkyl or U C1-C4 haloalkyl; Ai is oxygen; A2 is CR7R8; Y is Yl / Y- 4, Y-5 or Y-6; R2 and R4 are independently hydrogen, C1 alkyl, C1-C haloalkyl, C1C4-alkoxy-C1-C4-alkyl or Ct-C-alkylthio-C1-C4-alkyl uila; and R3 and R9 are, independently, hydrogen, C1-4 alkyl or C1-4 haloalkyl.
In another embodiment of the invention, a compound of formula (D is provided where: G is G-2; Bi is N; B2, B3, B4 AND B5 ARE 'EVERY' C-R9; R is C1-C4 alkyl or C1-C4 haloalkyl; phenyl, which may be unsubstituted A2 is CH2; Y & y — 4 or Y-6; R10 and R11 together form = 0; R12 and Ris ™ together form = 0; R2 is hydrogen, C1-C4 alkyl, CX-C4 haloalkyl C1-C4 alkyl or C1-C4 alkylthio CI-CA alkyl, R3 and R9 are independently hydrogen, C4 alkyl or C4 haloalkyl, R7 and Rs are independently hydrogen or C1-C4 alkyl; en is 1, 2 or 3.
In another embodiment of the invention, a compound of formula (D is provided in which: G is G-2; Bi, B2, B3 <B4 and B5 are each C-R9; Ri is C1-C4 haloalkyl; X is phenyl, which can be unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C1-C4 haloalkyl; Ai is oxygen; A2 θ CH2; Y is Y-4 or Y-6; Rio and Rn, together, form = 0; R12 and Ria together form = 0; C1-C4 alkyl, C1-C4 haloalkyl <independently, hydrogen, C C4 alkyl or C C4 haloalkyl, R7 AND R8 are independently C1-C4; en is 1, 2 or 3.
In another embodiment of the invention, a formula compound (D θ provided where: G is Gl; B3 is N; Bi B2Z B4 ® Bs are each C — R9, "R1 is C1-C4 haloalkyl; x is phenyl, which may be unsubstituted ° u, _ x-1 or substituted by one or more halogens, C1-4 alkyl C1-C4 haloalkyl; Ai is oxygen; A2 is CH2; Y is Y-4 or Y-6; R10 and Rn together form = 0; R12 and R13 together form = 0; R2 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkyl, or C1-C4 alkylthio C1-C4 alkyl R3 and R9 are independently hydrogen, C4 alkyl or Cx-C4 haloalkyl; R7 and Rs are independently hydrogen or Cx-C4 alkyl; and n is 1, 2 or 3.
In another embodiment of the invention, a compound of formula (D θ provided where. G is G-2; Bi is N; B2Z B3, B4 and B5 are each C-R9; R1 is Cx-C4 haloalkyl; v ó phenyl, which can be unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C1-C4 haloalkyl; Ax is oxygen; A2 is CH2> Y is y-4 OR Y-6; R10 and Ru, together , form = 0; R12 and R13 together f ° rmam = 0; RA hydrogen, Cx-C4 alkyl, Cx Co r 2 σ C-C alkoxy Cx-C4 alkyl or Cx-C4 alkyl Cx-C4 alkyl, „ p B. are, independently, hydrogen, Cf C4 alkyl or Cx-C4 haloalkyl; D p Rs are independently hydrogen or alkyl n is 1, 2 or 3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; 81, B2, BS, B4 AND B5 ARE 'each, C-R9; Ri is CF3; X is phenyl, which can be unsubstituted or substituted by one or more, methyl, fluorine, chlorine or trifluoromethyl; A1 is oxygen; A2 is CH2; Y is Y-4 or Y-6; R10 and Rn, together, form = 0; R and R13 together form = 0; R2 is hydrogen, C1-C4 alkyl, C1-4 haloalkyl, C1-C4 alkoxy C1-C4 alkyl or C1-C4 alkylthio C1-C4 alkyl; R3 AND R9 are, independently, hydrogen, C1-4 alkyl or C1-C4 haloalkyl; R7 AND R8 are, independently, hydrogen or C1-4 alkyl; and n is 1, 2 or 3.
In another embodiment of the invention, a compound of formula (I) θ is provided in which: G is G-2; B1, Ba, B3, B4 and B5 are each C-R9; Ri is CF3; X is phenyl, which can be unsubstituted or substituted by one or more, methyl, fluorine, chlorine or trifluoromethyl; A1 is oxygen; A2 is CH2; Y is Y-4 or Y-6; R10 and R11 / together, form -O; R12 and R13 together form = 0; θ hydrogen, C1-4 alkyl, C1-4 haloalkyl / C1-4 alkoxy C1-4 alkyl or C1-4 alkylthio C1-4 alkyl independently, hydrogen, C1-4 alkyl or C1-4 haloalkyl; D „R” are, independently, r 7 and 0 C1-C4; and n is 1/2 or 3. G is G-1, B3 is N; B1, B2 <B4 AND B5 ARE 'EVERY' C-R9 '’RI is CF3; phenyl, which may be unsubstituted or substituted by one or more, methyl, trifluoromethyl; Ai is oxygen; A2 is CH2; Y is Y-4 or Y-β; R10 and Rn together form = 0; R12 and R13 together form = 0; R2 © hydrogen, C1-C4 alkyl, C1-C4 haloalkyl C1-C4 alkyl C1-C4 alkyl or C1-C4 alkylthio C1-C4 alkyl / R3 AND R9 are, independently, hydrogen, C4 C4 alkyl or C1-C4 haloalkyl; R7 AND R8 are, independently, hydrogen or C1-C4 alkyl; and n is 1, 2 or 3.
In another embodiment of the invention, a compound of the formula (D is provided where: G is G-2; Bi is N; 82, B3, B4 and B5 are each C-R9; Ri is CF3; X is phenyl, which can be unsubstituted or substituted by one or more, methyl, fluorine, chlorine or trifluoromethyl; Ai is oxygen; A2 ® CLÍ2;, v-4 or Y-6; Y and i p-Li together form = 0; R13 together form = 0; hydrogen, C1-C4 alkyl, C1-haloalkyl, r-C4 C1 -C4 alkyl or C1-C4 alkyl C1-C4 alkyl <C1-4 alkoxy are independently hydrogen, alkyl® R3 β C. or haloaWuila C1-C4; RE RB are independently hydrogen or C1-C4 alkyl; en is lz 2 or 3.
In another embodiment of the invention, a compound of the formula (D ® provided where: G is Gl, 'Bi, B2, B3 / B4 θ B5 are each CH; Ri is CF3; X is phenyl, which can be unsubstituted or substituted by one or more, methyl, fluorine, chlorine or trifluoromethyl; Ai is oxygen; A2 is CH2; Y is Y-4 or Y-6; Rio and Riir together, form = 0; R12 θ R13 together form = 0; R2 is hydrogen or methyl; R3 is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl; R7 and Rs are hydrogen; and n is 1, 2 or 3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-2; Bi, B2r B3, B4 AND B5 are each C-H; Ri is CF3; X is phenyl, which can be unsubstituted or substituted by one or more, methyl, fluorine, chlorine or trifluoromethyl; Ai is oxygen; A2 is CH2; Y is Y-4 or Y-6; Rio and Rn together form = 0; R12 and R13 together form = 0; R2 is hydrogen or methyl; R3 is hydrogen, C1-C4 alkyl or C1-C4Z haloalkyl R7 and Rs are hydrogen; and n is 1, 2 or 3.
In another embodiment of the invention, a compound of formula (I) is provided in which: G is G-1; B3 is N; BLZ B2, B4 and B5 are each C-H; Ri is CF3; X is phenyl, which can be unsubstituted or substituted by one or more, methyl, fluorine, chlorine or trifluoromethyl; Ai is oxygen; A2 is CH2; Y is Y-4 or Y-6; R10 and R11 together form = 0; R12 and R13 together form = 0; R2 is hydrogen or methyl; R3 is hydrogen, C1-C4 alkyl ∞ C1-C4 haloalkyl; R7 and Rs are hydrogen; and n is 1, 2 or 3.
In another embodiment of the invention, a compound of formula (D is provided where: G is G-2; Bi is N; B2, B3, B4 and B5 are each CH; Ri is CF3; X is phenyl, which can be unsubstituted or substituted by one or more, methyl, fluorine, chlorine or trifluoromethyl; it is oxygen; A2 is CH2; Y is Y-4 or Y-6; g10 and Rn together form = 0; g12 and RI3 in set form = 0; p> 2 is hydrogen or methyl; R3 is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl; R7 and Rs are hydrogen; and n is 1, 2 or 3.
Stereoisomers and polymorphic forms It will be understood by those skilled in the art that the compounds of the invention can exist and be isolated in optically active and racemic forms. Compounds having one or more chiral centers, including cases where a sulfur atom is included, can be present as individual enantiomers or diastereomers or as mixtures of enantiomers and / or diastereomers. For example, it is well known in the art that sulfoxide compounds can be optically active and can exist as individual enantiomers or racemic mixtures. In addition, the compounds of the invention can include one or more chiral centers, which results in a theoretical number of optically active isomers. In cases where the compounds of the invention include n chiral centers, the compounds can comprise up to 2n optical isomers. The present invention encompasses the specific enantiomers or diastereomers of each compound, as well as mixtures of enantiomers and / or diastereomers different from the compounds of the invention that have the useful properties described herein. Optically active forms can be prepared, for example, by resolving racemic forms by selective crystallization techniques, by synthesis from optically active precursors, by chiral synthesis, by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
The compounds of the present invention can also be present in different solid forms, such as different crystalline forms or in the form of an amorphous solid. The present invention encompasses different crystalline forms as well as the amorphous forms of the compounds of the invention.
In addition, the compounds of the invention can exist as hydrates or solvates, in which a certain stoichiometric amount of water or a solvent is associated with the molecule in crystalline form. The hydrates and solvates of the compounds of formula (I) or (II) are also the subject of the present invention. Salts
In addition to the neutral compounds of general formula (I), salt forms of the compounds are also active against animal pests. The terms "veterinarily acceptable salt" and "agriculturally acceptable salt" are used throughout the specification to describe salts of compounds that are acceptable for administration for veterinary and agricultural applications, and which provide the active compound after administration.
In cases where compounds are sufficiently basic or acidic to form stable non-toxic acid or base salts, the compounds can be in the form of a veterinarily or agriculturally acceptable salt. Veterinary or agriculturally acceptable salts include those derived from veterinarily or agriculturally acceptable inorganic or organic acids and bases. Suitable salts include those of alkali metals, such as lithium, sodium or potassium, alkaline earth metals such as calcium, magnesium and barium. Salts comprising transition metals, including, but not limited to, manganese, copper, zinc and iron are also suitable. In addition, salts comprising ammonium cations (NHJ, as well as substituted ammonium cations, in which one or more of the hydrogen atoms are replaced by alkyl or aryl groups are encompassed by the invention.
Salts derived from inorganic acids, including, but not limited to, hydrohalide acids (HCl, HBr, HF, Hl), sulfuric acid, nitric acid, phosphoric acid, and the like are particularly suitable. Acceptable inorganic salts also include, but are not limited to, bicarbonate and carbonate salts. In some embodiments, examples of veterinary and agriculturally acceptable salts of organic addition acids formed with organic acids, including, but not limited to, maleate, dimaleate, fumarate, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate , benzoate, ascorbate, alpha-ketoglutarate and alpha-glycerophosphate. It should be understood that other acceptable organic acids can be used.
Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salts of the compounds can also be made by reacting a sufficiently acidic residue of the compounds with an alkali metal or alkali metal hydroxide - earthy.
Veterinarily and agriculturally acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid functional group present in the compound or by reacting a suitable acid with a functional group suitable basic form of the compound of the invention. Definitions
For the purposes of this application, unless otherwise indicated in the specification, the following terms have the terminology cited below: (1) alkyl refers to both straight and branched carbon chains and cyclic hydrocarbon groups. In one alkyl embodiment, the number of carbon atoms is from 1 to 20, in other alkyl embodiments, the number of carbon atoms is from 1 to 12, from 1 to 10 or from 1 to 8 atoms of carbon. In yet another embodiment of alkyl, the number of carbon atoms is 1 to 6 or 1 to 4 carbon atoms. Other ranges of carbon numbers are also contemplated, depending on the location of the alkyl radical in the molecule; Examples of C1-10 alkyl include, but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1/2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. A C1-C4 alkyl group means for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl. Cyclic alkyl groups, which are covered by the term "alkyl", can be referred to as "cycloalkyl" and include those with 3 to 10 carbon atoms with one or more fused rings. Non-limiting examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The alkyl and cycloalkyl groups described herein can be unsubstituted or substituted with one or more radicals selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- or dialkylamino, starch, arylamino, alkoxy, aryloxy, nitro, cyano, azido, thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanil, sulfinyl, sulfamonyl, ester, phosphonyl, phosphoryl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrazine , carbamate, phosphonic acid, phosphate, phosphonate or any other viable functional group that does not inhibit the biological activity of the compounds of the invention, either unprotected or protected as necessary, as known to those skilled in the art, for example, as taught by Greene, et al ., Protective Groups in Organic Sinthesis, John Wiley and Sons, Fourth Edition, 2007, incorporated herein by reference. (2) Alkenyl refers to both straight and branched carbon chains that have at least one carbon-carbon double bond. In an alkenyl embodiment, the number of double bonds is 1 to 3, in another alkenyl embodiment, the number of double bonds is 1. In an alkenyl embodiment, the number of carbon atoms is from 2 to 20, in other alkenyl embodiments, the number of carbon atoms is 2 to 12, from 2 to 10, from 2 to 8 or from 2 to 6. In yet another embodiment of alkenyl, the number of atoms carbon is 2 to 4. Other ranges of double carbon-carbon bonds and other carbon numbers are also contemplated, depending on the location of the alkenyl radical in the molecule; "C2-C10 alkenyl" groups can include more than one double bond in the chain. Examples include, but are not limited to, ethylene, 1-propenyl, 2-propenyl, 1-methyl-ethylen, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl- l -propenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-l-butenyl, 2-methyl-l- butenyl, 3-methyl-l-butenyl, l-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl 2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4- methyl-l-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, l-methyl-3-pentenyl, 2-methyl 3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4- pentenyl, 1, l-diinetyl-2-buten yl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1- butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2- butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-l-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-l-butenyl, l-ethyl-2-butenyl, l- ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl- 2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl. (3) Alquinyl refers to both straight and branched carbon chains that have at least one carbon-carbon triple bond. In an alkynyl embodiment, the number of triple bonds is 1 to 3; in another alkynyl embodiment, the number of triple bonds is one. In an alkynyl embodiment, the number of carbon atoms is 2 to 20, in other alkynyl embodiments, the number of carbon atoms is 2 to 12, from 2 to 10, from 2 to 8 or from 2 to 6. In yet another modality of alkynyl, the number of carbon atoms is 2 to 4. Other ranges of double carbon-carbon bonds and other carbon numbers are also contemplated, depending on the location of the alkenyl radical in the molecule; For example, the term "C2-C10 alkynyl" as used herein refers to a straight or branched chain containing an unsaturated hydrocarbon group having from 2 to 10 carbon atoms and containing at least one triple bond, such as ethynyl, prop -l-in-l-yl, prop-2-in-l-yl, n-but- 1-in-l-yl, n-but-l-in-3-yl, n-but-l-in -4-yl, n-but-2-in-1-yl, n-pent-l-in-l-yl, n-pent-l-in-3-yl, n-pent-l-in-4 - ila, n-pent-l-in-5-yl, n-pent-2-in-l-yl, n-pent-2-in-4-yl, n-pent-2-in-5-yl , 3-methylbut-l-in-3-yl, 3-methylbut-l-in-4-yl, n-hex-l-in-l-yl, n-hex-l-in-3-yl, n -hex-1- in-4-yl, n-hex-l-in-5-yl, n-hex-l-in-6-yl, n-hex-2-in-l-yl, n-hex -2-in-4-yl, n-hex-2-in-5-yl, n-hex-2-in-6-yl, n-hex-3-in-1-yl, n-hex-3 -in-2-yl, 3-methylpent-l-in-l-yl, 3-methylpent-l-in-3-yl, 3-methylpent-l-in-4-yl, 3-methylpent-l-in -5-yl, 4-methylpent-1-in-1-yl, 4-methylpent-2-in-4-yl or 4-methylpent-2-in-5-yl and the like. (4) Aryl refers to a C6-C14 carbocyclic aromatic ring structure having a single ring or multiple fused rings. In some embodiments, the aryl ring can be fused to a non-aromatic ring, as long as the attachment point for the core structure is through the aromatic ring. Aryl groups include, but are not limited to, phenyl, biphenyl and naphthyl. In some modalities, aryl includes tetrahydronafty and indanyl. Aryl groups may be unsubstituted or substituted by one or more radicals selected from halogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, halocycloalkyl, halocycloalkyl alkoxy, alquenilaxi, alquinilaxi, haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy, cycloalkenyloxy, halocycloalkoxy, halocicloalquenilóxi, alkylthio, haloalkylthio, arylthio, cycloalkylthio, halocicloalquiltio, alquilasulfinil, alquenilsulfinil, alcinila-sulfinyl, haloalquilasulfmil, haloalquenilsulfinil, haloalquinilsulfinil, alquilsulfonila, alquenilsulfonil, alquinilsulfonil, haloalkylsulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl, alkylcarbonyl, haloalkylacarbonyl, alkylamino, alkenylamino, alkynylamino, di (alkyl) amino, di (alkenyl) - amino, di (alkynyl) amino or SF5. In an aryl embodiment, the radical is phenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl and indanyl; in another aryl embodiment, the radical is phenyl. (5) Aloxy refers to -O-alkyl, where alkyl is as defined in (1); (6) Alkoxycarbonyl refers to -C (= 0) -O-alkyl, where alkoxy is as defined in (5); (7) The term cycle, as a prefix (for example, cycloalkyl, cycloalkenyl, cycloalkynyl), refers to a cyclic, saturated or unsaturated ring structure having three to eight carbon atoms in the ring that is intended to be separated and distinct from the definition of aryl above. In a cycle embodiment, the ring size range is 4 to 7 carbon atoms; in another embodiment of the cycle, the range of ring sizes is 3 to 4. Other ranges of carbon numbers are also contemplated, depending on the location of the radical cycle in the molecule; (8) Halogen means the fluorine, chlorine, bromine and iodine atoms. The designation "halo" (for example, as illustrated in the term haloalkyl) refers to all degrees of substitutions for a single substitution of a perhalo substitution (for example, as illustrated with methyl as chloromethyl (-CH2C1), dichloromethyl (-CHCI2), trichloromethyl (-CC13)); (9) Heterocycle, heterocyclic or heterocycle refers to fully saturated or unsaturated cyclic groups, for example, ring systems of 4 to 7 monocyclic members, 7 to 11 bicyclic members or 10 to 15 tricyclic members, which have at least one heteroatom at least one carbon atom of the ring that contains it. Each ring of the heterocyclic group containing a hetero atom can have 1, 2, 3 or 4 hetero atoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur hetero atoms can be optionally oxidized and the hetero atoms nitrogen can be optionally quaternized. The heterocyclic group can be attached to any heteroatom or carbon atom in the ring system or in a ring. (10) heteroaryl refers to a monovalent aromatic group of 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, having one or more heteroatoms oxygen, nitrogen and sulfur in the ring, preferably 1 to 4 heteroatoms or 1 to 3 heteroatoms. The nitrogen and sulfur heteroatoms can be optionally oxidized. Such heteroaryl groups may have a single ring (eg, pyridyl or furyl) or multiple fused rings, provided that the point of attachment is through an atom of the heteroaryl ring. Preferred heteroaryls include pyridazinyl, pyridyl, pyrimidinyl, triazinyl, pyrrolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinnil, furanyl, thienyl, furila, imidazolyl, oxazolyl, isoxazolyl, isothiazyl, benzine and pyrazol. Heteroaryl rings can be unsubstituted or replaced by one or more radicals, as described for the term aryl, above.
Examples of monocyclic heterocyclic group or heteroaryl groups also include, but are not limited to, pyrrolidinyl, oxetanil, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolidinyl, tetrazolidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinil, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, tymorpholinyl, tiamorfolinyl, tiamorpholinyl, tyrorpholamine, tincorolinamine and tetra-1,1-dioxothienil, triazolyl and the like.
Examples of bicyclic heterocyclic groups include, but are not limited to, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonil, chirinilin, chromonyl, chirinilin, chromonil, chromonil, chromonil, chromonil, chromonil, chromonil, chromonil, chromonil, chromon, chromon, chromon, chromon, chromon, chromon , furopyridinyl (such as [2,3-c] pyridinyl, hole [3,2-b] pyridinyl] or [2,3-b] pyridinyl]), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro- 4-oxo-quinazolinyl), tetrahydroquinolinyl, and the like.
Examples of tricyclic heterocyclic groups include, but are not limited to, carbazolyl, benzidolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
Unless otherwise specifically indicated or by context, "active agent" or "active ingredient" or "therapeutic agent" used in this specification, means a dihydroazole compound of the invention.
The term "locus" is understood to mean a habitat, nursery, area, material or environment in which a parasite is grown or can grow, including, on or on an animal. Synthesis of Compounds
The dihydroazole compounds of formula (I) can be prepared by processes described herein or by adapting these processes or processes known in the art to prepare compounds with different substitution patterns.
For example, Scheme 1, below, describes the preparation of compounds of formula (I) in which G is G-2, Bi and B2 are CH, B3 is CH or C-R9, Ai is oxygen, A2 is CH2, Ri is CF3, X is an optionally substituted phenyl group, and Y can be Yl, Y-2, Y-4, Y-5, Y-6, Y-7, Y-8 or Y-9, where Rio ® Rn, together form C = 0, and R2, R3, R4, R , Rs, R12, RI3 EN are as defined above. It will be apparent to those skilled in the art that certain functional groups present in the compounds used in the synthesis can be protected, if necessary, by a suitable protecting group such as an alkyl ester, as described in "Protective Groups in Organic Sinthesis (Fourth Edition) ", eds. Peter GM Wuts and Theodora W. Greene, Wiley-Interscience Publishers, (2007). In addition, it will be apparent to those skilled in the art that the described reactions can be carried out in suitable solvents, depending on the reaction conditions. Reaction times and temperatures can be optimized to produce the desired product in good yield and purity.
In addition, final and intermediate products can be isolated and purified, if appropriate, or transported to the next step without isolation and / or purification, where possible. Purification of intermediates and products can be carried out by suitable methods, including chromatographic methods such as flash column chromatography, HPLC and the like. Purification of the intermediates and products can also be achieved by crystallizing the intermediates and products from an appropriate solvent or mixture of solvents or a combination of crystallization and chromatography. Scheme 1;
(Ila) (Illa) (IVa) (Va, Q = H) (Vc) (Vb, Q = Halogen) Where R2, R3, R4, R7, R8, R12, R13 and n are as defined «ní ™
The reaction of a 2-halo-6-methyl nicotinic acid derivative of formula (Ila) wherein R "is H or a hydroxy protecting group (PG), including, but not limited to, the 2-chloro-acid compound β-methyl nicotinic, with a dialkylacetal dialkylformamide, including dimethylformamide, dimethyl acetal, produces a derivative of 2-halo-6- (2-dialkylaminovinyl) -niconitinic acid of the formula (Ilia). used are described in "Protective Groups in Organic Sinthesis (Fourth Edition)", eds Peter GM Wuts and Theodora W. Greene, Wiley-Interscience Publishers, (2007). An example of such a transformation can be found in the literature, as in Tetrahedron Letters, 1994, 35, 219-222 ("A mild method for the convertion of activated aryl methyl groups to carboxadehydes via the uncatalyzed periodate cleavage of enamines" by MG Vetelino and JWCoe). If necessary, the carboxyl group of the acid derivative nicotinic can be protected before the reaction not including, but not limited to, as an ester such as 2-chloro-β-methyl-nicotinic methyl ester.
The aldehydes of formula (IVa) can be prepared by oxidative dividing the alkene portion of the compound of formula (Ilia). Such a transformation is well known to those skilled in the art and can be carried out, for example, with ozone, potassium permanganate and sodium metaperiodate. The process can be carried out optionally in a solvent such as methylene chloride, diethyl ether, chloroform, and generally at temperatures between about -100 ° C and about 100 ° C. A summary of such methods is found in "Comprehensive Organic Transformations", VCH Publishers, (1989), RC Larock, pp 595-596.
The reaction of the formyl nicotinic acid derivative of formula (IVa) with hydroxylamine provides the 2-halo-6-hydroxyiminomethyl pyridine derivative of formula (Va).
Treatment of the pyridine derivative 2-halo-6-hydroxyiminomethyl of formula (Va) with a halogenating reagent to give intermediate chlorooxime of formula (Vb), followed by treatment with a vinylbenzene derivative of formula (VII), including, but not limited to, not limited to, 1,3-bisfluoromethyl-5- (1-trifluoromethylvinyl) -benzene or 1,3-dichloro-5- (1-trifluoromethylvinyl) -benzene, provides the isoxazoline ring in the compound of formula (Via). The reaction proceeds through a cycloaddition reaction [3 + 2] 1,3-dipolar of a vinylbenzene derivative of formula (VII) with an intermediate nitrile oxide of formula (Vc), which is produced from the chlorooxime dehydrohalogenation intermediate of formula (Vb). In some embodiments, the reaction can be conducted in the presence of a suitable base, including an amine base such as triethylamine, diisopropylethylamine, N-ethylmorpholine, pyridine, and the like, to facilitate the formation of the nitrile oxide compound of formula ( You). Suitable halogenating reagents include, but are not limited to, N-chlorosuccinimide, W-bromosuccinimide, sodium hypochlorite, chloramine T and the like.
A summary of these cycloaddition reactions [3 + 2] 1,3-dipoles is available in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" (Sixth Edition) ", Michael B. Smith and Jerry March, Wiley- Publishers Interscience , (2007), pp 1187 - 1192 and references cited therein.
The formation of the bicyclic group G-2 in compounds of formula (la-d), can be achieved by treating a substituted pyridine-2-alkynyl derivative of formula (VIb) with a transition metal catalyst, such as, but not limited to, copper (I), platinum (II), silver or gold, in a suitable solvent. Examples of such transition metals to catalyze cycloisomerization to form the heterocyclic structure are described in the literature (V. Gevorgyan et al, Organic Letters, 2008, 10, 2307-2310; 2007, 9, pages 3433-3436 ;. J. Am. Chem. Soc., 2001, 123, 2074-2075; J. Am. Chem, 2006, 128, 12050-12051, J. Ara. Chem, 2007, 129, 9868-9878; Y. Liu et al, Organic Letters , 2007, 9, 409-412 and 4323-4326; J. Org. Chem, 2007, 72, 7783-7786; A. Hayford et al., Organic Letters, 2005, 7, 4305-4308; R. Sarpong et al ., Organic Letters, 2007, 9, 1169-1171 and 4547-4550; 2007, 9, 1169-1171M-M Cid et al., Organic Letters, 2009, 11, 4802-4805 ;. L. Sun et al., Organic Process Reseacrh and Development, 2007, 11, 1246-250).
The 2-alkynyl-substituted compound of formula (VIb) can be prepared by coupling a 2-halo-nicotinic acid derivative of formula (Via) with an optionally substituted alkaline compound of formula (Vllla-c) and a catalyst palladium. Those skilled in the art will recognize this coupling reaction when the substituted alkaline is a compound of formula (Villa) as a Sonogashira coupling reaction. See, for example, K. Sonogashira, Y. Tohda, N. Hagihara, "A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines". Tetrahedron Letters, 1975, 16, 4467-4470. When the substituted alkaline is a compound of formula (VIIIb), including the alkynyl stannane compound, this coupling reaction is known as a Stille coupling reaction. See, for example, D. Milstein, JK Stille, J. Am. Chem. Soc., 1978, 100, 3636 and J.K. Stille, Angew. Chem. Int. Ed. Engl., 1986, 25, 508-524. The description of such methods is also found in "March 's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (sixth edition)", Michael B. Smith and Jerry March, Wiley-Interscience Publishers, (2007), pp 792-795 . When the substituted alkaline is a compound of formula (VIIIc), including, but not limited to, alkynyl boronate ester or boronic acid compound, this coupling reaction is known as a Suzuki-Miyaura coupling reaction. Examples of such reactions can be found in A. Coehlo et al, Synlett, 2002, 12, 2062-2064 and an overview of Suzuki-Miyaura coupling reactions is described in N. Miyaura, A. Suzuki, Chem. Rev., 1995, 95, 2457-2483. The solvent to be used in the reaction includes, for example, but is not limited to, ethers such as tetrahydrofuran, dioxane and the like, halogenated hydrocarbons such as such as 1,2-dichloroethane and the like, aromatic solvent such as benzene, toluene, xylene and the like. The reaction temperature is usually in the range of 0 ° C to 200 ° C, preferably in the range of 20 ° C to 120 ° C and the reaction time is usually in the range of about 0.5 to 72 hours.
If desired, the carboxyl group present in the compound of formula (Ia) can be deprotected and coupled with a suitable amine using well known coupling conditions to provide the desired compound of formula (Id). Many procedures are available for the formation of amide bonds between a carboxylic acid derivative of formula (Ib) and an amine using coupling agents. The procedures were developed to use reagents such as carbodiimides as amide coupling agents. These carbodiimides include, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDO) and the like. Other amide coupling agents known in the art, such as 1-ethoxycarbonyl-2-dihydroquinoline (EEDQ), phosphonium (for example, phosphonium hexafluorophosphate (BOP), and others) or uranium-based reagents (for example, TBTU , HATU and others) can also be used to form amide bonds. In addition, anhydrides can also be used to form the desired amide bond. Catalysts such as 1-hydroxybenzotriazole (HOBT) and its derivatives have also been used. A summary of such methods is found in "Comprehensive Organic Transformations", RC Larock, VCH Publishers (1989) pp 972-972. An overview of such transformations is also available in "March 's Advanced Organic Chemistry: reactions, Mechanisms, and Structure (Sixth edition)", Michael B. Smith and Jerry March, Wiley- Interscience Publishers, (2007), pp 1431- 1434.
Another general reaction for the preparation of amide derivatives such as the compounds of formula (Id) is the treatment of acyl halides, such as the compound of formula (Ic) with an amine. Such transformations are well known to those skilled in the art and an overview of such transformations is available in "March - Advanced Organic Chemistry: Reactions, Mechanisms And Structure (Sixth Edition)", Michael B. Smith and Jerry March, Wiley-Interscience Publishers, (2007), pp. 1427-1429.
The compounds of formula (I) in which G is G 2, Bi 'r 3 is CH, B2 is CH or C-R17, Al is oxygen, A2 and CH2, Ri and CF3' X is optionally a substituted phenyl group, and P Yl, Y-2, Y-4, Y-5, Y-6, Y-7, Y-8 or Y-9, where Rio θ D RI3 ® ft are together, form C = O, and R2, ^ 3 / R / Βr 12r as defined above, can be prepared p shown in Scheme 2, below. Scheme 2;
(VId) (le, R = OR ") (| h) (lg, R = Halogen) including, but not limited to, 2,6-dichloronicotinic acid, which can be protected if necessary, is reacted with ammonium hydroxide or other suitable equivalent amine in a suitable solvent to provide a 2-amino-6-nicotinic acid derivative of formula (IIc), such as 2-amino-6-chloro nicotinic acid, where R 'is H or a protected derivative of Protective groups suitable for hydroxy groups that can be used are described in "Protective Groups in Organic Sinthesis (Fourth Edition)", eds. Peter GM Wuts and Theodora W. Greene, Wiley-Interscience Publishers, (2007). such transformations can be found in Y. Wensheng et al, Schering Corp and Pharmacopeia Drug Discovery, WQ2006088836.
The product of formula (IIc) is coupled with a vinyl metal reagent in the presence of a suitable catalyst such as a palladium catalyst to produce a compound of formula (Illb), such as nicotinic acid 2-amino-6-vinyl, where R 'and R "are H or a protected derivative thereof, where R' and / or R" is PG. When stanane vinyl reagents are used, this coupling reaction is known as a Stille coupling reaction with references from the literature previously cited above. The 2-amino group can be protected, if necessary, where R 'are amino protecting groups (PG) as defined in "Protective Groups in Organic Sinthesis (Fourth Edition)", eds. Peter GM Wuts and Theodora W. Greene, Wiley-Interscience Publishers, (2007), pp.696-926. The aldehydes of formula (IVb) can be prepared as in scheme 1 by oxidative cleavage of the alkene portion of the compound of formula (Illb).
The reaction of formyl nicotinic acid derived from formula (IVb) with hydroxylamine or a hydroxylamine equivalent provides the hydroxyiminomethyl pyridine derivative of formula (Vd). A similar treatment of the hydroxyiminomethyl pyridine derivative of formula (Vd) as in Scheme 1 with a halogenating reagent to give the intermediate chlorooxime of formula (Ve), followed by treatment with a vinylbenzene derivative of formula (VII) provides the isoxazoline ring in compound of formula (VIc) through a cycloaddition reaction [3 + 2] 1,3-dipolar of a vinylbenzene derivative of formula (VII) with an intermediate nitrile oxide of formula (Vf).
The removal of any amine protecting group, if necessary, can be achieved by standard methods known to those skilled in the art as described in "Protective Groups in Organic Sinthesis (Fourth Edition)", eds. Peter GM Wuts and Theodora W. Greene, Wiley-Interscience Publishers, (2007), pp.696-926. Treatment of the amino pyridine compound of formula (Vid) with an alpha-halocarbonyl compound, including, but not limited to, alpha-chloroacetaldehyde, provides the bicyclic aromatic group G-2, where Bi is nitrogen, present in the compound of formula (le - g). Deprotection of the carbocyclic acid group, if necessary, followed by coupling with a desired amino group in a manner similar to the method described in scheme 1 produces the compounds of formula (Ih).
The compounds of formula (I) where G is Gl, Bi is CH ■ -n 'f'U Ri is CF3, X is C-R14, B2 and B3 are CH, Ai is oxygen, A2 θ ^ «2/1 optionally a substituted phenyl group and Y PoC * Y-2, Y-4, Y-5, Y-β, Y-7, Y-8 or Y-9, where R1 ° T-> Rn θ B SãO D Ro R12Z * ^ 13 together form C = O, and R2, R3 / R4 'K7' 8 ', = 5 the same process as defined above, can be prepared shown in Scheme 3, below. Layout 3
Where R2, R3, R4, Pp Re, R12, R „en are <= as defined above.
Aldehydes of formula (IVa) can be prepared following methods similar to those described in Scheme 1. Selective reduction of aldehyde of formula (IVa) can be accomplished by treatment with a reducing agent such as, but not limited to, cyanoborohydride of sodium, sodium borohydride, sodium triacetoxyborohydride, L-Selectride® (lithium tri-sec-butyl (hydroxide) borate), decaborane and the like to produce the alcohols derived from formula (IXa). A summary of such methods is found in "Comprehensive Organic Transformations", VCH Publishers, (1989), RC Larock, pp 527-536. The solvent to be used in the reaction includes, for example, but is not limited to, ethers such as diethyl ether, tetrahydrofuran and the like, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane and the like. The reaction temperature is usually in the range of -78 ° C to 150 ° C, preferably in the range of 0 ° C to 80 ° C and the reaction time is usually in the range of 1 to 72 hours.
The hydroxyl group present in alcohol derivatives of formula (IXa) can be protected to produce compounds of formula (IXb) with a suitable protecting group (PG) such as, but not limited to, silyl ethers such as tert-butyldimethylsilyl (tBDMS ) and the like. An overview of the methods available to protect the hydroxyl group is given in "Protective Groups in Organic Synthesis (Fourth Edition)", eds. Peter GM Wuts and Theodora W. Greene, Wiley- Interscience Publishers, (2007), pp.16-299.
The acid or ester group present in compounds of formula (IXb) can be reduced by treatment with a reducing agent such as, but not limited to, aluminum lithium hydride, lithium borohydride, sodium borohydride and the like for obtaining alcohol derivatives of formula (IXc) or directly obtaining aldehydes derived from formula (IXd) with a reducing agent such as, but not limited to, diisobutyl aluminum hydride (DIBAL-H). The reaction is generally carried out in a solvent such as dialkyl ether (diethyl ether, for example), tetrahydrofuran (THF) and, generally, at temperatures between about -100 ° C and about 40 ° C. A summary of such methods is found in "Comprehensive Organic Transformations", VCH Publishers, (1989), RC Larock, pp 548-552.
The hydroxyl group present in derivatives of formula (IXc) can be oxidized to obtain the aldehydes of formula (IXd) by treatment with oxidizing agents, such as, but not limited to, reagents based on dimethyl sulfoxide (DMSO), reagents with radicals nitroxyl such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), hypervalent iodine reagents such as 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) - one (the so-called Dess-Martin periodinane reagent) and the like. An overview of these transformations is available in "March's Advanced Organic Chemistry: reactions, mechanisms, and Structure (Sixth Edition)", Michael B. Smith and Jerry March, Wiley- Interscience Publishers, (2007), section 19-3 "Oxidation or Dehydrogenation of Alcohols to Aldehydes and Ketones "pp. 1715-1728.
The reaction of the aldehyde derivatives of formula (IXd) with hydroxylamine or a hydroxylamine equivalent provides the hydroxyiminomethyl pyridine derivatives of formula (Vf). A similar treatment of the hydroxyiminomethyl pyridine derivative of formula (Vf), as in Scheme 1 with a halogenating reagent to give a chlorooxime as an intermediate of formula (Vg), followed by treatment with a vinylbenzene derivative of formula (VII) provides the isoxazoline ring in a compound of formula (VIe) through a cycloaddition reaction [3 + 2] 1,3-dipolar of a product derived from vinylbenzene of formula (VII) with an intermediate nitrile oxide of formula (Vh).
The alkynyl-substituted compound of formula (Vlf) can be prepared by coupling a halo derivative of formula (Vie) with an optionally substituted alkaline compound of formula (VIIIa-c) and a palladium catalyst using a methodology similar to described in scheme 1.
The formation of the bicyclic group Gl in compounds of formula (li-j), can be achieved by treating an alkynyl-substituted pyridine derived from the formula (Vlf) with a transition metal catalyst, such as, but not limited to, copper (I), platinum (II), silver or gold, in a suitable solvent using a methodology similar to that described in Scheme 1.
The removal of the hydroxyl protecting group present in compounds of formula (Ii) to obtain the alcohol derivatives of formula (Ij) can be accomplished by standard methods known to those skilled in the art. A summary of such methods can be found in "Protective Groups in Organic Synthesis (Fourth Edition)", eds. Peter GM Wuts and Theodora W. Greene, Wiley-Interscience Publishers, (2007), pp. 16-299.
The hydroxyl group present in derivatives of formula (Ij) can be oxidized to obtain derivatives of aldehyde of formula (Ik) by treatment with oxidizing agents, such as, but not limited to, those described above, to produce compounds of formula (IXd ). The hydroxyl group present in derivatives of formula (Ij) or aldehyde derivatives of formula (Ik) can be oxidized to obtain the acid of formula (In) by treatment with oxidizing agents, such as, but not limited to, permanganate potassium, chromic acid, a combination of tetramethylpiperidine-l-oxyl (TEMPO) and sodium chloride. An overview of these transformations is available in "March's Advanced Organic Chemistry: reactions, Mechanisms, and Structure (Sixth Edition)", Michael B. Smith and Jerry March, Wiley-Interscience Publishers, (2007), section 19-22, "Oxidation of Primary Alcohols to Carboxilic Esters "pp.1768-1769 and section 19-23" Oxidation of Aldehydes to Carboxilic Acids "pp.1769-1773.
Coupling the acid derivative of formula (In) or the acyl derivative of formula (Ip) with a desired amino group in a manner similar to the method described in scheme 1 produces the compound of formula (Iq).
It will be understood by those skilled in the art that alternative reagents and conditions can be used to produce compounds with different substitution patterns.
The present invention further contemplates the separation of enantiomers in whole or in part of the present invention or synthesizes enantiomerically enriched compounds of the invention. The composition can be prepared by separating the enantiomers in whole or in part, by standard methods, for example, by chemical resolution using optically active acid or by using column chromatography or chromatography. column reverse phase using a substantially optically active (or "chiral") stationary phase as is known to those skilled in the art. The formation and / or isolation of specific enantiomers of a compound is not routine, and there are no general methods that can be used to obtain specific enantiomers of all compounds. The methods and conditions used to obtain specific enantiomers of a compound must be determined for each specific compound. The enantiomerically enriched compounds of the invention can also be obtained from enantiomerically enriched precursors. Veterinary compositions
Another aspect of the invention is the formation of parasiticidal compositions comprising the dihydroazole compounds of the invention. The composition of the invention can also be in a variety of forms which include, but are not limited to, oral formulations, injectable and topical formulations, dermal or subdermal formulations. The formulations are intended to be administered to an animal that includes, but is not limited to, mammals, birds and fish. Examples of mammals include, but are not limited to, humans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys, dogs, cats and other livestock or domestic mammals. Examples of birds include turkeys, chickens, ostriches and other wild animals or domestic birds.
The composition of the invention may be in a form suitable for oral use, for example, as baits (see, for example, U.S. Patent No. 4,564,631, incorporated herein by reference), dietary supplements, cachets, lozenges, chewable, tablets, hard capsules or soft capsules, emulsions, aqueous or oily suspensions, aqueous or oily solutions, oral formulations soak, dispersible powders or granules, premixes, syrups or elixirs, enteric or pasty formulations. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, bitterning agents, flavoring agents, coloring agents and preservative agents, in order to provide pharmaceutically elegant and tasty preparations.
The tablets may contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable excipient elements, which are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc, the tablets may be uncoated or may be coated by techniques known to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a long period. For example, a time-delaying material, such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated by the technique described in US patent documents No. 4,256,108; 4,166,452 and 4,265,874 (hereby incorporated by reference), to form therapeutic osmotic tablets for controlled release.
Formulations for oral use can be hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. The capsules can also be soft gelatin capsules, in which the active ingredient is mixed with water or miscible solvents such as propylene glycol, polyethylene glycols (PEG) and ethanol or an oily medium, for example peanut oil, liquid paraffin or olive oil.
The compositions of the invention can also be in the form of oil-in-water or water-in-oil emulsions. The oily phase may be a vegetable oil, for example, olive oil or peanut oil or a mineral oil, for example, liquid paraffin or mixtures thereof. As emulsifying agents can be naturally occurring phosphatides, for example, soy, lecithin, and partial esters or esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monoleate, and condensation products of said partial esters with ethylene oxide , for example, polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening agents, bitterness agents, flavoring agents, and / or preservatives.
In one embodiment of the formulation, the composition of the invention is in the form of a microemulsion. Microemulsions are suitable as the liquid carrier. Microemulsions are quaternary systems comprising an aqueous phase, an oil phase, a surfactant and a co-surfactant. They are translucent and isotropic liquids.
Microemulsions are composed of stable dispersions of microdroplets of the aqueous phase in the oil phase or, conversely, of microdroplets of the oil phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surfactant (SA) and active co-surface (Co-SA) molecules, by reducing the interfacial tension, which allows the microemulsion to be formed spontaneously.
In an embodiment of the oil phase, the oil phase can be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or, alternatively, from mixtures of such compounds. In an embodiment of the oil phase, the oil phase comprises triglycerides; in another embodiment of the oil phase, triglycerides are medium chain triglycerides, for example caprylic / capric triglycerides Cg-Cio * In another embodiment of the oil phase it will represent a% v / v range selected from the group consisting of about 2 to about 15%; about 7 to about 10%; and about 8 to about 9% v / v, of the microemulsion.
The aqueous phase includes, for example, water or glycol derivatives, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. In an embodiment of the glycol derivatives, the glycol is selected from the group consisting of propylene glycol, diethylene glycol monoethyl ether, dipropylene glycol monoethyl ether and mixtures thereof. Generally, the aqueous phase will represent a proportion of about 1 to about 4% v / v in the microemulsion.
Surfactants for the microemulsion include diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, Cs-Ciθ polyglycolated glycerides or polyglyceryl-6 dioleate. In addition to these surfactants, co-surfactants include short-chain alcohols, such as ethanol and propanol.
Some compounds are common to the three components discussed above, namely, the aqueous phase, the surfactant and the co-surfactant. However, it is well within the skill level of the practitioner to use different compounds for each component of the same formulation. In one embodiment the amount of surfactant / co-surfactant, the ratio of co-surfactant to surfactant will be about 1/7 to about 1/2. In another embodiment for the amount of co-surfactant, it will be about 25 to about 75% v / v surfactant and between about 10 to about 55% v / v co-surfactant in the microemulsion.
Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as sucrose, saccharin or aspartame, bitterness agents, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid or other known preservatives.
Aqueous suspensions may contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. These excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and acacia gum; dispersing or wetting agents can be a naturally occurring phosphatide, for example lecithin or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long chain aliphatic alcohols, for example , heptadecaetilenoxicetanol or ethylene oxide condensation products with partial esters derived from fatty acids and hexitol, such as a polyoxyethylene sorbitol mono-oleate or ethylene oxide condensation products, with partial esters derived from fatty acids and hexitol anhydrides , for example of polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents and / or bitterness agents, such as those set out above.
Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Dispersing or wetting agents and suspending agents are exemplified by the examples already mentioned above. Additional excipients, for example, sweeteners, bitterness, flavoring and coloring agents, may also be present.
Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring agent (s) and / or coloring agent (s).
In another embodiment of the invention, the composition can be in the form of a paste. Examples of embodiments in a paste form include, but are not limited to, those described in U.S. Patent Documents No. 6,787,342 and 7,001,889 (each of which are incorporated herein by reference). In addition to the dihydroazole compound of the invention, the paste can also contain colloidal silica; a viscosity modifier; a vehicle; optionally, an absorbent and, optionally, a dye, stabilizer, surfactant or preservative.
The process for preparing a paste formulation comprises the steps of: (a) dissolving or dispersing the dihydroazole compound in the vehicle by mixing; (b) adding colloidal silica to the vehicle containing the dissolved dihydroazole compound and mixing until the silica is dispersed in the vehicle; (c) allowing the intermediate formed in (b) to settle for a sufficient time, in order to allow the air trapped during step (b) to escape; and (d) adding the viscosity modifier to the intermediate, mixing to produce a uniform paste.
The steps above are illustrative, but not limiting. For example, step (a) can be the last step.
In an embodiment of the formulation, the formulation is a paste containing the compound dihydroazole, colloidal silica, a viscosity modifier, an absorbent, a dye and a hydrophilic vehicle that is triacetin, a monoglyceride, a diglyceride or a triglyceride.
The paste may also include, but is not limited to, a viscosity modifier, including PEG 200, PEG 300, PEG 400, PEG 600, monoethanolamine, triethanolamine, glycerol, propylene glycol, polyoxyethylene (20) sorbitan mono-oleate (Polysorbate 80 or Tween 80), and polyoxamers (for example, Pluronic L 81); an absorbent including magnesium carbonate, calcium carbonate, starch and cellulose and their derivatives and a dye selected from the group consisting of iron oxide titanium dioxide from FD&C Blue # 1 ALUMINUM LAKE.
The compositions can be in the form of a sterile aqueous injectable suspension or oleaginous suspension or a solution for injection. This suspension can be formulated according to the known technique using the suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a diluent or solvent, parenterally acceptable, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol glycols or formal polyethylene glycerol can also be used. Preservatives, such as benzyl alcohol or phenol, can be used.
In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose any soft fixed oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acids find use in the preparation of injectables.
Topical formulations, dermal and subdermal formulations can include emulsions, creams, ointments, gels, pastes, powders, shampoos, pour-on formulations, spot-on solutions and suspensions, pressures and sprays. Topical application of an inventive compound or a composition including at least one inventive compound among the agents mentioned here, in the form of a spot-on or pour-on composition, can allow the compound of the invention to be absorbed through the skin to achieve systemic levels, distributed through sebaceous glands or over the surface of the skin to reach levels throughout the coat. When the compound is distributed through the sebaceous glands, they can act as a reservoir, through which there can be a long-lasting effect (several months). Spot-on formulations are typically applied in a localized region that refers to a relatively small area in the animal, rather than a large portion of the animal's surface. In an embodiment of a localized region, the location is between the shoulders. In another embodiment of a localized region it is a band, for example, a band from the head to the tail of the animal.
Pour-on formulations are described in U.S. Patent Document No. 6,010,710, incorporated herein by reference. In some embodiments, pour-on formulations may be oily, and generally comprise a diluent or carrier and also a solvent (for example, an organic solvent) for the active ingredient, if the latter is not soluble in the diluent. In other embodiments, pour-on formulations can be non-greasy, including alcohol-based formulations.
Organic solvents that can be used in the invention include, but are not limited to: acetyltributyl citrate, fatty acid esters such as dimethyl ester, 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, propylene glycol, 2-pyrrolidone glycols, including N-methylpyretholine, ether diethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, ethylene glycol, adipate diisobutyl, adipate diisopropyl (also known as CERAPHIL 230), triacetin, butyl acetate, octyl acetate, propylene carbonate, butylene carbonate, dimethylsufoxide, organic amides, including dimethylformamide and dimethylacetamide, and ft diethyl alate or a mixture of at least two of these solvents.
In an embodiment of the invention, the pharmaceutically or veterinarily acceptable carrier of the formulation comprises Î ± -C10 alcohols esters thereof (including acetates, such as ethyl acetate, butyl acetate and the like), C1-Cβ saturated fatty acids or esters of these , Cio-Cis monounsaturated fatty acids or their esters, monoesters or diesters of aliphatic diacids, glycerol monoesters (eg monoglycerides), glycerol diesters (eg diglycerides) and glycerol triesters (eg triglycerides, such as triacetin ), glycols, glycolic ethers, glycol esters or glycol carbonates, polyethylene glycols of varying degrees (PEGs) or monoethers and diethers, monoesters or diesters thereof (for example, diethylene glycol monoethyl ether) or mixtures thereof.
Vegetable oils, such as, but not limited to, soy oil, peanut oil, castor oil, corn oil, cotton oil, olive oil, grape seed oil, can be mentioned as a vehicle or diluent. sunflower oil, coconut oil, etc; mineral oils such as, but not limited to, petrolatum, silicone paraffin, etc .; aliphatic or cyclic hydrocarbons or, alternatively, for example, medium chain triglycerides (such as C8-C12).
In another embodiment of the invention, an emollient and / or dispersion-forming agent and / or film-forming agent can be added. In one embodiment, the emollient and / or dispersion-forming agent and / or film-forming agent are those agents selected from the group consisting of: (a) polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate and vinylpyrrolidone copolymers, polyethylene glycols , benzyl alcohol, 2-pyrrolidones, including, but not limited to N-methylpyrrolidone, mannitol, sorbitol, glycerol, polyoxyethylene sorbitan esters; sodium carboxylcellulose, lecithin, silicone, polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS)), for example, those containing silanol or a 45 V2 oil, (b) anionic surfactants such as alkaline stearates, sodium stearates , potassium or ammonium; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulfates (for example, sodium lauryl sulfate and cetyl sodium sulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate; fatty acids (for example, those derived from coconut oil), (c) cationic surfactants such as water-soluble quaternary ammonium salts of the formula N + R'R "R" 'R "", Y "where the radicals R are optionally hydroxylated hydrocarbon radicals and Y ”is an anion of a strong acid such as sulfate, halide and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used, (d) amine salts of formula N + R'R "R" 'R "" where the R radicals are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants that can be used, (e) non-ionic surfactants, such as sorbitan esters , which are optionally polyoxyethylene (for example, polysorbate 80) and polyoxyethylene alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene styrene; polyethylene glycol stearate, polyoxyethylene castor oil derivatives, are polyglycerol esters and polyoxyethylene fatty alcohols, polyoxyethylene fatty acids, ethylene oxide and propylene oxide copolymers, (f) amphoteric surfactants such as the substituted betaine lauryl compounds, or (g) a mixture of at least two of these agents. The solvent will be used in proportion to the concentration of the dihydroazole compound and its solubility in this solvent. Always try to have the lowest possible volume. The vehicle makes the difference to 100%. In an embodiment of the amount of emollient, the emollient is used in a proportion of 0.1 to 50% and 0.25 to 5% by volume. In another embodiment of the invention, the composition may be in ready-to-use form of a localized topical solution, including a spot-on formulation, as described in US patent document No. 6,395,765, incorporated herein by reference. In addition to the dihydroazole compound, the solution may contain a crystallization inhibitor, an organic solvent and an organic co-solvent. In an embodiment of the amount of crystallization inhibitor, the amount of crystallization inhibitor can be present in a proportion of about 1 to about 30% (w / v) in the composition. In other embodiments, the crystallization inhibitor can be present in a proportion of about 1 to about 20% (w / v) and about 5 to about 15%. Acceptable inhibitors are those whose addition to the formulation inhibits the formation of crystals when the formulation is applied. In some embodiments, the formulations may include compounds that function as crystallization inhibitors other than those listed here. In these embodiments, the suitability of a crystallization inhibitor can be determined by a test in which 0.3 ml of a solution comprising 10% (w / v) of dihydroazole compound in the liquid carrier and 10% of the inhibitor are deposited on a glass slide at 20 ° C and left to stand for 24 hours. The laminula is then seen with the naked eye. Acceptable inhibitors are those whose addition provides few crystals (for example, less than ten crystals) or no crystals. In one embodiment, the organic solvent has a dielectric constant of about 2 to about 35, about 10 to about 35 or about 20 to about 30. In other embodiments, the solvent will have a dielectric constant of about from about 2 to about 20 or between about 2 and about 10. The content of this organic solvent in the overall composition will complement 100% of the composition. As discussed above, the solvent can comprise a mixture of solvents, including a mixture of an organic solvent and an organic co-solvent. In one embodiment, the organic co-solvent has a boiling point of less than about 300 ° C or less than about 250 ° C. In other embodiments, the co-solvent has a boiling point of less than about 200 ° C or below about 130 ° C. In yet another embodiment of the invention, the organic co-solvent has a boiling point of less than about 100 ° C or below about 80 ° C. In yet other embodiments, the organic co-solvent will have a constant range selected from the group consisting of about 2 to about 40, about 10 to about 40 or typically about 20 to about 30. In some embodiments of the invention, the co-solvent may be present in the composition in an organic co-solvent / organic solvent weight / weight (w / w) of about 1/15 to about 1/2. In some embodiments, the co-solvent is volatile, in order to act as a drying promoter and is miscible with water and / or with the organic solvent. The formulation can also comprise an anti-oxidant agent designed to inhibit oxidation to air, this agent being present in a proportion selected from a range consisting of about 0.005 to about 1% (w / v) and about 0 , 01 to about 0.05%. Crystallization inhibitors, which are useful for the invention include, but are not limited to: (a) polyvinylpyrrolidone, polyvinyl alcohols, vinyl acetate and vinylpyrrolidone copolymers, polyethylene glycols of varying degrees, benzyl alcohol, 2-pyrrolidones, including, but not limited to N-methylpyrrolidone, dimethylsulfoxide, mannitol, glycerol, sorbitol esters or sorbitan polyoxyethylene; sodium lecithin or carboxyl cellulose; a solvent, as described herein that is capable of inhibiting the formation of crystals; acrylic derivatives, such as acrylates and methacrylates or other polymers derived from acrylic monomers and others; (b) anionic surfactants, such as alkaline stearates (for example, sodium, potassium or ammonium stearate); calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulfates, which include but are not limited to sodium lauryl sulfate and cetyl sodium sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate or fatty acids (for example, coconut oil); (c) cationic surfactants, such as water soluble quaternary ammonium salts of the formula R 'RN "R"' R "" Y ", where the radicals R are identical or optionally different hydroxylated hydrocarbon radicals and Y is an anion a strong acid, such as sulfate, anion halide and sulfonate; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used; (d) amine salts of formula N + HR'R'R '", in which the radicals R are identical or optionally different radicals of hydroxylated hydrocarbons; octadecylamine hydrochloride is one of the cationic surfactants that can be used; (e) nonionic surfactants, such as, optionally, polyoxyethylene sorbitan esters, for example, polysorbate 80 or polyoxyethylene alkyl ethers; polyethylene glycol stearate, polyoxyethylenates derived from castor oil, polyglycerol esters and polyoxyethylene fatty acids, polyoxyethylene glycols or copolymers of ethylene oxide and propylene oxide; (f) amphoteric surfactants, such as betaine lauryl substituted compounds, or (g) a mixture of at least two of the compounds listed in items (a) - (f) above.
In an embodiment of the crystallization inhibitor, a pair of crystallization inhibitor will be used. Such pairs include, for example, the combination of a polymeric film-forming agent and a surface active agent. These agents will be selected from the compounds mentioned above as a crystallization inhibitor.
In an embodiment of the film-forming agent, the agents are of the polymeric type which include but are not limited to varying degrees of polyvinylpyrrolidone, polyvinyl alcohols, and vinyl acetate and vinylpyrrolidone copolymers.
In one embodiment of the surface active agents, the agents include but are not limited to those made of nonionic surfactants, in another embodiment of the surface active agents, the agent is a sorbitan and polyoxyethylene ester In yet another embodiment of the surfactant, agents include varying degrees of polysorbate, for example Polysorbate 80.
In another embodiment of the invention, the film-forming agent and the surfactant can be incorporated in identical or similar amounts, within the limit of the total amounts of crystallization inhibitor mentioned above.
In an embodiment of the antioxidant agents, the agents are those conventional in the art and include, but are not limited to butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate or a mixture of no more of two of them.
The non-active components of the formulation discussed above are well known to the practitioner in this art and can be obtained commercially or by known techniques. These concentrated compositions are generally prepared by simply mixing the components, as defined above; advantageously, the starting point is to mix the active material in the main solvent and then the other ingredients are added.
The volume of topical formulations applied is not restricted as long as the amount of substance administered has been shown to be safe and effective. Typically, the volume applied depends on the size and weight of the animal, as well as the concentration of active substance, the extent of parasite infestation and the type of administration. In some embodiments, the volume applied can be on the order of about 0.3 to about 5 ml or about 0.3 ml to about 1 ml. In an embodiment for volume, the volume is on the order of about 0.5 ml for cats and on the order of about 0.3 to about 3 ml for dogs, depending on the weight of the animal. In other embodiments, the volume applied can be about 5 ml to about 10 ml, about 5 ml to about 15 ml, about 10 ml to about 20 ml, or about 20 ml to about 30 ml, depending on the size of the treated animal and the concentration of the active agent in the formulation, among other factors.
In another embodiment of the invention, application of a spot-on formulation according to the present invention can also provide long-term and broad-spectrum efficacy when the solution is applied to the mammal or bird. Spot-on formulations provide topical administration of a concentrated solution, suspension, microemulsion or emulsion for intermittent application to a point on the animal, usually between the two shoulders (spot-on solution).
For spot-on formulations, the carrier can be a liquid carrier, as described in US patent document No. 6,426,333 (incorporated herein by reference). In one embodiment, the spot-on formulation comprises a solvent and a co-solvent in which the solvent can be acetone, acetonitrile, benzyl alcohol, diglycol butyl, dimethylacetamide, dimethylformamide, n-butyl dipropylene glycol ether, monomethyl propylene glycol ether , monoethyl propylene glycol ether, diisobutyl adipate, diisopropyl adipate (also known as Ceraphil 230), triacetin, butyl acetate, octyl acetate, propylene carbonate, butylene carbonate, dimethylsulfoxide, organic amides including dimethylformamide and dimethylacetamide, ethanol, ethanol, ethanol methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene monomethyl ether, polyoxyethylene glycol liquid glycols, propylene glycol, 2-pyrrolidone including N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol acids, ethylene glycol, ethylene diethyl phthalate greases, such as diethyl ester or diisobutyl adipate and a mixture of p minus two of these solvents. In another embodiment, spot-on formulations include a co-solvent which is absolute ethanol, isopropanol or methanol or a mixture thereof. In another embodiment, the compositions include benzyl alcohol as a co-solvent.
In an embodiment of the invention, the pharmaceutically or veterinarily acceptable carrier of the formulation comprises Ci-Cio alcohols or esters thereof (including acetates, such as ethyl acetate, butyl acetate and the like), saturated Cio-Cia fatty acids or esters of them, mono-unsaturated fatty acids, Cio-Cis or esters thereof, monoesters or diesters of aliphatic diacids, glycerol monoesters (eg monoglycerides), glycerol diesters (eg diglycerides) and glycerol triesters (eg triglycerides, such as triacetin), glycols, glycolic ethers, glycol esters or glycol carbonates, polyethylene glycols of varying degrees (PEGs) or monoethers and diethers and monoesters or diesters thereof (for example, diethylene glycol monoethyl ether) or mixtures thereof.
The liquid carrier can optionally contain a crystallization inhibitor including an anionic surfactant, a cationic surfactant, a nonionic surfactant, an amine salt, an amphoteric or polyvinylpyrrolidone surfactant, polyvinyl alcohols, vinyl acetate and vinylpyrrolidone copolymers, 2-pyrrolidone including N-methyl-pyrrolidone (NMP), dimethylsulfoxide, polyethylene glycols, benzyl alcohol, mannitol, sorbitol, glycerol, polyoxyethylene sorbitan esters; lecithin, sodium carboxylcellulose, solvents as defined herein that can inhibit the formation of crystals, and acrylic acrylate or methacrylate derivatives such as as well as other polymers derived from acrylic monomers or a mixture of these crystallization inhibitors.
Spot-on formulations can be prepared by dissolving the active ingredients in the pharmaceutically or veterinarily acceptable carrier. Alternatively, the spot-on formulation can be prepared by encapsulating the active ingredient to leave a residue of the therapeutic agent on the animal's surface. These formulations will vary with respect to the weight of the therapeutic agent in the combination, depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host.
Dosage forms can contain from about 0.5 mg to about 5 g of an active agent. In an embodiment of the dosage form, the dose is about 1 mg to about 500 mg of an active agent. More typically, the dose is from about 1 mg to about 25 mg, from 1 mg to about 50 mg, from 10 mg to about 100 mg or 20 mg to about 200 mg. In other embodiments, the dosage is about 50 mg to about 300 mg, 50 mg to about 400 mg, 50 mg to about 500 mg, 50 mg to about 600 mg, 50 mg to about 800 mg, or 100 mg to about 1000 mg.
In an embodiment of the invention, the active agent is present in the formulation at a concentration of about 0.05% to about 50% weight / volume. In other embodiments, the active agent can be present in the formulation in a concentration of about 0.1% to about 30%, about 0.5% to about 20% (w / v) or about 1% to about 10% (w / v). In another embodiment of the invention, the active agent is present in the formulation as a concentration of about 0.1 to 2% w / v. In yet another embodiment of the invention, the active agent is present in the formulation as a concentration of about 0.25 to about 1.5% weight / volume. In yet another embodiment of the invention, the active agent is present in the formulation as a concentration of about 1% weight / volume.
In a particularly advantageous embodiment of the invention, the dose of the compounds of the invention is from about 0.01 mg / kg to about 100 mg / kg of animal weight. In another embodiment, the dose is from about 0.1 mg / kg to about 100 mg / kg of the animal's weight. In other embodiments, the dose of the compounds of the invention is from about 0.5 mg / kg to about 70 mg / kg, about 0.5 mg / kg to about 50 mg / kg or about 0.5 mg / kg to about 30 mg / kg. In other preferred embodiments, the dose is 0.5 mg / kg to about 30 mg / kg, 0.5 mg / kg to about 20 mg / kg or 0.5 mg / kg to about 10 mg / kg. More typically, in some embodiments, the dose of the active compounds is about 0.01 mg / kg to 5 mg / kg, 0.1 mg / kg to about 5 mg / kg, about 0.1 mg / kg at about 3 mg / kg or about 0.1 mg / kg to 1.5 mg / kg. In still other embodiments of the invention, the dose can be as low as 0.1 mg / kg (0.02 mg / ml), about 0.2 mg / kg (0.04 mg / ml), about 0.3 mg / kg (0.06 mg / ml), about 0.4 mg / kg (0.08 mg / ml), about 0.5 mg / kg (0.1 mg / ml), to about 0.6 mg / kg (0.12 mg / ml), to about 0.7 mg / kg (0.14 mg / ml), to about 0.8 mg / kg (0.16 mg / ml), about 0.9 mg / kg (0.18 mg / ml), about 1.0 mg / kg (0.2 mg / ml). Agricultural compositions
The compounds of formula (I) can be formulated in several ways, depending on the predominant biological and / or physicochemical parameters. Examples of possible formulations that are suitable are: wettable powders (WP), water-soluble powders (SP), water-soluble concentrates, emulsifiable concentrates (EC), emulsions (EW), such as oil-in-water and water- emulsions. in-oil, sprayable solutions, suspension concentrates (SC), dispersions in an oil or water base, oil-miscible solutions, suspension in capsules (CS), dust (DP), seed coating products, granules for diffusion and application to soil, granules (GR) in the form of microgranules, spray granules, coated granules and adsorption granules, water dispersible granules (WG), water soluble granules (SG), ULV formulations, microcapsules and waxes.
Solid state forms of the compounds of formula (I) can be prepared by methods known in the art, for example, by Byrn et al "Solid-State Chemistry of Drugs", 2nd Edition, SSCI Inc., (1999); Glusker et al "Crystal Strcuture Analysis - a Primer", 2nd Edition, Oxford University Press, (1985).
The mentioned formulations can be prepared in a manner known per se, for example by mixing the active substances with at least one solvent or diluent, emulsifier, dispersant and / or binder or fixative, water repellent and, optionally, one or more than one desiccant, UV stabilizer, a dye, a pigment and other processing aids.
These types of individual formulations are known, in principle, and described, for example, in: Winnacker-Kuchler, "Chemische Technologie" [Chemical Technology], Volume 7, C. Hauser Verlag, Munich, 4th Edition 1986; Wade Van Valkenburg, "Pesticide Formulations", Maree Dekker, NY, 1973; Martens K., "Spray Drying Handbook", 3rd ed. 1979, G. Goodwin Ltd. London.
Necessary formulation aids such as inert materials, surfactants, solvents and other additives are also known and described, for example, in: Watkins, "Handbook of Insecticide Dust Diluents and Carriers", 2nd Ed., Darland Books, Caldwell NJ; Hv Olfen, "Introduction to Clay Colloid Chemistry", 2nd Ed, J. Wiley & Sons, NY; C. Marsden, "Solvents Guide", 2nd Ed, Interscience, NY, 1963; McCutcheon "Detergents and Emulsifiers Annual", MC Publ. Corp, Ridgewood NJ; Sisley and Wood, "Encyclopedia of Surface Active Agents", Chem. Publ. Co. Inc., NY, 1964; Schonfeldt "Grenzflachenaktive Athilenoxidaddukte" [Surface-Active ethylene oxide adducts], Wiss. Verlagsgesell, 1976 Stuttgart; Winnacker- Kuchler "Chemische Technologie" [Chemical Technology],
Volume 7, C. Hauser Verlag, Munich, 4th ed.1986.
Wettable powders are preparations that are uniformly dispersible in water and that, in addition to the compounds of formula (I), also comprise ionic and / or non-ionic surfactants (wetting, dispersing), for example, polyoxyethylated alkylphenols and polyoxyethylated fatty alcohols, amines polyoxyethylated greases, fatty polyglycolic alcohol ethers sulphates, alkanesulphonates or alkylabenzenesulphonates and sodium lignosulphonate, 2,2'-dinaftilmethane-6,6'-disulphonate sodium dibutylnaphthalenesulphonate or other sodium hydroxide in addition to a sodium hydroxide derivative. To prepare wettable powders, the compounds of formula (I) are, for example, finely ground in conventional apparatus, such as hammer mills, fan mills and arbor mills and mixed with the formulation aids, either concurrently or then this stage.
Emulsifiable concentrates are prepared, for example, by dissolving the compounds of formula (I) in an organic solvent, for example butanol, cyclohexanone, dimethylformamide, xylene or other aromatic solvent or higher boiling point hydrocarbon, or mixtures of the with the addition of one or more ionic and / or non-ionic surfactants (emulsifiers).
Emulsifiers that can be used are, for example: calcium salts of alkylarylsulfonic acids, such as calcium dodecylbenzenesulfonate or non-ionic emulsifiers, such as polyglycol esters of fatty acids, polyglycol ethers, fatty alcohol polyglycol ethers, condensed propylene oxide / ethylene oxide, alkyl polyethers, sorbitol esters, such as sorbitol fatty acid esters or polyoxyethylene sorbitol esters, such as polyoxyethylene sorbitan fatty acid esters.
Dusts are obtained by grinding the active substance with finely divided solid substances, for example talc or natural clays, such as kaolin, bentonite or pyrophyllite or diatomaceous earth.
Suspension concentrates can be water-based or oil-based. They can be prepared, for example, by wet grinding, by means of commercially available ball mills, if appropriate with the addition of surfactants, of the same type as those mentioned above, for example, in the case of other types of formulation.
Emulsions, for example oil-in-water (EW) emulsions, can be prepared for example by means of agitators, colloid mills and / or static mixtures using aqueous organic solvents and, if appropriate, surfactants that have already been mentioned above, for example in other types of formulation.
Granules can be prepared either by spraying the compounds of formula (I) on inert, adsorptive granular material, or by applying concentrated active substance to the surface of vehicles, such as sand, kaolinite or granulated inert material, using binders, for example polyvinyl alcohol, sodium polyacrylate or, alternatively, mineral oils. Suitable active substances can also be granulated in the form that is conventional for the production of fertilizer granules, if desired, in a mixture with fertilizers.
Water dispersible granules are prepared, as a rule, by the usual processes, such as spray drying, fluid bed granulation, disc granulation, mixing in high speed mixers and extrusion without inert solid material. To prepare with the disc, fluidized bed, extruder and spray granule technique, see, for example, processes in Spray-Drying Handbook "3rd ed. 1979, G. Goodwin Ltd., London; JE Browning," Agglomeration ", Chemical Engineering, 1967, pages 147 and following; Perry's Chemical Engineer's Handbook", 5th Ed., McGraw-Hill, New York 1973, p. 8-57. In general, agrochemical preparations comprise a range selected from the group consisting of about 0.1 to about 99% by weight and about 0.1 to about 95% by weight, of compounds of formula (I).
The concentration of the compounds of formula (I) in wettable powders is, for example, about 10 to about 90% by weight, the remainder being 100% by weight, composed of usual components of the formulation. In the case of emulsifiable concentrates, the concentration of compounds of formula (I) may rise at intervals selected from the group consisting of about 1% to about 90% and about 5% to about 80% by weight. Formulations in the form of dust, usually comprise the range selected from the group consisting of about 1% to about 30% by weight of compounds of formula (I) and about 5% to about 20% by weight, of compounds of formula (I). For sprayable solutions, they comprise a range selected from the group consisting of about 0.05% to about 80% by weight of compounds of formula (I) and about 2% to about 50% by weight of compounds of formula (I). In the case of water-dispersible granules, the content of compounds of formula (I) depends in part on whether the compounds of formula (I) are in liquid or solid form and which granulation aids, fillers and the like are being used. Water-dispersible granules, for example, comprise a
range selected from the group consisting of between about 1 and about 95%, and between about 10% and about 80% by weight.
In addition, the formulations of compounds of formula (I) mentioned comprise, if appropriate, adhesives, humectants, dispersants, emulsifiers, penetrating regulators, preservatives, antifreeze agents, solvents, fillers, vehicles, dyes, defoamers, evaporation inhibitors, regulators of pH and viscosity regulators that are conventional in each case.
The following are examples of agricultural compositions: 1. Products for dilution with water. For seed treatment purposes, such products can be applied to diluted or undiluted seeds. A) Water-soluble concentrates: 10 parts by weight of the active compound are dissolved in 90 parts by weight of water or a water-soluble solvent. As an alternative, humidifiers or other auxiliaries are added. The active compound dissolves in dilution with water, according to which a formulation with 10% (w / w) of active compound is obtained. B) Dispersible concentrates (DC): 20 parts by weight of the active compound are dissolved in 70 parts by weight of cyclohexanone with the addition of 10 parts by weight of a dispersant, for example, polyvinylpyrrolidone. Dilution with water gives a dispersion, in which a formulation with 20% (w / w) of active compounds is obtained. C) Emulsifiable concentrates (EC): 15 parts by weight of the active compounds are dissolved in 7 parts by weight of xylene, with the addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight). Dilution with water gives an emulsion, according to which a formulation with 15% (w / w) of active compounds is obtained. D) Emulsions: 25 parts by weight of the active compound are dissolved in 35 parts by weight of xylene, with the addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight). This mixture is introduced into 30 parts by weight of water by means of an emulsifier machine (for example, Ultraturrax) and transformed into a homogeneous emulsion. Dilution with water gives an emulsion, according to which a formulation with 25% (w / w) of active compound is obtained. E) Suspensions: In a stirring ball mill, 20 parts by weight of the active compound are crushed with the addition of 10 parts by weight of dispersants, humidifier and 70 parts by weight of water or an organic solvent to give a suspension of compound thin active. Dilution with water gives a stable suspension of the active compound, in which a formulation with 20% (w / w) active compound is obtained. F) Water-dispersible granules and water-soluble granules (WG, SG): 50 parts by weight of the active compound are finely ground, with the addition of 50 parts by weight of dispersing and humidifying agents and water-dispersible or water-soluble granules they are made by means of technical devices (for example extrusion, tower spray, fluidized bed). Dilution with water gives a stable dispersion or solution of the active compound, in which a formulation with 50% (w / w) active compound is obtained. G) Water-dispersible powders and water-soluble powders: 75 parts by weight of the active compound are ground in a rotor-stator mill, with the addition of 25 parts by weight of dispersants, humidifiers and silica gel. Dilution with water gives a stable dispersion or solution of the active compound, in which a formulation with 75% (w / w) active compound is obtained. H) Gel formulation (GF): In a ball mill under agitation, 20 parts by weight of the active compound are crushed with the addition of 10 parts by weight of dispersing agents, 1 part by weight of a humidifying gelling agent and 70 parts in weight of water or an organic solvent to give a fine suspension of active compound. Dilution with water gives a stable suspension of the active compound, in which a formulation with 20% (w / w) active compound is obtained. 2. Products to be applied without dilution, for foliar applications. For seed treatment purposes, such products can be applied to diluted or undiluted seeds. I) Dustable powders: 5 parts by weight of the active compound are finely ground and mixed intimately with 95 parts by weight of finely divided kaolin. This gives a powderable product having 5% (w / w) active compound. J) Granules: 0.5 part by weight of the active compound is finely ground and associated with 95.5 parts by weight of vehicles, according to which a formulation with 0.5% (w / w) of active compound is obtained. Current methods are extrusion, spray drying or fluidized bed. This gives granules to be applied directly, without dilution, for foliar use. K) ULV solutions (UL): 10 parts by weight of the active compound are dissolved in 90 parts by weight of an organic solvent, for example xylene. This gives a product having 10% (w / w) of active compound, which is applied undiluted for foliar use. Treatment Methods
In another embodiment, the invention provides a method for the treatment or prevention of parasitic infestation or infection in an animal (for example, a mammal or bird) comprising administering an effective amount of a dihydroazole compound of formula (I) or a composition comprising the compound for the animal. Mammals that can be treated include, but are not limited to, humans, cats, dogs, chickens, cattle, deer, goats, horses, lamas, pigs, sheep and yaks. In an embodiment of the invention, the treated mammals are humans, dogs or cats. In another modality, the animals treated are cattle, horses, sheep, goats or pigs.
In one embodiment, the invention provides a method for treating or preventing an ectoparasite infestation in an animal. In various modalities, ectoparasite is one or more insects or arachnids including the genera Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes, Boophilus, Ambilomma, Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes, Hypoderma, Trichodectes and Felicola.
In another embodiment for the treatment against ectoparasites, ectoparasite is one from the genera, Ctenocephalides, Rhipicephalus, Dermacentor, Ixodes and / or Boophilus. Ectoparasites include, but are not limited to, fleas, ticks, mites, mosquitoes, flies, lice, blowflies and their combinations. Specific examples include, but are not limited to, dog and cat fleas (Ctenocephalides felis, Ctenocephalides sp. And the like), ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyoma sp. And the like), and mites (Demodex sp., Sarcoptes sp., Otodectes sp. and the like), lice (Trichodectes sp., Cheyletiella sp., Lignonathus sp. and the like), mosquitoes (Aedes sp., Culex sp., Anopheles sp., and the like) and flies (Hematobia sp., Musca sp., Stomoxys sp., Dematobia sp., Cochliomyia sp., And the like).
Additional examples of ectoparasites include but are not limited to ticks of the genus Boophilus, especially those of microplus species (bovine tick) and decoloratus and annulatus; myiasis such as Dermatobia hominis (known as berne in Brazil) and Cochliomyia hominivorax (greenbottle); sheep miiases, such as Lucilia sericata, Lucilia cuprina (known as blowfly strike in Australia, New Zealand and South Africa). Flies themselves, especially those whose adult forms the parasite, such as Haematobia irritans (horn fly); lice, such as Linognathus vitulorum, etc., and mites, such as Sarcoptes scabici and Psoroptes ovis. The above list is not exhaustive and other ectoparasites are well known in the art as being harmful to animals and humans. These include, for example, dipteran migration larvae.
In another embodiment, the invention provides a method for treating or preventing an endoparasitic infection in an animal, comprising administering an effective amount of a compound of the invention dihydroazole to the animal. In some embodiments, the compounds of the invention can be used against endoparasites including Anaplocephala, Ancylostoma, Anecator, Ascaris, Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius, Fasciola, Haemonchus, Oesophagostum, Ostertagia, Toxocara, Toxocara, Toxocara Trichuris, and Trichostrongylus.
In a particularly preferred embodiment, the invention provides a method for the prevention and / or treatment of infections by Dirofilaria immitis, comprising administering to the animal a parasitically effective amount of a compound of formula (I). It has surprisingly been found that the compounds of the invention are active against both ectoparasites and endoparasites of animals that suffer damage.
In another embodiment of the invention, the compounds and compositions of the invention are suitable for pest control at a locus. Therefore, a further embodiment of the invention is a method for controlling pests at a locus, comprising applying a pesticidally effective amount of the compound of formula (I) or a composition comprising the compound to the locus. Pests that can be controlled with the compounds of the invention include insects, such as Blatella germanica, Heliothis virescens, Leptinotarsa decemlineata, Tetramorium caespitum and combinations thereof.
In yet another embodiment, the compounds and compositions of the invention are effective in protecting crops, plants and materials made of wood against pests. Thus, the invention provides a method for protecting crops, plants, plant propagating materials and material made from wood against pests that harm these materials which comprises the application of the compounds of the invention or the compositions comprising the compounds to the crops, plants, plant propagating material and material made of wood.
In other embodiments, the compounds and compositions of the invention can be used against phytoparasitic nematodes including, for example, Anguina spp., Aphelenchoides spp., Belonoaimus spp., Bursaphelenchus spp., Ditylenchus dipsaci, Globodera spp., Heliocotylenchus spp. ., Heterodera spp., Longidorus spp., Meloidogyne spp., Pratylenchus spp., Radopholus similis, Rotylenchus spp., Trichodorus spp., Tylenchorhynchus spp., Tylenchulus spp., Tylenchulus semipenetrans, Xiphinema spp.
In addition, the compounds and compositions of the invention can also be used against pests that include, but are not limited to, the following pests: (1) Of the order Isopoda, for example, Oniscus asellus, Armadillidium vulgare and Porcellio scaber; (2) Of the order Diplopoda, for example, Blaniulus guttulatus; (3) Of the order Chilopoda, for example, Geophilus carpophagus and Scutigera spp .; (4) Of the order Symphila, for example, Scutigerella immaculata; (5) Of the order Thysanura, for example, Lepisma saccharina; (6) Of the order Collembola, for example Onychiurus armatus; (7) Of the order Blattaria, for example Blatta orientalis, Periplaneta americana, Leucophaea maderae and Blattella germanica; (8) Of the order Hymenoptera, for example Diprion spp, Hoplocampa spp, Lasius spp, Monomorium pharaonis and Vespa spp .; (9) Of the order Siphonaptera, for example Xenopsylla cheopis and Ceratophyllus spp .; (10) Of the order Anoplura (Phthiraptera), for example, Damalinia spp., Haematopinus spp, Linognathus spp, Pediculus spp, Trichodectes spp .; (11) Of the class of Arachnida, for example, Acarus siro, Aceria sheldoni, Aculops spp., Aculus spp., Amblyomma spp., Argas spp., Boophilus spp., Brevipalpus spp., Bryobia praetiosa, Chorioptes spp., Dermanyssus gallinae , Eotetranychus spp., Epitrimerus pyri, Eutetranychus spp., Eriophyes spp., Hemitarsonemus spp., Hyalomma spp., Ixodes spp., Latrodectus mactans, Metatetranychus spp., Oligonychus spp., Polithodoros spon. latus, Psoroptes spp, Rhipicephalus spp, Rhizoglyphus spp. , Sarcoptes spp, Scorpio maurus, Stenotarsonemus spp, Tarsonemus spp, Tetranychus spp, Vasates lycopersici; (12) Of the Bivalva class, for example, Dreissena spp .; (13) Of the order Coleoptera, for example, Acanthoscelides obtectus, Adoretus spp., Agelastica alni, Agriotes spp., Amphimallon solstitialis, Anobium punctatum, Anoplophora spp., Anthonomus spp., Anthrenus spp., Apogonia spp., Atomaria spp., Atomaria spp. Attagenus spp., Bruchidius obtectus, Bruchus spp., Ceuthorhinchus spp., Cleonus mendicus, Conoderus spp., Cosmopolites spp., Costelytra zealandica, Curculio spp., Cryptorhinchus lapathi, Dermestes spp., Diabrotica spp., Epbrotica spp. , Gibbium psilloides, Heteronychus arator, Hilamorpha elegans, Hilotrupes bajulus, Hypera postica, Hypothenemus spp., Lachnosterna consanguínea, Leptinotarsa decemlinaata, issorhoptrus oryzophilus, Lixus spp., Lyctus spp., Meligetol. , Monochamus spp., Naupactus xanthographus, Niptus hololeucus, Rhino rhinoceros, Oryzaephilus surinamensis, Otiorrhinchus sulcatus, Oxicetonia jucunda, Phaedon cochleariae, Phillophaga spp. Sitophilus spp., Sfenophorus spp., Sternechus spp, Symphiletes spp, Tenebrio molitor, Tribolium spp, Trogoderma spp, Tychius spp, Xilatrechus spp, Zabrus spp .; (14) Of the order Diptera, for example, Aedes spp., Anopheles spp. , Bibio hortulanus, Calliphora erythrocephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia spp., Cordilobia anthropophaga, Culex spp., Cuterebra spp., Dacus oleais, Dermatobia hominis, Drosophila spp., Fannia spp. , Hyppobosca spp., Hypoderma spp., Liriomyza spp., Lucilia spp., Musca spp., Nezara spp., Oestrus spp., Oscinella frita, Pegomyia hyoscyami, Phorbia spp., Stomoxis spp., Tabanus spp., Tannia spp. , Tipula paludosa, Wohlfahrtia spp .; (15) of the class Gastropoda, for example, Arzon spp, Biomphalaria spp, Bulinus spp, Deroceras spp, Galba spp, Lymnaea spp, Oncomelania spp, Succinea spp .; (16) Of the helminth class, for example, Ancilostoma duodenale, Ancilostoma ceilanicum, Braziliensis Acilastoiαa, Ancilostoiαa spp., Ascaris Lubicoides, Ascaris spp., Brugia malayi, Brugia timori, Bunostomum spp., Chabertia spp., Clonorchpp. ., Dicrocoelium spp, Dictyocaulus filaria, Diphillobothrium latum, Dracunculus medinensis, Echinococcus granulosus, Echinococcus multilocularis, Enterobius vermicularis, Faciola spp., Haemonchus spp., Heterakis spong., Hymenole spp., Hymenole , Oesophagostomum spp., Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., Paragonimus spp., Schistosomen spp., Strongiloides fuelleborni, Strongiloides stercoralis, Stroniloides spp., Taenia saginata, Taenia solium, Trichinella spiralis, Trichinella spiralis nelsoni, Trichinella pseudopsiralis, Trichostrongulus spp, Trichuris trichuria, Wuchereria bancrofti; (17) Of the order Heteroptera, for example, Anasa tristis, Antestiopsis spp., Blissus spp., Calocoris spp. , Campilomma livida, Cavelerius spp., Cimex spp., Creontiades dilutus, Dasinus piperis, Dichelops furcatus, Diconocoris hewetti, Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis spp., Horciaglosspuspus, Lepisthorpe Lygus spp., Macropes excavatus, Miridae, Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, Piezodorus spp, Psallus seriatus, Pseudacysta Persea, Rhodnius spp, Sahlbergella singularis, Scotinophora spp, Stephanitis nashi, Tibracap sp. (18) Of the order Homoptera, for example, Acyrthosipon spp., Aeneolamia spp., Agonoscena spp., Aleurodes spp., Aleurolobus barodensis, Aleurothrixus spp., Amrasca spp., Anuraphis cardui, Aonidiella spp., Apphisostigma piri. , Arboridia apicalis, Aspidiella spp., Aspidiotus spp., Atanus spp., Aulacorthum solani, Bemisia spp., Brachycaudus helichrysii, Brachycolus spp., Brevicorine brassicae, Calligypona marginata, Carneocephala fulgida. , Chionaspis tegalensis, Chlorita onukii, Chromaphis juglandicola, Ficus Chrysomphalus, Cicadulina mbila, Coccomytilus halli, Coccus spp., Cryptomyzus ribis, Dalbulus spp., Dialeurodes spp., Diaphorina spp., Dorspis spp. Dysaphis spp., Dysmicoccus spp., Empoasca spp., Eriosoma spp., Erythroneura spp., Euscelis bilobatus, Geococcus coffeae, Homalodisca coagulata, Hyalopterus arundinis, leery an spp., Idiocerus spp., Idiospus spp., Idios striatellus, Lecanium spp., Lepidosaphes spp., Lipaphis erysimi, Macrosiphum spp., Mahanarva fimbriolata, Melanafis sacchari, Metcalfiella spp., Metopolophium dirhodum, Monellia costalis, Monelliopsis pecanis, Myzuspeppis, Naszov spp. Oncometopia spp., Orthezia praelonga, Parabemisia myricae, Paratrioza spp., Parlatoria spp., Penfigo spp., Peregrinus maidis, Fenacoccus spp., Phloeomyzus passerinii, Phorodon humuli, Philloxera spp., Pinnaspis spid. , Protopulvinaria piriformis, Pseudaulacaspis pentagons, Pseudococcus spp., Psilla spp., Pteromalus spp., Pirilla spp., Quadraspidiotus spp., Quesada gigas, Rastrococcus spp., Rhopalosiphum spp., Saissetia spp., Sissetia spid. , Sogata spp., Sogatella furcifera, Sogatodes spp., Stictocephala festina, Tenalaphara malayensis, Tinocallis caryaefoliae, Tomaspis spp., Toxoptera spp., Trialeurodes vaporariorum, Trioza spp, Typhlocyba spp, Unasp; (19) Of the order Isoptera, for example, Reticulitermes spp, Odontotermes spp .; (20) Of the order Lepidoptera, for example, Greater Acronic, Aedia leucomelas, Agrotis spp., Alabama argillacea, Anticarsia spp., Barathra brassicae, Bucculatrix thurberiella, Bupalus piniarius, Cacoecia podana, Capua reticulana, Carpocapsa pomonella, Chimatobia, Cheimatobia ., Choristoneura fumiferana, Clysia ambiguella, Cnafalocerus spp., Earias insulana, Ephestia kuehniella, Euproctis chrysorrhoea, Euxoa spp., Feltia spp., Galleria mellonella, Helicoverpa spp., Heliothis spp., Hofmannophila pseudos, Hommann spp., LithocoUetis blancardella, Lithophane antennata, Loxagrotis albicosta, Lymantria spp., Malacosoma neustria, Mamestra brassicas, Mods repanda, Mythimna separata, Oria spp., Oulema oryzae, Panolis flammea, Pectinophora gossypiella, Phillocistisella, Phillocnis , Prodenia spp., Pseudaletia spp., Pseudoplusia includens, Pirausta nubilalis, Spodoptera spp., Thermesia gemmatalis, pellioneUa Tinea, Tin eola bisseUiella, Tortrix viridana, Trichoplusia spp .; (21) Of the order Orthoptera, for example, Acheta domesticus, Blatta orientalis, German Blattella, Grillotalpa spp, Leucophaea maderae, Locusta spp, Melanoplus spp, American periplaneta, Schistocerca gregaria; (22) Of the order Thysanoptera, for example, Baliothrips biformis, Enneothrips flavens, FranklinieUa spp., Heliothrips spp., Hercinothrips femoralis, Kakothrips spp., Rhipiphorothrips cruentatus, Scirtothrips spp, Taeniothrips cardamoni. (23) Of the class of protozoa, for example, Eimeria spp. Combinations of active agents The compounds of formula (I) or their salts can be used as tai or in the form of their preparations (formulations) as combinations with other active substances. For agricultural uses, the compounds of formula (I) can be used in combination with, for example, insecticides, attractants, sterilizers, acaricides, nematicides, herbicides, fungicides, and with protective agents, fertilizers and / or growth regulators, for example example as a ready-to-use pre-mix / mix.
Fungicide classifications are well known in the art and include classifications by FRAC (Fungicide Resistance Action Committee). Fungicides that can optionally be mixed with the compounds of formula (I) include, but are not limited to, methyl benzimidazole carbamates, such as benzimidazoles and thiophanates; dicarboximides; methylation inhibitors, such as imidazoles and piperazines, pyridines, pyrimidines, and triazoles; phenylamides, such as acylalanines and oxazolidinones, and butyrolactones; amines, such as morpholines, piperidines, and spirocetalamines; phosphorothiolates; dithiolans; carboxamides; hydroxy- (2-amino-) pyrimidines; anilino-pyrimidines; N-phenyl carbamates; quinone inhibitors; phenylpyrroles; quinolines; aromatic hydrocarbons; heteroaromatics; melanin reductase biosynthesis inhibitors; inhibitors of melanin dehydratase biosynthesis; quinone inhibitors; hydroxyanilides (SBI class III), such as phenhexamide; Class IV SBI, such as thiocarbamates and allylamines; polyoxins; phenylureas; quinone inhibitors from within; benzamides, enopyranuronic acid antibiotic; hexopyranosil antibiotic; glycopyranosyl antibiotic; glycopyranosyl antibiotic; cyanoacetamides; carbamates; decoupler from oxidative phosphorylation, organo-tin compounds; carboxylic acids; heteroaromatics; phosphonates; phthalamic acids; benzotriazines; benzenesulfonamides; pyridazinones; carboxylic acid amides; tetracycline antibiotic; thiocarbamate; benzo-thiadiazole BTH; benzisothiazole; thiadiazolcarboxamide; thiazolcarboxamides; benzamidoxime; quinazolinone; benzophenone; acylpicolide; inorganic compounds, such as copper and sulfur salts; dithiocarbamates and relatives; phthalimides; chloronitriles; sulfamides; guanidines; triazines; quinones.
Other fungicides that can optionally be mixed with the compounds of formula (I) can also be of the classes of compounds described in U.S. Patent Documents No. 7,001,903 and 7,420,062, each of which is incorporated herein by reference.
Herbicides that are known in the literature and classified by HRAC (Herbicide Action Committee - "Herbicide Resistance Action Committee") and can be combined with the compounds of the invention are, for example: aryloxyphenoxy-propionate; cyclohexanedione; phenylpyrazoline; sulfonylurea; imidazolinone, such as imazapic and imazetapyr; triazolopyrimidine; pyrimidinyl (thio) benzoate; sulfonylaminocarbonyl triazolinone; triazine, such as atrazine; triazinone; triazolinone; uracil; pyridazinone; carbamate-phenyl; urea; amide; nitrile; benzothiadiazinone; phenyl-pyridazine; bipyridylium, such as paraquat; diphenylether; phenylpyrazole; N-phenylphthalimide; thiadiazole; thiadiazole; triazolinone; oxazolidinedione; pyrimidindione; pyridazinone; pyridinocarboxamide; tricetone; isoxazole; pyrazole; triazole; isoxazolidinone; urea, such as linuron; diphenylether; glycine, such as glyphosate; phosphinic acid, such as glufosinate-ammonium; carbamate; dinitroaniline, such as pendimethalin, phosphoramidate; pyridine; benzamide; benzoic acid; chloroacetamide; metolachlor; acetamide; oxyacetamide; tetrazolinone; nitrile; benzamide; triazolocarboxamide; quinoline carboxylic acid; dinitrophenol; thiocarbamate; phosphorodithioate; benzofuran; chloro-carbonic acid; phenoxycarboxylic acid, such as 2,4-D; benzoic acid, such as dicamba, pyridine carboxylic acid, such as clopyralide, triclopyr, fluroxypyr and picloram, quinoline carboxylic acid; semicarbazone phthalate; qrilaminopropionic acid; organoarsenic acid.
Other herbicides that can be optionally mixed are the compounds described in U.S. Patent Documents No. 7,432,226, 7,012,041 and 7,365,082, all of which are incorporated herein by reference.
Suitable herbicide protection agents include, but are not limited to, benoxacor, cloquintocet, ciometrinil, cyprosulfamide, dichlormid, dicyclonon, diethylate, fenclorazole, fenclorim, flurazol, fluxofenim, furilazol, isoxadifen, mefenpiral, oxyphenidate and anhydride.
Bactericides include, but are not limited to, bronopol, dichlorophen, nitrapirin, nickel dimethyldithiocarbamate, casugamycin, octylinin, furancarboxylic acid, oxytetracycline, probenazole, streptomycin, keyboard software, copper sulfate and other copper preparations.
Insecticides / acaricides / nematicides include the compounds mentioned in US patent documents No. 7,420,062, 7,001,903 and US patent publication 2008/0234331, each of which is incorporated herein by reference, and compounds classified by IRAC (Insecticide Resistance Action Committee - "Insecticide Resistance Action Committee"). Examples of insecticides / acaricides / nematicides include, but are limited to, carbamates; triazemate; organophosphates; cyclodienes organochlorines; phenylpyrazoles; DDT; methoxychlor; pyrethroids; pyrethrins; neonicotinoids; nicotine; bensultap; cartap hydrochloride; nereistoxin analogues; spinosyns; avermectins and milbemycins; analogues of youth hormone; phenoxycarb; phenoxycarb; alkyl halides; chloropicrin; sulfuryl fluoride; cryolite; pymetrozine; Flonicamid; clofentezine; hexithiazox; ethoxazole; Bacillus sphaericus; diafentiuron; organotinic acaricides, propargite; tetradifon; chlorfenapyr; DNOC; benzoylureas; buprofezin; cyromazine; diacylhydrazines; azadiractin; amitraz; hydrametilnon; acequinocil; fluacrypirim; METI acaricides; rotenone; indoxacarb; metaflumizone; tetronic acid derivatives; aluminum phosphide; cyanide; phosphine; biphenazate; fluoroacetate; P450 monooxygenase dependent inhibitors; esterase inhibitors; diamides; benzoxime; quinomethinate; dicofol; pyridalil; borax; emetic tartar; fumigants, such as methyl bromide; ditera; clandosan; sincocin.
Veterinary compositions can include a compound of formula (I) in combination with other pharmaceutically or veterinarily acceptable active agents. In some embodiments, the additional agents can be one or more parasiticidal compounds, including acaricides, anthelmintics, endectocides and insecticides. Antiparasitic agents can include both ectoparasiticides and endoparasiticides.
Veterinary pharmaceutical agents that can be included in the compositions of the invention are well known in the art (see, for example, "Plumb's Veterinary Drug Handbook" 5th Ed, ed. Donald C. Plumb, Blackwell Publishing, (2005) or "The Merck Veterinary Manual ", 9 Edition, (January 2005)) and include, but are not limited to acarbose, acepromazine maleate, acetaminophen, acetazolamide, sodium acetazolamide, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, albendazole, sulfate albuterol, alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproic acid, aminopentamide hydrogen sulfate, aminophylline / theophylline, amiodarone, amitraz, amitriptyline, amlodine chloride, amlodine chloride, amlodine chloride potassium, amphotericin B deoxycholate, lipid-based amphotericin B, ampicillin, amprolium, antacids (oral), antivenom, apomorphine, apramycin sulfate, ascetic acid orbic, asparaginase, aspirating, atenolol, atipamezole, atracurium besylate, atropine sulphate, aurnofim, aurothioglycosis, azaperone, azathioprine, azithromycin, baclofen, barbiturates, benazepril, betamethasone, betamethylate, bisaccharide, bisaccharide, bisaccharate boldenone, bromides, bromocriptine mesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanol tartrate, cabergoline, salmon calcitonin, calcitrol, calcium salts, captopril, carbanicillin, indanil sodium, carbimazole, carboplatin, caritene, carprofen, carbitol, carprofen, carprofen, carprofil, carprofen, carprofen, carprofil, carprofen, carprofil, caritol, carprofen, carprofil. , sodium cefazolin, cefixime, clorsulon, sodium cefoperazone, sodium cefotaxime, disodium cefotetan, sodium cefotetan, cefoxitin, proxetil cefpodoxime, ceftazidime, sodium ceftiofur, cefiofur, cefiexine, cefiaxine, activated cefiaxone, sodium chlorambucil, chloramphenicol, chlordiazepoxide, chlordiazepoxide +/- clidinidium bromide, chlorothiazide, clo maleate rphenphenine, chlorpromazine, chlorpropamide, chlortetracycline, human chorionic gonadotropin (HCG), chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin, clemastine fumarate, clenbuterol, clenbuterol, clindamine, clindamine, clindamine, clindamine, clindamine, clindamine, clindamine dipotassium chlorazepate, clorsulon, cloxacillin, codeine phosphate, colchicine, corticotropin (ACTH), cosintropin, cyclophosphamide, cyclosporine, cyproheptadine, cytarabine, dacarbazine, dactinomycin / actinomycin D, dalteparin, danzodine, dinasteparin, danazolate deferoxamine, deracoxib, deslorelin acetate, desmopressin acetate, poxate deoxycorticosterone, detomidine, dexamethasone, dexpanthenol, dexrazoxane, dextran, diazepam, diazoxide (oral), diclorfenamide, diclofenacil, diethylamine, citrate; difioxacin, digoxin, dihydrotaquisterol (DHT), diltiazem, dimenhydrinate, dimer caprol / BAL, dimethylsulfoxide, tromethamine dinoprost, diphenylhydramine, disopyramide phosphate, dobutamine, docusate / DSS, dolasetron mesylate, domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin, calcium doxycycline, edetate, disodium and calcium hydroxide , enalapril / enalaprilat, enoxaparin sodium, enrofioxacin, ephedrine sulfate, epinephrine, epoetin / erythropoietin, eprinomectin, epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrinate acid / ethanolhydrate, ethanolhydrate, ethanol ethanol (ethanol), ethanol ethanol (ethanol) , euthanasia agents with pentobarbital, famotidine, fatty acids (essential / omega), felbamate, fentanyl, ferrous sulphate, filgrastim, finasteride, fipronil, florfenicol, fluconazole, flucytosine, fludrocortisone acetate, flumazenil, flumazenil, flumzenone, flumazenil, flumzenone -FU), fluoxetine, fluticasone propionate, fiuvoxamine maleate, hungrypizol (4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon, glucocorticoid agents, glucosamine / chondroitin sulphate, glutamine, glyburide, glycerin (oral), glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane, hemoglobin glutamer-200 (oxiglobin, ®) hetastarch, sodium hyaluronate, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate, impenem-cilastatin sodium, human iminpramine, lactate, recombinate, lactate , (sodium / potassium) iodide, ipecacuanha (syrup), sodium ipodate, iron-dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine, itraconazole, kaolin / pectin ivermectin, ketamine, ketoconazole, ketoprofen, ketoprofen, ketoprofen, ketoprofen, ketoprofen, ketoprofen levamisole, levetiracetam, levothyroxine sodium, lidocaine, lincomycin, sodium liotironin, lisinopril, lomustine (CCNU), lufenuron, lisi na, magnesium, mannitol, marbofloxacin, meclorethamine, meclizine, meclofenamic acid, medetomidine, medium chain triglycerides, medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin, meloxican, melphalan, meperidine, metaptopurine, metaptopurine, metaptopurine, meropen, meropen methenamine mandelate / hypurate, methimazole, methionine, metocarbamol, sodium methohexital, methotrexate, methoxyflurane, methylene blue, methylphenidate, methylprednisolone, metoclopramide, metoprolol, metronidaxole, mexiletine, mibolin, minibol, methanol, milibolone, minilol, methanol mitoxantrone, morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen, narcotic agonists (opioids), analgesics, neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpiram, sodium nitrofurantoin, nitroglycerin, nitro, glycyrin, nitro , octreotide acetate, sodium olsalazine, omeprazole, ondans etrone, opioid antidiarrhea, orbifloxacin, sodium oxacillin, oxazepam, oxybutynin chloride, oxymorphone, oxytretracycline, oxytocin, disodium pamidronate, pancreplipase, pancuronium bromide, paromycin sulphate, penicillin, penicillin, penicillin, pencil potassium, pentazocine, sodium pentobarbital, sodium polysulfate pentosan, pentoxifylline, pergolide mesylate, phenobarbital, phenoxybenzamine, phenylbutazone, phenylephrine, phenipropanolamine, sodium phenytoin, pheromone, parenteral phosphate, phytonobycin / vitamin Kl, pimimimine, pimimimine, pimimimine, pimimimine, pimimimine, pimimimine, pimimimine, pimimimine, pimimimine, pimimimine, pimetimine, pimimimine, pimimimine, pimetimine, pimimimine piroxicam, polysulfated glycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride, prazosin, prednisolone / prednisone, primidone, procainamide, procarbazine, prochlorperazine, propantheline bromide injection, propionibacterium acnes, propofol, protamine, propanol, propanol, protamine, propanol, protamine, propanol, propanol, protamine, propanol, propanol, protamine, propanol, protamine, propanol, propanol, protamine, propanol, hydrophilic, pyridostigmine bromide, pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampicin, S-adenosylmethionine (SAME), laxative saline / hyperosmotic solution, selamectin, selegiline / l-deprenyl, sertraline, sevelamer, seofamer, sevoflurane, silymarin / milk thistle, bicarbonate sodium, sodium polystyrene sulfonate, sodium stibogliconate, sodium sulfate, sodium thiosulfate, somatotropin, sotalol, spectinomycin, spironolactone, stanozolol, streptokinase, streptozocin, succimer, succinylcholine chloride, sucralate sulfate , sulfadiazine / trimethoprim, sulfamethoxazole / trimethoprim, sulfadimentoxine, sulfadimethoxine / ormetoprim, sulfasalazine, taurine, tepoxaline, terbinaflin, terbutaline sulphate, testosterone, tetracycline, sodium tiacetarsine, thiamine, thioquinone, thioquinone, thioquinone, thioquinone, thioquinone , tiletamine / zolazepam, tilmocsin, thiopronine, tobramycin sulfate, tocainide, tolazoline, acid o telphenic, topiramate, tramadol, trimcinolone acetonide, trientine, trilostane, trimepraxin tartrate with prednisolone, tripelinen, tylosin, urdosiol, valproic acid, vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil, vimblastine sulphate, vimcrastine sulfate E / selenium, sodium warfarin, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zinc sulfate / zinc acetate, zonisamide and mixtures thereof.
In an embodiment of the invention, arylpyrazole compounds, such as phenylpyrazoles (for example, fipronyl pyriprole), may be suitable for combination with the dihydroazole compounds of the invention. Examples of such arylpyrazole compounds include, but are not limited to, those described in U.S. Patent Documents No. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954 and 6,998,131, all of which are incorporated herein by reference and each attributed to Merial, Ltd., Duluth, GA.
In another embodiment of the invention, nodulisporic acid and its derivatives (a class of known acaricides, anthelmintics, anti-parasitic agents and insecticides) can be added to the compositions of the present invention. These compounds are used to treat or prevent infections in humans and animals and are described, for example, in US patent documents No. 5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are incorporated herein by reference.
In another embodiment, anthelmintic compounds of the class of amino acetonitrile compounds (DAA) such as monepantel (ZOLVIX) and the like can be added to the compositions of the invention. These compounds are described, for example, in document W02004 / 024704; Sager et al "Veterinary Parasitology", 2009, 159, 49-54; Kaminsky et al, Nature vol. 452, March 13, 2008, 176-181.
In another embodiment, the compositions of the invention can advantageously include one or more isoxazoline compounds having different structures than the compounds of the invention. Various active agents that have an isoxazoline ring system are described in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/024541, WO 2005/085216 and US 2007/0066617 and WO 2008/122375, all of which are incorporated herein by reference in their entirety.
The compositions of the invention can also be combined with paraherquamide compounds and derivatives of these compounds, including derquantel (see Ostlind et al, "Research in Veterinary Science", 1990, 48, 260-61; and Ostlind et al, "Medical and Veterinary Entomology" , 1997, 11, 407-408). The paraherquamide family of compounds is a known class of compounds that include an indole-core spirodioxepine with activity against certain parasites (see Tet Lett 1981, 22, 135; J. Antibiotics 1990, 43, 1380 and J. Antibiotics 1991, 44, 492 ). In addition, the structurally related family of marcfortin, with compounds such as marcfortins AC which are also known and can be combined with the formulations of the invention (see J. Chem Soc. Chem Comm 1980, 601 and Tet Lett. 1981, 22, 1977 ). Further references to paraherquamide derivatives can be found, for example, in WO 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, WO 09/004432, American patents no. US 5,703,078 and US 5,750,695, all of which are incorporated herein by reference in their entirety.
In another embodiment, the compositions of the invention can be combined with cyclodepipeptide anthelmintic compounds, including emodepside (see Willson et al, Parasitology, Jan. 2003, 126 (Pt 1): 79-86).
In some embodiments, the compositions of the invention may include one or more antinematode agents including, but not limited to, active agents of the benzimidazole class, the imidazothiazole class, the tetrahydropyrimidine class or the organophosphate class. In some benzimidazoles, including, but not limited to, thiabendazole, cambendazole, parbendazole, oxybendazole, mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel, thiophanate and their analogue o, dimethyl may be included.
In other embodiments, the compositions may include an imidazothiazole compound including, but not limited to, levamisole, tetramisole and butamisole. In still other embodiments, the compositions of the invention may include tetrahydropyrimidine active agents, including, but not limited to, pyrantel, oxantel, and morantel. Suitable active organophosphate agents include, but are not limited to, coumafos, trichlorfon, haloxon, naphthalophos and dichlorvos.
In other embodiments, the compositions may include anti-nematode compounds, phenothiazine, piperazine as the neutral compound and in various salt forms, diethylcarbamazine, phenols such as disophenol, arsenics such as arsenamide, ethanolamine, such as bephenium, tenio closylate and metyridine; cyanine dyes including pyrvinium chloride, pyrvinium pamoate and dithiazanine iodide; isothiocyanates including bitoscanate, sodium suramin, phthalophine and various natural products, including, but not limited to, hygromycin B, santonin and kainic acid.
In other embodiments, the compositions of the invention can include antitrematodal agents. Suitable antitrematodal agents include, but are not limited to, miracilli such as miracil D and mirasan; praziquantel, clonazepam and its 3-methyl derivative, oltipraz, lucantone, hycantone, oxamniquine, amoscanate, niridazole, nitroxynil, various bisphenol compounds known in the art, including hexachlorophene, bitionol, bitionol sulfoxide and meniclofolan; several salicylanilide compounds, including tribromsalan, oxyclozanide, clioxanide, rafoxanide, brotianide, bromoxanide and closantel; triclabendazole, diamfenetide, clorsulon, hetolin and emetina.
Anticestodal compounds can also be advantageously used in the compositions of the invention, including, but not limited to, arecolines in various forms of salt, bunamidine, niclosamide, nitroscanate, paromomycin and paromomycin II.
In still other embodiments, the compositions of the invention can include other active agents that are effective against arthropod parasites. Suitable active agents include, but are not limited to, bromocyclene, chlordane, DDT, endosulfan, lindane, methoxychloride, toxaphene, bromophos, bromophos-ethyl, carbofenotion, chlorfenvinphos, chlorpyrifos, crotoxifos, citioate, diazinon, diclorention, ethanol, diemtoate, ethanol , famfur, fenitrothiom, fentiom, fospirate, iodofenphos, malation, naled, fosalone, fosmete, foxima, propetanfos, ronnel, stirofos, carbaril, promacil, propoxur, aletrine, cyhalothrin, cypermethrin, deltamethrin, pyrethrin, pyrethrin, pyrethrin, pyretholine, pyrethrin, pyrethrin, pyrethrin, pyrethrin, pyrethrin, pyrethrin, pyrethrin, pyrethrin, pyrethrin, pyrethrin, pyrethyrin, pyrethyrin, pyrethyrin, pyrethyrin, pyrethyrin, pyrethrin, pyrethyrin, pyrethyrin, pyrethyrin, pyrethyrin, pyrethyrin, pyrethyrin, pyridine, pyridine. , resmethrin, amitraz, benzyl benzoate, carbon disulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanate acetate, metroprene, monosulfiram, pyrenonylbutoxide, rotenone, triphenyl acetate, triphenyl hydroxide, and dimethane, dimethane, and dimethane compounds 1,5a, 6,9,9a, 9b-hexahydro-4a (4H) -dibenzofurancarboxaldehyde (MGK-11), 2- (2-ethylhexyl) -3a, 4,7,7a-tetrahydro-4,7- methane-1H-isoindole-1,3 (2H) dione (MGK-264) , dipropyl-2,5-pyridinedicarboxylate (MGK-326) and 2- (octylthium) ethanol (MGK-874).
In another embodiment of the invention, one or more macrocyclic lactones, which act as an acaricide, anthelmintic and insecticide, can be added to the compositions of the invention. Macrocyclic lactones also include, but are not limited to, avermectins, such as abamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin, and milbemycines, such as milbemectin, milbectin D, moxin and midinectin, midinine and moxin. Also included are derivatives of 5-oxo and 5-oxime and of said avermectins and milbemycins. Examples of combinations of macrocyclic lactones with other active agents are described in U.S. Patent Documents No. 6,426,333; 6,482,425; 6,962,713 and 6,998,131, all attributed to Merial, Ltd., Duluth, GA, all incorporated herein by reference.
Macrocyclic lactone compounds are known in the art and can be obtained commercially or through synthetic techniques known in the art. Reference is made to the widely available and commercial technical literature.
For avermectins, ivermectin, and abamectin, reference can be made, for example, to the work "Ivermectin and Abamectin", 1989, by MH Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag, "Macrocyclic Lactones in Antiparasitic Therapy ", 2002, by J Vercruysse and RS Rew, published by CABI Publishing or Albers-Schonberg et al. (1981), "Avermectins Strcuture Determination", J. Am. Chem. Soc, 103, 4216-4221. For doramectin, "Veterinary Parasitology", vol. 49, No. 1, July 1993, 5-15, can be consulted. For milbemycins, reference may be made, inter alia, to Davies HG et al, 1986, "Avermectins and Milbemycins", Nat. Prod. Rep., 3, 87-121, Mrozik H. et al, 1983, "Synthesis of Milbemycins and Avermectins", Tetrahedron Lett., 24, 5333-5336, US patent documents 4,134,973 and EP 0 677 054.
Macrocyclic lactones are both natural products and semi-synthetic derivatives. The structures of avermectins and milbemycins are closely related, for example, by sharing a complex 16-member macrocyclic lactone ring; milbemycins lack the glycosidic portion of avermectins. Natural avermectin products are disclosed in U.S. Patent Documents No. 4,310,519 to Albers-Schonberg et al., And 22,23-dihydro avermectin compounds are disclosed in Chabala et al, US patent document. US No. 4,199,569. Mention is also made of Kitano, US patent document No. 4,468,390, Beuvry et al., US patent document No. 5,824,653, EP 0 007 812 Al, UK patent document 1 390 336, EP 0 002 916, and NZ patent document No. 237 086, inter alia. Naturally occurring milbemycins are described in Aoki et al, US patent document No. 3,950,360, as well as in the various references cited in "The Merck Index" 12th ed., S. Budavari, ed., Merck and Co., Inc. Whitehouse Station, New Jersey (1996). Latidectin is described in "International Nonproprietary Names for Pharmaceuticals substances (INN)", WHO Drug Information, vol. 17, n. 4, pp 263-286, (2003). Semi-synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in: US patent document No. 5,077,308, US patent document No. 4,859,657, patent document US Patent No. 4,963,582, US Patent Document No. 4,855,317, US Patent Document No. 4,871,719, US Patent Document No. 4,874,749, US patent document No. 4,427,663, US patent document US No. 4,310,519, US patent document US No. 4,199,569, US patent document US No. 5,055,596, US patent document US No. 4,973,711, US patent document US No. 4,978,677, US patent document No. 4,920,148 and EP 0 667 054.
In another embodiment of the invention, the class of acaricides or insecticides known as insect growth regulators (IGRs) can also be added to the compositions of the invention. The compounds belonging to this group are well known in the art and represent a wide range of different chemical classes. These compounds all act by interfering in the development or growth of insect pests. Insect growth regulators are described, for example, US patent document US American US American US American US No. 3,748,356; No. 3,818,047; No. 4,225,598; No. 4,798,837; US Patent Document Document North Patent Document North Patent US Patent No. 4,751,225, EP 0 179 022 or UK Patent Document 2 140 010 as well as in US Patent Documents No. 6,096,329 and 6,685,954 (all of which are incorporated by reference). Examples of suitable IGRs for use include, but are not limited to, methoprene, pyriproxyphene, hydroprene, cyromazine, fluazuron, lufenuron, novaluron, pyrethroids, formamidines and 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- (trifluoromethyl) phenylurea.
An insecticidal agent that can be combined with the compound of the invention to form a composition can be a spinosyn (e.g., spinosad) or a substituted pyridylmethyl derivative compound, such as imidacloprid. Agents of this class are described above, and, for example, in U.S. Patent Document No. 4,742,060 or EP 0 892 060, both of which are incorporated herein by reference. It is a common skill for a person skilled in the art to decide which individual compound can be used in the inventive formulation to treat a particular parasitic infection / infestation. For ectoparasites, active agents that can be combined also include, but are not limited to, pyrethroids, organophosphates and neonicotinoids, such as imidacloprid, as well as compounds such as metaflumizone, amitraz, and ryanodine receptor antagonists.
If necessary, the anthelmintic, parasiticidal and insecticidal agent can also be selected from the group of compounds described above as being suitable for agrochemical use.
In general, the additional active agent is included in a dose of between about 0.1 pg and about 1000 mg. More typically, the additional active agent can be included in a dose of about 10 pg to about 500 mg, about 1 mg to about 300 mg, about 10 mg to about 200 mg, or about 10 mg to about 100 mg. In an embodiment of the invention, the additional active agent is included in a dose between about 1 pg and about 10 mg.
In other embodiments of the invention, the additional active agent can be included in a dose of about 5 pg / kg to about 50 mg / kg by weight of the animal. In other embodiments, the additional active agent may be present at a dose of about 0.01 mg / kg to about 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg or about 0, 1 mg / kg to about 10 mg / kg of animal weight. In other embodiments, the additional active agent can be present at a dose of about 5 pg / kg to about 200 pg / kg or about 0.1 mg / kg to about 1 mg / kg of the animal's weight. In yet another embodiment of the invention, the additional active agent is included in a dose ranging from about 0.5 mg / kg to about 50 mg / kg.
The proportions, by weight, of the dihydroazole compound and the additional active agent are, for example, between about 5/1 and about 10,000 / 1. However, a person skilled in the art would be able to select the appropriate proportion of dihydroazole compound and additional active agent for the intended host and for its use.
Another aspect of the invention is the process for making the dihydroazole compounds of the invention.
The compounds of formula (I) can be prepared according to the processes described herein or by applying or adapting known methods (i.e., methods hitherto used or described in the chemical literature).
The present invention will now be described further by means of the following non-limiting examples. EXAMPLES
All temperatures are given in degrees Centigrade; room temperature means 20 ° C to 25 ° C. The reagents were purchased from commercial sources or prepared according to literature procedures. DCM = dichloromethane THE = tetrahydrofuran MeOH = methanol EtOH = ethanol EA = ethyl acetate DMF = dimethylformamide DMA = dimethylacetamide DMFDMA = dimethylformamide dimethyl acetal AcOH = acetic acid TFA = trifluoroacetic acid TEA = triethylamine resin DIEA = diisopropylethylamine DIEA = diisopropylamine and fluorine (respectively 1H NMR and 19F NMR) were recorded on a Varian Inova NMR spectrometer [400 MHz (1H) or 500 MHz (1H) and 377 MHz (19F)]. All spectra were determined on the indicated solvents. The chemical shifts are shown in low field, ppm, of tetramethylsilane (TMS), referenced with the residual proton peak of the respective solvent peak in 1H NMR. Interproton coupling constants are reported in Hertz (Hz). LC-MS spectra were obtained using two different systems. For LCMS of method 1, LC-MS spectra were obtained using an Agilent 1200SL HPLC equipped with a 6130 operating mass spectrometer with electrospray ionization; chromatographic data were obtained using a Shimadzu Shim-pack XR-ODS, 3.0 x 30 mm, column with particle size of 2.2 microns and a gradient of 15% methanol to 95% methanol in 2.2 minutes under a flow of 1.5 ml / min; a 95% methanol retention was applied at the end of the gradient for 0.8 minutes; and both the mobile phases of water and methanol contained 0.1% formic acid. For the LCMS of method 2, LCMS spectra were obtained using a Waters ACQUITY UPLC ™ equipped with a Thermofinnigan ™ AQA operational mass spectrometer with electrospray ionization; chromatographic data were obtained using a Supelco® Analytical Ascentis® Express, 2.1 x 50 mm, column particle size of 2.7 microns (Cie) θ a water: acetonitrile gradient of 5% acetonitrile to 100% acetonitrile at 0 , 8 minutes under a flow of 1.5 ml / min; a 100% methanol retention was applied at the end of the gradient for 0.05 minutes; and mobile water phase was buffered with ammonium acetate (10 mmolar) and 0.1% v / v acetic acid. When LCMS retention times are reported as RT, LCMS method 1 or 2 is then specified. When the semi-preparative HPLC was performed to purify the reaction mixture, a modified Gilson HPLC system was used with the regeneration turned off; chromatographic data were obtained using a Varian Pursuit ™ XRS column, 21.4 x 50 mm, a 10 micron particle size column (C18) and a water: methanol gradient from 40% methanol to 100% methanol in 5 minutes, under a flow rate of 28 mL / min; wherein the mobile phase of water was buffered with ammonium acetate (10 mmolar) and 0.1% v / v ammonium hydroxide.
Compound No. 1.008, from Example 1, was prepared according to the following general reaction scheme 4: Scheme 4:
according to a general reaction scheme similar to the above, except that 1,3-dichloro-5- (1-trifluoromethylvinyl) -benzene was used in the cycloaddition step [3 + 2] instead of 1,3-bistrifluoromethyl-5- (1-trifluoromethylvinyl) -benzene and / or 2-methylthioethylamine was used in the last step of amide coupling instead of 2-amino-ΔZ- (2,2,2-trifluoroethyl) -acetamide.
In addition, it will be apparent to one skilled in the art that the synthetic sequence described in Scheme 4 can be used to prepare additional compounds with different substitution patterns using alternative styrene derivatives having the desired substitution pattern and alternative amines or alcohols in the last step.
EXAMPLE 1.5- [5- (3,5-bistrifluoromethylphenyl) 5- trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indozilin-8-carboxylic acid [(2,2,2-trifluoroethylcarbamoyl) methyl] -amide (compound No 1,008) 5- [5- (3,5-bistrifluoromethylphenyl) 5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indoziline-8-carboxylic acid (50 mg), 1-ethyl- (3-dimethylaminopropyl) carbodiimide (EDAG.HC1, 22.5 mg), 1-hydroxybenzotriazole monohydrate (HOBt.H2O, 20 mg) and N-methylmorpholine (22 pl) were stirred in a mixture of DMF-DCM (1/2, 1 ml) for 20 minutes at room temperature before the addition of 2-amino-2V- (2,2,2-trifluoroethyl) -acetamide (50 mg, Ukrorgsinthesis Ltd. Kiev, Ukraine). The reaction mixture was stirred overnight at room temperature. The mixture was diluted with water and EA. The organic layer was collected, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (Si02, DCM / MeOH) to give the title compound as an orange-solid. reddish (11.1 mg, 17%). MS (ES): M / Z [M + H] = 649. 1H NMR (400 MHz, chloroform-d): 3.88-4.04 (m, 3H), 4.33 (d, J = 5.3 Hz, 2H), 4.39 (d, J = 16, 6 Hz, 1H), 6.84 (d, J = 7.4 Hz, 1H), 7.05-7.08 (m, 1H), 7.08-7.21 (m 3H), 7.33 (t, J = 4.9 Hz, 1H), 8.01 (s, 1H), 8.13 (s, 2H), 8.72 (d, J = 1.8 Hz, 1H). 19F NMR (376 MHz, chloroform-d): -80.0 (s, 3F), -72.9 (t, J = 9.2 Hz, 3F), -63.3 (s, 6F). The starting material, 5- [5- (3,5-bistrifluoromethylphenyl) 5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indoziline-8-carboxylic acid, was prepared as follows: a. Oxalyl chloride (9.3 ml) was added to a solution of 2-chloro-6-methyl nicotinic acid (9 g) in DCM (500 ml). After stirring for 30 minutes, the mixture was concentrated under reduced pressure to give a residue which was treated with MeOH (500 ml) at 0 ° C. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue that was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-6-methyl-nicotinic acid methyl ester (9.7 g, 99%). 1H NMR (400 MHz, chloroform-d): 2.60 (s, 3H), 3.95 (s, 3H), 7.17 (d, J = 7.8 Hz, 1H), 8.09 (d , J = 7.8 Hz, 1H). B. A mixture of 2-chloro-6-methyl-nicotinic acid methyl ester (2 g) in DMF (10 ml) and DMFDMA (3 ml) was heated to 110 ° C for 16 hours before adding more DMFDMA (1 ml). After 3 hours at 110 ° C, the mixture was cooled to room temperature, diluted with water and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane / EA / MeOH) to give 2-chloro-6- ester (-2-dimethylaminovinyl) - methyl nicotinic acid (1.2 g, 46%). 1H NMR (400 MHz, chloroform-d): 2.96 (s, 6H), 3.87 (s, 3H), 5.09 (d, J = 12.9 Hz, 1H), 6.71 (d , J = 8.4 Hz, 1H), 7.68 (d, J = 12.9 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H). ç. Sodium periodate (2.14 g) was added to a solution of 2-chloro-6 ester - (- 2-dimethylaminovinyl) - methyl nicotinic acid (1.2 g) in a mixture of THF (40 mL) and water (10 mL). After one hour of stirring at room temperature, the mixture was chelated with an aqueous solution of sodium thiosulfate and filtered through a plug of Celite®. The filtrate was diluted with more water and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-6-formyl-methyl nicotinic acid ester (1.02 g) which was used without further purification in next step. d. A 50% solution of hydroxylamine in water (1 ml) was added to a solution of 2-chloro-6-formyl-methyl nicotinic ester in a mixture of THF (40 ml) and water (10 ml). After one hour at room temperature, the reaction was chelated with an aqueous solution of sodium thiosulfate and extracted three times with EA. The organic layer was collected, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2-chloro-6- (hydroxyiminomethyl) methyl nicotinic acid as a solid residue (1 g) which was used without further purification in the next step. and. N-chlorosuccinimide (667 mg) was added to a solution of 2-chloro-6- (hydroxyiminomethyl) methyl nicotinic acid in DMF (5 ml) and the mixture was heated at 40 ° C for 20 minutes. The mixture was cooled to about 0 ° C (ice bath) and then 1,3-bistrifluoromethyl-5- (1-trifluoromethylvinyl) -benzene (2 g, prepared from commercially available reagent 2-bromo-3, 3,3- trifluoropropene and 3,5-bistrifluoromethylphenylboronic acid by the method described in. J. Fluorine Chem. 1999, 95, 167- 170) and TEA (0.75 mL) were added and the mixture was stirred at room temperature during night. The mixture was diluted with water and extracted three times with EA. The organic layer was collected, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane / EA) to give 6- [5- (3, 5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-chloro-methyl nicotinic acid (500 mg, 22% over 3 steps). MS (ES): M / Z [M + H] = 521. RT = 2.24 min (LCMS method 1). f. 6- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-chloro-nicotinic methyl ester (490 mg), tributyl (1-propyl)-tin ( 426 mg) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (39.5 mg) in toluene (10 ml) were stirred heated to 90 ° C overnight. The mixture was allowed to cool to room temperature and then stirred with a saturated aqueous solution of potassium fluoride. The mixture was extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered through a plug of Celite® and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane / EA) to give 6- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-prop-1-ynyl-methyl ester of nicotinic acid (360 mg, 64%). 1HRMN (400 MHz, chloroform-d): 2.21 (s, 3H), 3.87-4.04 (m, 4H), 4.43 (d, J = 18.4 Hz, 1H), 7, 97 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 8.08 (s, 2H), 8.26 (d, J = 8.4 Hz, 1H). 19FRMN (376 MHz, chloroform-d): -80.2 (s, 3F), -63.3 (s, 6F). g. 6- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2-prop-1-ynyl-methyl ester of nicotinic acid (250 mg), copper (I) chloride (35 mg), TEA (0.3 ml) in DMA (3 ml) was stirred heated to 130 ° C overnight. The mixture was cooled to room temperature and diluted with water. The mixture was extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (Si02, heptane / EA) to give 5- [5] methyl acid ester - (3,5-bis-trifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indolizine-8-carboxylic, as a reddish-orange solid (54 mg). MS (ES): M / Z [M + H] = 525. RT = 2.35 min (LCMS method 1). H. 5- [5- (3,5-bis-trifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indolizine-8-carboxylic acid methyl ester (94.5 mg) and lithium hydroxide ( 16 mg) were stirred in a 4 to 1 THF / water (4 ml) mixture at room temperature for 6 hours before diluting with more water. The mixture was acidified to a pH of about 3 with a 10% aqueous hydrochloric acid solution and extracted with EA. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a reddish-orange residue (88 mg) used directly in the next amide coupling step.
EXAMPLE 2 .5- [5- (3,5-Bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dioisoxazol-3-yl] - indolizine-8-carboxylic acid (2-methylthioethyl) -amide (compound No. 1,009) Using a procedure similar to that described in Example 1, except that 2-methylthioethylamine was used, the title compound was isolated as an orange-red solid (10.1 mg, 23%). MS (ES): M / Z [M + H] = 584. 1H NMR (400 MHz, chloroform-d): 2.18 (s, 3H), 2.83 (t, J = 6.2 Hz, 2H), 3.76 (q, J = 6.0 Hz, 2H ), 3.98 (d, J = 16.6 Hz, 1H), 4.41 (d, J = 16.6 Hz, 1H), 6.79 (t, J = 4.8 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 7.05-7.11 (m, 1H), 7.13 (d, J = 3.1 Hz, 1H), 7.20 (d , J = 7.4 Hz, 1H), 8.00 (s, 1H), 8.13 (s, 2 H), 8.75 (d, J = 1.6 Hz, 1H). 19F NMR (376 MHz, chloroform-d): -80.0 (s, 3F), -63.3 (s, 6F).
EXAMPLE 3. 5- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] - indolizine-8-carboxylic acid [(2,2,2-trifluoroethylcarbamoyl) methyl] - amide (compound No 1,011)
Using a procedure similar to that described in Example 1, except that 5— [5— (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indolizine-8- carboxylic (73 mg), the title compound was isolated as an orange-red solid (25.2 mg, 26%>). MS (ES): M / Z [M + H] = 581. 1H NMR (400 MHz, chloroform-d): 3.80-4.01 (m, 3H), 4.24 (d, J = 16.6 Hz, 1H), 4.29 (d, J = 5, 1 Hz, 2H), 6.77 (d, J = 7.4 Hz, 1H), 6, 97-7.05 (m, 1H), 7.09 (d, J = 3.3 Hz, 1H) , 7.12 (d, J = 7.4 Hz, 1H), 7.22 (br. S, 1H), 7.34. (t, J = 5.0 Hz, 1H), 7.43 (t, J = 1.6 Hz, 1H), 7.52 (s, 2H), 8.69 (d, J = 1.8 Hz , 1H). 19F NMR (376 MHz, chloroform-d): -79.8 (s, 3F), -72.8 (s, 6F).
The starting material, 5- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indolizine-8-carboxylic acid, was prepared using a procedure similar to that described in the Example 1, except that it was used in Part 'e' 1,3-dichloro-5- (1-trifluoromethylvinyl) -benzene (prepared from 2-bromo-3,3,3-trifluoropropene and 3,5 acid - commercially available dichlorophenylboronic).
EXAMPLE 4. 5- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indolizine-8-carboxylic acid (2-methylthioethyl) -amide (compound No 1,013)
Using a procedure similar to that described in Example 1, except that 5— [5— (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -indolizine-8- was used carboxylic (37 mg, described above in Example 3) and 2-methylthioethylamine, the title compound was isolated as an orange-red solid (21.2 mg, 49%). MS (ES): M / Z '[M + H] = 516. 1H NMR (400 MHz, chloroform-d): 2.17 (s, 3H), 2.83 (t, J = 6.2 Hz, 2H), 3.75 (q, J = 6.0 Hz, 2H ), 3.91 (d, J = 16.6 Hz, IH), 4.28 (d, J = 16.6 Hz, IH), 6.83 (d, J = 7.4 Hz, IH), 7.02-7.08 (m, IH), 7.17 (d, J = 7.2 Hz, IH), 7.46 (t, J = 1.7 Hz, IH), 7.55 (s , 2 H), 8.73 (d, J = 1.6 Hz, IH). 19F NMR (376 MHz, chloroform-d): -79.8 (s, 3F).
Compound No. 1.006 of Example 5 was prepared according to the following general reaction scheme 5: Scheme 5
except for the fact that 2-methylthioethylamine was used 5 in the last amide coupling step, instead of 2-amino-N- (2,2,2-trifluoroethyl) acetamide.
Furthermore, it will be apparent to one skilled in the art that the synthetic sequence depicted in Scheme 5 can be used to prepare additional compounds that have different substituents using alternative styrene derivatives that have the desired substitution pattern and alternative amines or alcohols to obtain the desired amide or ester in the last step.
EXAMPLE 5 .5- [5- (3,5-Bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo [1,2-a] pyridine-8-carboxylic acid [(2,2 , 2-trifluoroethylcarbamoyl) methyl] -amide (compound No 1.006) Using a procedure similar to that described in Example 1, except using 5- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazole -3-yl] imidazo [1,2-a] pyridine-8-carboxylic acid (45 mg), the title compound was isolated as an orange-red solid (13.1 mg, 23%). MS (ES): M / Z [M + H] = 650. 1H NMR (400 MHz, chloroform-d): 3.85- 4.08 (m, 3H), 4.33 (d, J = 6.1 Hz, 2H), 4.44 (d, J = 16, 8 Hz, 1H), 6, 86-7.04 (m, 1H), 7.22 (d, J = 7, 6 Hz, 1H), 7.87 (d, J = 1.0 Hz, 1H) , 8.02 (s, 1H), 8.12 (s, 2H), 8.26 (d, J = 7.6 Hz, 1H), 8.92 (d, J = 1.0 Hz, 1H) , 10.85-11.06 (m, 1H). 19F NMR (376 MHz, chloroform-d): -80.1 (s, 3F), -72.9 (t, J = 9.2 Hz, 3F), -63.3 (s, 6F).
The starting material, 5— [5— (3,5— bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] imidazo [1,2-a] pyridine-8-carboxylic acid, was prepared as follows: a. Oxalyl chloride (11.1 ml) was added to a solution of 2,6-dichloronicotinic acid (8g) in a mixture of DCM (300 ml) and DMF (0.2 ml). After stirring for 2 hours, the mixture was concentrated under reduced pressure to give a residue which was treated with MeOH (300 ml) at 0 ° C. The mixture was stirred at room temperature and then was concentrated under reduced pressure to give a residue that was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the 2,6-dichloronicotinic acid methyl ester (8 g, 93%). IH NMR (400 MHz, chloroform-d): 3.96 (s, 3H), 7.36 (d, J = 8.2 Hz, IH), 8.16 (d, J = 8.0 Hz, IH ). B. A concentrated ammonium hydroxide solution (2 ml) was added to a solution of 2-chloro-6-methyl-nicotinic acid methyl ester (2 g) in 1,4-dioxane (2 ml). The mixture in 10 ml of microwave Pyrex tube was sealed and heated to 100 ° C for 20 minutes, using a Discover CEM microwave unit (CEM, Matthews, NC, USA). This reaction was established three more times using exactly the same conditions. The 4 reaction mixtures were combined and concentrated under reduced pressure to give a residue that was diluted with water and extracted three times with EA.
The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (Si02, heptane / EA) to give the methyl ester of 2-amino acid 6-chloro-nicotinic (3.44 g, 47%). 1H NMR (400 MHz, chloroform-d): 3.89 (s, 3H), 6.63 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H ).
The 2-amino-6-chloro-nicotinic acid methyl ester (3.44 g) was combined with tributyl (vinyl) tin (5.4 mL) and tetrakis (triphenylphosphine) palladium (0) (6.5 g) in xylene (200 mL) and were stirred and heated to 130 ° C. After 1.5 hours, the mixture was allowed to cool to room temperature and then stirred with a saturated aqueous solution of potassium fluoride for 1.5 hours and filtered through a plug of Celite®. The filtrate was extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give nicotinic acid 2-amino-6-vinyl-methyl ester (1.7 g, 52%). 1H NMR (400 MHz, chloroform-d): 3.89 (s, 3H), 5.54 (dd, J = 10.6, 0.9 Hz, 1H), 6.27 (d, J = 17, 4 Hz, 1H), 6.46 (br., 2H), 6.59-6.74 (m, 2H), 8.10 (d, J = 8.0 Hz, 1H). Methyl ester 2-amino-6-vinyl-nicotinic acid (1.7 g), di-tert-butyl-dicarbonate (8.3 g) and 4-dimethylaminopyridine (1.4 g) in DCM (100 mL) were heated to 40 ° C overnight. The mixture was concentrated under reduced pressure to give a residue which was purified by chromatography (SiO2, heptane / EE / MeOH) to give nicotinic acid 2-bis (tert-butoxycarbonyl) amino-6-vinyl-methyl ester (2.85 g, 79%). 1H NMR (400 MHz, chloroform-d): 1.40 (s, 18H), 3.90 (s, 3H), 5.63 (d, J = 10.9 Hz, 1H), 6.33 (d , J = 17.4 Hz, 1H), 6.83 (dd, J = 17.4, 10.7 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H). 2-bis (tert-butoxycarbonyl) amino-6-vinyl-methyl ester of nicotinic acid (2.85 g) dissolved in a mixture of DCM (75 ml) and methanol (25 ml) was treated with ozone gas for 10 minutes . After stirring for 15 minutes at -78 ° C, the mixture was purged with oxygen and 20 minutes with nitrogen and then chelated with dimethyl sulfide (0.5 mL) followed by a 10% sodium thiosulfate solution (10 mL) and diluted with DCM. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give nicotinic acid 2-bis (tert-butoxycarbonyl) amino-6-formyl-methyl ester which was used without further purification in the next step. 1H NMR (400 MHz, chloroform-d): 1.42 (s, 18H), 3.95 (s, 3H), 8.01 (d, J = 7.8 Hz, 1H), 8.52 (d , J = 7.8 Hz, 1H), 10.07 (s, 1H). f. A 50% solution of hydroxylamine in water (1.5 ml) was added to a solution of 2-bis (tert-butoxycarbonyl) amino-6-formyl-methyl ester of nicotinic acid in EtOH (50 ml). After one hour at room temperature, the reaction was diluted with water and concentrated under reduced pressure to remove EtOH. The residual mixture was extracted three times with EA. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2-bis (tert-butoxycarbonyl) amino-6- (hydroxyiminomethyl) - nicotinic acid methyl ester as a solid residue ( 2.77 g, 93% in two steps). 1H NMR (400 MHz, chloroform- d): 1.40 (s, 18H), 3.92 (s, 3H), 7.87 (d, J = 8.2 Hz, 1H), 8.22 (s , 1H), 8.37 (d, J = 8.0 Hz, 2H). g. 2 7-chlorosuccinimide (0.94 g) was added to a solution of 2-bis (tert-butoxycarbonyl) amino-6- (hydroxyiminomethyl) methyl nicotinic acid ester (2.77 g) in DMF (10 mL) and the mixture was heated to 40 ° C for 2 hours. The mixture was cooled to about 0 ° C (ice bath) and then 1,3-bistrifluoromethyl-5- (1-trifluoromethylvinyl) -benzene (2.8 g described in Example 1) and TEA (1.05 ml ) were added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted three times with EA. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (Si02, heptane / EA) to give 6- [5- (3.5 - bistrifluoromethyl-phenyl) -5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -2-bis (tert-butoxycarbonyl) amino-nicotinic acid methyl ester (2.14 g, 43%). 1H NMR (400 MHz, chloroform-d): 1.43 (s, 18H), 3.93 (d, J = 18.0 Hz, IH), 3.93 (s, 3H), 4.33 (d , J = 18.2 Hz, 1 H), 7.98 (s, IH), 8.04-8.13 (m, 3H), 8.44 (d, J = 8.0 Hz, IH). 19F NMR (376 MHz, chloroform-d): -80.2 (s, 3F), -63.3 (s, 6F). H. TFA (5 mL) was added to a solution of 6— [5— (3,5-bistrifluoromethyl-phenyl) -5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -2-bis (tert-butoxycarbonyl ) -amino-methyl ester of nicotinic acid (2.14 g) in DCM (40 ml). After stirring overnight at room temperature, the mixture was chelated with a saturated aqueous solution of sodium bicarbonate and extracted three times with DCM. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-amino-6- [5- (3,5-bistrifluoromethyl-phenyl) -5-trifluoromethyl-4, Nicotinic acid 5-dihydro-isoxazol-3-yl] -ester (1.12 g, 73%) as a solid. 1H NMR (400 MHz, chloroform-d): 3.84 (d, J = 18.2 Hz, IH), 3.91 (s, 3H), 4.30 (d, J = 18.4 Hz, IH ), 6.44 (br. S, 2H), 7.34 (d, J = 8.0 Hz, IH), 7.97 (s, IH), 8.08 (s, 2H), 8.19 (d, J = 8.0 Hz, IH). 19F NMR (376 MHz, chloroform-d): -80.1 (s, 3F), -63.3 (s, 6F). i. 2-amino-6- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -methyl ester of nicotinic acid (200 mg) and a 50% aqueous solution chloroacetaldehyde (0.4 ml) in isopropanol (2 ml) were stirred at 50 ° C over the weekend. The mixture was cooled to room temperature and diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, DCM / MeOH) to give 5- [5- (3.5 -bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo [1,2-a] pyridine-8-carboxylic acid methyl ester as a solid (200 mg). j. 5- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo [1,2-a] pyridine-8-carboxylic acid methyl ester, (200 mg) and lithium hydroxide (45 mg) were stirred in a mixture of 4 to 1 THF / water (2 ml) at room temperature for 20 minutes before diluting with more water. The mixture was acidified to a pH of about 3 with a 10% aqueous hydrochloric acid solution and extracted with EA. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue used directly in the next amide coupling step.
EXAMPLE 6. 5- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo [1,2— a] pyridine-8-carboxylic acid (2-methylthioethyl) -amide (compound No 1.007) Using a procedure similar to that described in Example 1, except that 5- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazole-3- was used yl] -imidazo [1,2-a] pyridine-8-carboxylic (45 mg) and 2-methylthioethylamine (0.016 ml), the title compound was isolated as an orange-red solid (11.9 mg, 23%) MS (ES): M / Z [M + H] = 585. 1H NMR (400 MHz, chloroform- d): 2.22 (s, 3 H), 2.85 (t, J = 6.8 Hz, 2 H), 3.82 (q, J = 6, 6 Hz , 2 H), 4.01 (d, J = 17.0 Hz, IH), 4.44 (d, J = 16.8 Hz, 1 H), 7.21 (d, J = 7.6 Hz , 1H), 7.85 (s, 1H), 8.02 (s, 1 H), 5 8.12 (s, 2H), 8.28 (d, J = 7.6 Hz, 1H), 8 , 90 (d, J = 1.0 Hz, 1H), 10.67 (broad s, 1H). 19F NMR (376 MHz, chloroform-d): -80.0 (s, 3F), -63.3 (s, 6F). Compound No. 2.004 of Example 7 was prepared according to the following general reaction scheme 6: Scheme 6

It will be apparent to a person skilled in the synthetic sequence described in Scheme 6, to prepare additional compounds having different 5 substituents, using the appropriate reagents. For example, compounds having different substituents on the phenyl ring can be prepared using an alternative styrene derivative having the desired substitution pattern. In addition, it will be apparent that a variety of amines or alcohols can be used to obtain the desired amide or ester in the last step.
EXAMPLE 7 .8- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo [1,2-a] pyridine-5-carboxylic acid [(2,2 , 2-trifluoroethylcarbamoyl) methyl] -amide (compound No 2.004) Using a procedure similar to that described in Example 1, except that 8- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4, 5-dihydroisoxazol-3-yl] -imidazo [1,2-a] pyridine-5-carboxylic acid, the title compound was isolated as a solid (2.9 mg). MS (ES): M / Z [M + H] = 650. IH NMR (400 MHz, chloroform-d): 3.91 - 4.07 (m, 2H), 4.27 (d, J = 4.9 Hz, 2H), 4.33 - 4.47 (m, IH), 4.76-4.89 (m, 1H), 6, 20-6, 38 (m, IH), 7.10-7.22 (m, IH), 7.30-7.40 ( m, IH), 7.77 (s, IH), 7.84 - 7.92 (m, IH), 7.97 (s, 1H), 8.15 (s, 2H), 8.62 (s , IH). 19F NMR (376 MHz, chloroform-d): -80.1 (s, 3F), -72.9 (m, 3F), -63.3 (s, 6F).
The starting material, 8- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo [1,2-a] pyridine-5-carboxylic acid, was prepared as follows: a. Sulfuric acid was added to a solution of β-aminopyridine-2-carboxylic acid (10 g) in methanol (300 ml) and the mixture was heated to reflux overnight. The mixture was cooled to room temperature and then concentrated under reduced pressure to give a residue which was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-aminopyridine-2-carboxylic acid methyl ester (8.5 g, 77%). MS (ES): M / Z [M + H] = 153. 1HRMN (400 MHz, chloroform-d): 3.96 (s, 3H), 4.77 (br. S., 2H), 6.67 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 7.0 Hz, 1H) and 7.55 (t, J = 7.7 Hz, 1H). B. A solution of bromine (2.57 ml) in chloroform (40 ml) was slowly added over 30 minutes to a solution of 6-aminopyridine-2-carboxylic acid methyl ester (6.92 g) in chloroform (300 ml ). The mixture was stirred overnight at room temperature and then loaded onto silica and purified by chromatography (SiO2, heptane / EA) to give 6-amino-5-bromopyridine-2-carboxylic acid methyl ester as a solid (2 g, 19%) together with 6-amino-3-bromopyridine-2-carboxylic acid methyl ester (3 g, 29%) and β-amino-3,5-dibromopyridine-2-carboxylic acid methyl ester (2.6 g , 18%). IH NMR (400 MHz, chloroform-d): 3.97 (s, 3H), 5.22 (br. S., 2H), 7.38 (d, J = 7.8 Hz, IH) and 7, 79 (d, J = 7.8 Hz, IH). ç. 6-Amino-5-bromopyridine-2-carboxylic acid methyl ester (2 g) and a 50% aqueous solution of chloroacetaldehyde (2.8 ml) in isopropanol (100 ml) were stirred under heating at 70 ° C during night. More than 50% of the aqueous chloroacetaldehyde solution (0.35 ml) was added at room temperature and the mixture was stirred under heating at 80 ° C for an additional 3 hours. The mixture was cooled to room temperature, loaded onto silica and purified by chromatography (SiO2, heptane / EA) to give 8-bromoimidid [1,2-a] pyridine-5-carboxylic acid methyl ester as a solid ( 2.3 g). MS (ES): M / Z [M + H] = 255. IH NMR (400 MHz, chloroform-d): 4.00 (s, 3H), 7.51 (d, J = 7.6 Hz, IH), 7.63 (d, J = 7.8 Hz, IH ), 7.82 (s, IH), and 8.90 (s, IH). d. 8-Bromo-imidazo [1,2- a] pyridine-5-carboxylic acid methyl ester (2.03 g), tributyl (vinyl) tin (2.7 mL) and 1'-bis (diphenylphosphine) ferrocene-palladium (II) dichloride (323 mg) in toluene (100 ml) were stirred under heating at 70 ° C overnight. More room temperature and the mixture was stirred heated to 90 ° C overnight. The mixture was allowed to cool to room temperature and then stirred with a saturated aqueous solution of potassium fluoride for 1.5 hours and filtered through a plug of Celite®. The filtrate was extracted three times with EA. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane / EA) to give 8-vinyl imidazo acid methyl ester [1,2-a] pyridine-5-carboxylic (753 mg, 42%). IH NMR (400 MHz, chloroform-d): 4.02 (s, 3H), 5.75 (d, J = 11, 3 Hz, IH), 6.58 (d, J = 17.6 Hz, IH ), 7.28-7.38 (m, 2H), 7.71-7.85 (m, 2H) and 8.89 (s, 1H). and. Sodium periodate (216 mg) was added to a solution of 8-vinyl-imidazo [1,2- a] pyridine-5-carboxylic acid methyl ester (98 mg) in a mixture of THE (4 mL) and water (1 mL). After stirring at room temperature, an aqueous osmium tetroxide solution (4%) was added and the mixture allowed to stir for 4 hours. The mixture was then neutralized with an aqueous solution of sodium thiosulfate and filtered through a plug of Celite®. The filtrate was diluted with more water and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 8-formyl-imidazo [1,2-a] pyridine-5-carboxylic acid methyl ester (1, 02 g) that was used without further purification in the next step. f. A 50% solution of hydroxylamine in water (1.5 mL) was added to a solution of 8-formyl-imidazo [1,2-a] pyridine-5-carboxylic acid methyl ester (0.29 mmol) in EtOH (3 mL). After one hour at room temperature, the reaction was diluted with water and concentrated under reduced pressure to remove EtOH. The residual mixture was extracted three times with EA. The organic layers were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (Si02, heptane / EA) to give the 8- (hydroxyimino acid) methyl ester -methyl) -imidazo [1,2-a] pyridine-5-carboxylic acid, as a solid residue (12 mg). g. N-chlorosuccinimide (16.2 mg) was added to a solution of 8- (hydroxyimino-methyl) -imidazo [1,2-a] pyridine-5-carboxylic acid methyl ester (12 mg) in DMF (0.5 ml) and the mixture was heated to 40 ° C for 20 minutes. The mixture was cooled to about 0 ° C (ice bath) and then 1,3-bistrifluoromethyl-5- (1-trifluoromethylvinyl) benzene (22 mg described in Example 1) and TEA (15 pl) were added and the mixture was stirred at room temperature. The mixture was purified by chromatography (SiO2, heptane / EA) to give 8- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo acid methyl ester [1 , 2-a] pyridine-5-carboxylic (11 mg, 39%). MS (ES): M / Z [M + H] = 526. 19F NMR (376 MHz, chloroform-d): -80.2 (s, 3F) and -63.3 (s, 6F). H. 8- [5- (3,5-bistrifluoromethylphenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -imidazo [1,2-a] pyridine-5-carboxylic acid methyl ester (9 mg) and lithium hydroxide (3 mg) was stirred in a 5: 1 THF / water (0.6 ml) mixture at room temperature for 30 minutes before diluting with more water. The mixture was acidified to a pH of about 3 with a 10% aqueous hydrochloric acid solution and extracted with EA. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue used directly in the next amide coupling step.
Compound No. 1,018 of Example 8 was prepared according to the following general reaction (scheme 7): Scheme 7

It will be apparent to one skilled in the art that the synthetic depicted in Scheme 7 can be used to prepare additional compounds having different substituents using the appropriate reagents. For example, compounds having different substituents on the phenyl ring can be prepared using alternative styrene derivatives that have the desired substitution pattern and alternative amines or alcohols to obtain the desired amide or ester in the last step.
EXAMPLE 8. 5- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -1,3-dimethylindolysin-8-carboxylic acid (2,2,2-trifluoroethyl) -amide (compound N 1,018)
Using a procedure similar to that described in Example 1, except that 5- [5- 3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -1,3-dimethylindolysin was used -8-carboxylic (90 mg) and 2,2,2-trifluoroethylamine (38 mg), the title compound was isolated as a solid (85 mg, 81%). Rf = 0.35 (3: 7 EA / heptane). MS (ES): M / Z [M + H] = 552. 1 H NMR (400 MHz, DMSO-d6): 2.18 (s, 3H), 2.19 (s, 3H), 4.11 (qd, J = 9.7, 6.6 Hz, 2H), 4 , 48 (d, J = 18.7 Hz, IH), 4.56 (d, J = 18.6 Hz, 1 H), 6.57 (s, IH), 6.62 (d, J = 7 , 0 Hz, IH), 7.04 (d, J = 7.0 Hz, IH), 7.67 (d, J = 1.7 Hz, 2H), 7.84 (t, J = 1.9, Hz, IH), 9.21 (t, J = 6.3 Hz, IH). 19F NMR (376 MHz, DMSO-d6): -78.8 (s, 3F) and -70.6 (t, J = 9.9 Hz, 3 F)
The starting material, 5- [5-3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -1,3-dimethylindolysin-8-carboxylic acid, was prepared as follows: a . 2 7-chlorosuccinimide (1.6 g) was added to a solution of 2-chloro-6- (hydroxyiminomethyl) -nicotinic acid methyl ester (2.49 g, described in Example 1 ad) in DMF (5 ml) and the mixture was heated to 40 ° C for 20 minutes. The mixture was cooled to about 0 ° C (ice bath) and then 1,3-dichloro-5- (1-trifluoromethylvinyl) -benzene (3.1 g, prepared from 2-bromo-3.3 , 3-trifluoropropane and 3,5-dichlorophenylboronic acid commercially available, by the method described in J. Fluorine Chem. 1999, 95, 167-170) and TEA (1.8 mL) were added and the mixture was stirred at room temperature for in the evening. The mixture was diluted with water and extracted with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by chromatography (SiO2, heptane / EA) to give the 2-chloro-acid methyl ester. 6- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -nicotinic as a white solid (500 mg, 22% over 3 steps). Rf = 0.35 (2: 8 EA / heptane). 19F NMR (376 MHz, DMSO-d6): -80.1 (s, 3F). B. 2-Chloro-6- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -nicotinic acid methyl ester (1.75 g), 'but-3-in -2-ol '(0.33 g), copper (I) iodide (40 mg) and bis (triphenylphosphine) palladium chloride (0.13 g) in TEA (20 ml) were stirred at 50 ° C for about 40 hours. The mixture was allowed to cool to room temperature and concentrated under reduced pressure to give a residue which was diluted with EA. The mixture was filtered through a plug of Celite® and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane / EA) to give the 6- [5- (3.5 acid methyl ester) -dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2- (3-hydroxy-but- 1-ynyl) -nicotinic (0.5 g, 26%), together with recovered starting material 2-chloro-6- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -nicotinic acid methyl ester (1.2 g, 69%). Rf = 0.55 (1: 1 EA / heptane). ç. To a solution of 6- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2- (3-hydroxy-but-l-ynyl) - methyl ester nicotinic (0.5 g) in THE (15 ml) cooled to about -30 ° C TEA (0.21 ml) was added, followed by methanesulfonyl chloride (0.18 g). The mixture was allowed to rise to room temperature and stirred for one hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by chromatography (SiO2, heptane / EA) to give 6- [5-3,5-dichlorophenyl) -5-trifluoromethyl acid methyl ester -4,5-dihydroisoxazol-3-yl] -2- (3-methanesulfonyloxy-but-1-yl) -nicotinic (0.6 g). Rf = 0.7 (1: 1 EA / heptane). IH NMR (400 MHz, chloroform-d): 1.83 (d, J = 6.7 Hz, 3H), 3.25 (br.s., 3 H), 3.88 (d, J = 18, 4 Hz, 1H), 3.98 (s, 3H), 4.27 (d, J = 18.3 Hz, IH), 5.62 (q, J = 6.7 Hz, IH), 7.44 (t, J = 1.8 Hz, IH), 7.52 (d, J = 1.6 Hz, 2H), 8.08 (d, J = 8.3 Hz, IH) and 8.32 (d , J = 8.3 Hz, IH). 19F NMR (376 MHz, chloroform-d): -80.0 (s, 3F). d. To a suspension of copper cyanide (0.14 g) in THF (15 mL) cooled to about -50 ° C was added dropwise a solution of methyl lithium in dietoxymethane (0.5 mL of a solution 3 molar of Aldrich). The mixture was stirred for 30 minutes before being cooled to about -75 ° C. A solution of 6- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl] -2- (3-methanesulfonyloxy-but-l-ynyl) -nicotinic acid methyl ester (0.54 g) in THF (7 ml) was added dropwise to the mixture which was stirred at around -75 ° C for 2 hours before allowing the temperature to rise to room temperature overnight. The mixture was chelated with a saturated ammonium chloride solution, extracted with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane / EA) to give the alene intermediate (0.5 g) . Rf = 0.4 (2: 8 EA / heptane). This residue was then dissolved in DMA (10 ml) and copper (II) chloride (50 mg) and TEA (0.75 ml) was added to the mixture before heating at 130 ° C for 5 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to give a residue which was purified by chromatography (SiO2, heptane / EA) to give 5- [5- (3,5-dichlorophenyl) -5- acid methyl ester trifluoromethyl-4,5-dihydroisoxazol-3-yl] - 1,3-dimethylindolizine-8-carboxylic (0.3 g, 60%). Rf = 0.35 (2: 8 EA / heptane). IH NMR (400 MHz, chloroform-d): 2.28 (s, 3H), 2.31 (s, 3H), 3.73 (d, J = 17.8 Hz, IH), 3.96 (s , 3H), 4.07 (d, J = 17.7 Hz, IH), 6.53 (s, IH), 6.58 (d, J = 7.0 Hz, IH), 6.89 (d , J = 7.0 Hz, IH), 7.47 (t, J = 1.8 Hz, 1H) and 7.51 (d, J = 1.6 Hz, 2H). 19F NMR (376 MHz, chloroform-d): -79.5 (s, 3F). and. To a solution of 5- [5- (3,5-dichlorophenyl) -5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-1,3-dimethylindolizine-8-carboxylic acid methyl ester (280 mg) a 1: 1 THF / MeOH mixture (10 ml) was added a 1.5 molar aqueous solution of lithium hydroxide (1.5 ml) and the mixture was stirred at room temperature overnight. The mixture was acidified to a pH of about 3 with a molar hydrochloric acid solution and extracted with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a solid (270 mg) used directly in the next amide coupling step. IH NMR (400 MHz, chloroform-d) 2.29 (s, 3 H), 2.40 (s, 3H), 3.75 (d, J = 17.8 Hz, IH), 4.08 (d , J = 17.8 Hz, IH), 6.56 (s, IH), 6.60 (d, 10 J = 7.1 Hz, IH), 7.12 (d, J = 7.1 Hz, 1H), 7.48 (t, J = 1.8 Hz, IH) and 7.52 (d, J = 1.5 Hz, 2H). 19F NMR (376 MHz, Chloroform-d): -79.5 (s, 3F).
Tables 1 and 2, below, describe additional compounds of formula (I) prepared according to the 15 general synthetic schemes and examples 1-6 described above. Table 1
The numbers from 1,001 to 1,025 compounds mentioned above in Table 1 for identification and reference below

The numbers from 2,001 to 2,018 are assigned to the compounds above for identification and reference below. Biological Activity Against Parasites METHOD A: Screening method to test contact activities of compounds against ticks
A solution of the test compound was used to coat the inner wall of glass tubes and to treat two filter papers. Once dry, one filter paper was placed on the top of the bottle and the other on the bottom of the bottle. Each treated bottle was infested with 10 adults of Rhipicephalus sanguineus (Brown Dog Tick). The contact of the ticks with residues was induced by keeping the vials in a controlled environment (24 ° C, relative humidity of 90 to 95%) and the evaluation was carried out at 24, 48 hours after application, in comparison with untreated controls. Compounds of numbers 1,008, 1,009, 1,011 and 1,013 gave at least 80% of the control of Rhipicephalus sanguineus in the evaluation of 48 hours of a test concentration of 200 ppm or less. METHOD B: Screening method to test contact activities of compounds against fleas
A solution of the test compound was dispensed, using a pipette, on a filter paper placed in a glass vial. The filter paper was left to dry before infesting each vial with 10 adults of Ctenocephalides felis. The treated Ctenocephalides felis were kept in a controlled environment (24 ° C, 90 to 95% relative humidity) and the evaluation was performed at 24, 48 and 72 hours after application, compared to untreated controls. Compound number 1,009 gave at least 80% control in the 72 hour evaluation at a test concentration of 100 ppm or less. Method C: screening method to test the activity of compounds against fleas after ingestion.
A cylindrical test vessel was filled with 10 adult Ctenocephalides felis. A cylindrical well was closed at one end with a flexible self-sealing film and placed on top of the test container in a position such that fleas could pierce the film and feed on the contents of the cylinder. The test compound solution was then pipetted in bovine blood and added to the well. The part of the container with Ctenocephalides felis was kept at 20-22 ° C and 40-60% relative humidity, while the part of the well containing the treated blood was kept at 37 ° C and 40-60% relative humidity. The evaluation was performed 72 hours after application, compared to untreated controls. Compounds 1,001, 1,003, 1,005, 1,006, 1,007, 1,008, 1,009, 1,011 and 1,013 gave at least 80% of the control, at a test concentration of 50 ppm or less. METHOD D: Screening method to test contact activities of compounds against stable flies.
A solution of the test compound was used to treat a filter paper contained within a Petri dish and the filter paper was left to evaporate to dryness. A small piece of absorbent cotton wool moistened with 10% sucrose and ten adult flies (Stomoxis calcitrans) were added to each plate. The plates were covered and kept at room temperature. Assessments were performed 24 hours after infestation compared to untreated controls. Compound number 1013 resulted in at least 80% control, at a test concentration of 5 pg / cm2 or less. Method E: screening method to test the activity of compounds against Dirofilaria immitis microfilaria.
400 to 600 microfilariae of Dirofilaria immitis were added to wells of a microtiter plate containing RPMI-1640 medium (Fisher Scientific) and the test compound in DMSO. The microtiter plate was then maintained at 37 ° C in an environment containing 5% CO2. An evaluation was conducted after 5 days to determine the microfilaria's survival. Microfilaria exposed to DMSO and no test compounds served as controls. Compounds number 1,001 and 1,005 resulted in at least 60% inhibition of motility, at a test concentration of 5 ppm or less. The invention is further described by the following paragraphs numbered below: 1) Dihydroazole compound of formula (I), or a salt
(I) pharmaceutically acceptable thereof: where: Ri is hydrogen, halogen, -CN or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each of which is unsubstituted or replaced with one or more among halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2 -, R7C (O) -, R7R8NC (O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or -NO2; X is aryl or heteroaryl, which can be unsubstituted or substituted by one or more of halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy , alkylthio, haloalkylthio, R7S (O) -, R7S (O) 2-, R7C (O) -, R7R8NC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or -NO2; independently, oxygen, NR2 or CR7R8; G is Gl or G-2;
Bi B2, B3, B4 and are independently N or C-R9; Y is hydrogen, halogen, -CN or Y is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl or heterocyclyl or heteroaryl, 10 each of which is unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl- or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (0) -, R7S (O) 2-, R7C (O) -, R7R8NC (O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or - NO2; or Y is Yl, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-ll, Y-12 or Y -13;
5 haloalkynyl, cycloalkyl, R10S (0) -, RioS (0) 2, R10C (O) RloC (S) -, RIORIINC (O) -, RioRnNC (S) - RIQOC (O) -; R4, R5 and Re are independently hydrogen, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl R9 is hydrogen, halogen, -CN or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, alkylcycloalkyl, alkylcycloalkyl, alkylcycloalkyl, alkylcycloalkyl unsubstituted or substituted with one or more of halogen, hydroxy, amino, alkyl or di (alkyl) amino, alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R7S (O) - , R7S (O) 2-, R7C (O) -, R7R8NC (O) -, R7OC (O) -, R7C (O) O-, R7C (O) NR8-, -CN or -NO2; Rio, R11, R12 ® R13 are each independently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl; or R10, together with R11 form = 0, = S or = NR2; or R12 together with R13 form = 0, = S or = NR2; W is 0, S or NR2; n is 1-4; em is 0, 1 or 2. 2) The compound of paragraph 1, where G is Gl. 3) The compound of paragraph 1, where G is G-2. 4) The compound of paragraph 1, where: G and G-1; Ai is oxygen, and is optionally substituted aryl. The compound of paragraph 1, where: b G is G-2; ^ x is oxygen, and is optionally substituted aryl.
The compound of paragraph 1, where: and oxygen Y is optionally substituted aryl; p> x is hydrogen, halogen, alkyl or haloalkyl; and Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, „Y-12 OR Y-13. Y-11 '
The compound of paragraph 1, where: 7) ^ x is oxygen Y is optionally substituted aryl; Rj is hydrogen, halogen, alkyl or haloalkyl; and Y is pyrazolyl or triazolyl. The compound in paragraph 1, where: G is G-1; B2, B3, B4 θ Bs are each C Rg, R is C1-C4alkyl or C1-C4haloalkyl; Y is phenyl, which can be unsubstituted or, 4 - ituido by one or more of halogen, SUbStlUU-1-iα ^ t 'C4 haloalkyl, j ^ x is oxygen; A2 is CRVRΘ; Y is Yl, Y "4 'Y'5' Y-β; R2 and RÍ are independently hydrogen, Ci /" "ill C * 1 C1-C4haloalkyl, C1-C4alkoxy-C1-C4alkylalkylthioCi" C4 alkyl, © R3 and R9 is independently hydrogen, Ci 4 q 'or CX-C4 haloalkyl.
The compound in paragraph 1, where: G is G-2; BI, B2, B3, B4 and B5 are each C-R9; R 1 is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; X is phenyl, which can be unsubstituted or substituted by one or more of halogen, C1-C4alkyl or Ci- C4haloalkyl; Ai is oxygen; A2 is CR7R8Z Y is Y-1, Y-4, Y-5, Y-6; R2 and R4 are independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy-C1-C4alkyl or C1-C4alkylthioC1-C4 alkyl; and R3 and R9 are independently hydrogen, C1-4 alkyl or C1-C4 haloalkyl. 10) The compound of paragraph 1, where: G is G-1; 81, B2r θ s ^ ° each C-R9; B3 is N; R is Ci "C4-alkyl or C1-C4-haloalkyl; X is phenyl, which may be unsubstituted or replaced by one or more halogen, C1-C4alkyl or Ci ~ C4haloalkyl" Ai is oxygen; A2 is CR7R8Á Y is Yl, Y- 4, Y-5, Y-β; R2 and R4 are independently hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy-C1-C4alkyl or C1-C4 alkylthioC1 ~ C4 alkyl; and R3 And R9 are independently hydrogen, C1 -C4alkyl or C1-C4haloalkyl 11) The compound of paragraph 1, where: G is G-2; B2, B3, B4 and B5 are each C-R9; Bi is N; Ri is C1-C4alkyl or C1-C4haloalkyl ; X is phenyl, which can be unsubstituted or substituted by one or more of halogen, C1-C4alkyl or C1- C4haloalkyl; Ai is oxygen; A2 is CR7R8; Y is Yl, Y "4 'Y-5' Y-β ; . r.-C4alkyl, R2 and R4 are independently hydrogen, „. r. r. η ■ η OR Cl “C4haloalQuila, Ci ~ C4alkoxy Ci — C4alkia C4alkylthioC1-C4alkyl; and , . z. . C1-C4alkyl R and R9 are independently hydrogen, or C1-C4haloalkyl. 12) The compound of paragraph 8, where: A2 is CÜ2 R9 is hydrogen; R12 together with Ru form = 0, = S or = NR2> R2 and RÍ are independently hydrogen, hi d-Cβhaloalkyl; and R3, R7 and R8 are each hydrogen. 13)) The compound of paragraph 9, where: A2 is CH2 R9 is hydrogen; R12 together with Rn form = 0, = S or = NR2 '' R2 and R «are independently hydrogen, Ci'c4al <lulla C1-C4haloalkyl; and R3, R7 and R8 are each hydrogen. 4 'The compound of paragraph 8, where: 14) A2 is CH2 R9 is hydrogen; R10 together with Rn form = 0, = S or = NR2 <T_ * 1 - • r1-C4alkyl R2 and FU are independently hydrogen, C1-C4haloalkyl '’and I R f> 7 and RΘ are each hydrogen. compound of paragraph 9, where: is CH2 À is hydrogen; R10 together with Rn form = 0, = S or = NR2 'R2 And R4 are independently hydrogen, Ci "c4alkyl C1-C4haloalkyl; and R R7 and Re are each hydrogen. 0 compound of paragraph 8, where: A2 is CH2 'R9 is hydrogen; Rio together with Rn form = 0, = S or = NR2' ”R12 together with Rn form = 0, = S or = NR2> R2 and R4 are independently hydrogen, C1-C4alkyl, C1-C4haloalkyl; and R3, R7 and R8 are each hydrogen.17 The compound of paragraph 10, where: A2 is CH2 r R9 is hydrogen; Ri2 together with Rn form = 0, = S or = NR2; R2 and R4 are independently hydrogen, Ci ~ C4alkyl, R R7 AND RS ARE EACH hydrogel- 18) the compound of paragraph 11, where: A2 is CH2; R9 is hydrogen; R together with Rn form = 0, = S or = NR2 ', .,,. fi-'Caalkyl R2 and R4 are independently hydrogen, wm C1-C4haloalkyl; and R R7 and Rθ are each hydrogen 9- 19) The compound of paragraph 10, where: A2 is CH2; R9 is hydrogen ; River together with Rn form = 0, = S or = NR2 <R2 And R4 are independently hyd rogen, wm C1-C4haloalkyl; and R R7 and R8 are each hydrogen. 20) The compound of paragraph 11, wherein. is CÜ2r R9 is hydr ° gθnio '* Rio together with Ru form = 0, = S or = NR2' R2 and FU are independently hydrogen, Ci '^ alkyl C1-C4haloalkyl' '' and R3 R7 θ Re are each hydrogen. 21) The compound of paragraph 10, where: T 2 is CH2; Rs) is hydrogen; o n - together with Rn form = 0, = S or = NR2, XA10 J o „- together with Ri3 form = 0, = S or = NRa <R2 and R4 are independently hydrogen, C1-C4alkyl, C1-C4haloal <2uila; and R3, R7 and R8 are each hydrogen. the compound of paragraph 11, where: 2 f 7 2 is CH2; R9 is hydrogen; R10 together with R11 form = 0, = S or = NR2, ‘R12 together with R13 form = 0, = S or = NR2 <R2 and R4 are independently hydrogen, C1-C4alkyl, d-C4haloalkyl; and R3, R7 and R8 are each hydrogen. 23) Composition for the treatment or prevention of an infection or parasitic infestation in an animal comprising an effective amount of a compound formulated in paragraph 1 in combination with a pharmaceutically acceptable carrier. 24) Method for treating or preventing a parasitic infection or infestation in an animal which comprises administering to the animal a parasitically effective amount of a compound of paragraph 1 to the animal. 25) Use of the compound of paragraph 1 in the treatment or prevention of an infection or parasitic infestation in an animal. 26) Use of the compound of paragraph 1 in the preparation of a medicine for the treatment or prevention of an infection or parasitic infestation in an animal. ***
Having thus described the preferred embodiments of the present invention in detail, it should be understood that the invention defined in the preceding paragraphs should not be limited to the particular details defined in the description above, since many apparent variations thereof are possible without departing from the spirit or scope of the present invention.

权利要求:
Claims (30)
[0001]
1. Dihydroazole compound characterized by the fact that it has formula (I), or a pharmaceutically or agriculturally acceptable salt thereof:
[0002]
2. Compound, characterized by the fact that G is G-l.
[0003]
3. Compound according to claim 1 characterized by the fact that G is G-2.
[0004]
Compound according to claim 1 characterized by the fact that: X is unsubstituted or substituted phenyl by one or more halogens, C2-C4 alkyl or C2-C4 haloalkyl; R2 is C2-C4 haloalkyl.
[0005]
Compound according to claim 1, characterized by the fact that: X is unsubstituted or substituted phenyl by one or more halogens, C2-C4 alkyl or C2-C4 haloalkyl; R1 is C2-C4 haloalkyl; and Y is Y-1, Y-4, Y-5 or Y-6.
[0006]
6. Compound according to claim 1, characterized by the fact that: G is G-1; B2, B2, B3, B4 and Bs are each C-R9; R1 is C2-C4 haloalkyl; X is phenyl, which can be unsubstituted or substituted by one or more halogens, C2-C4 alkyl or C2-C4 haloalkyl; Y is Y-1, Y-4, Y-5 or Y-6; Ra and R4 are, independently, hydrogen, C-04 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy or C1-C4 alkyl or C1-C4 alkylthio, C1-C4 alkyl; and R2 and Rg are, independently, hydrogen, Cg-C4 alkyl or C1-C4 haloalkyl.
[0007]
7. Compound, according to claim 1, characterized by the fact that: G is G-2; Bi, B2, B3, B4 and Bs are each C-R9; R1 is C1-C4 haloalkyl; X is phenyl, which can be unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C2-c4 haloalkyl; À2 is CRgRg; Y is Y-1, Y-4, Y-5, Y-6; R3 and R4 are, independently, hydrogen, C2-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy-C1-C4 alkyl or C1-C4 alkylthio, C1-C4 alkyl; and R2 and Rg are, independently, hydrogen, C2-C4 alkyl or C1-C4 haloalkyl.
[0008]
8. Compound according to claim 1, characterized by the fact that: G is G-1; Bi, B2, B4 and Bs are each C-RQ; B3 is N; R1 is C1-C4 haloalkyl; X is phenyl, which can be unsubstituted or substituted by one or more halogens, C1-C4 alkyl or C-C4 haloalkyl; Y is Y-1, Y-4, Y-5 or Y-6; Ra and R4 are independently hydrogen, Cg-C4 alkyl, Cg-C4 haloalkyl, Cg-C4 alkoxy-Cg-C4 alkoxy or alkylthio, Cg-C4 alkyl; and R2 and Rg are independently hydrogen, Cg-C4 alkyl or Cg-C4 haloalkyl.
[0009]
9. Compound according to claim 1, characterized by the fact that: G is G-2; Bg, B3, B4 and Bs are each C-R9; Bg is N; Rg is Cg-C4 haloalkyl; X is phenyl, which can be unsubstituted or substituted by one or more halogens, Cg-C4 alkyl or Cg-C4 haloalkyl; Y is Y-1, Y-4, Y-5 or Y-6; R3 and R4 are, independently, hydrogen, Cg-C4 alkyl, Cg-C4 haloalkyl, Cg-C4 alkoxy-Cg-C4 alkyl or Cg-C4 alkylthio, Cg-C4 alkyl; and Rg and Rg are, independently, hydrogen, Cg-C4alkyl or Cg-C4 haloalkyl.
[0010]
10. Compound according to claim 6, characterized by the fact that: Ag is CHg; Rg is hydrogen; Rgo together with RX1 form = 0, = S or = NR2; R3 is hydrogen, Cg-C4 alkyl, Cg-C4 haloalkyl or Cg-C4 alkylthio, Cg-C4 alkyl; Rg, R- and Rg are each hydrogen; and Y is Y-1 or Y-4.
[0011]
11. Compound according to claim 7, characterized by the fact that: A2 is CJA; Rg is hydrogen; Rio together with Rn form = 0, = S or = NR2; R3 is hydrogen, C2-C4 alkyl, C2-C4 haloalkyl or C1-C4-alkylthio-C2-C4 alkyl; R2, R- and Rg are each hydrogen, and Y is Y-1 or Y-4.
[0012]
12. Compound according to claim 6, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R12 form = 0, = S or = NR2; R12 together with R13 form = 0, = S or = NR2 R3 is C2-C4 alkyl, C2-C4 haloalkyl or C2-C4-alkylthiθ-C2-C4_alkyl; R2, R- and Rg are each hydrogen, and Y is Y-1 or Y-4.
[0013]
13. A compound according to claim 7, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R21 form = 0, = S or = NR2; R12 together with R13 form = 0, = S or = NR2 R3 is C2-C4 alkyl, C2-C4 haloalkyl or C2-C4 alkylthio-C2-C4 alkyl; R2, Rg and Rg are each hydrogen; and Y is Y-1 or Y-4.
[0014]
14. A compound according to claim 6, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R21 form = 0; R12 together with R13 form = 0; R3 is C1-C4 haloalkyl or C4-C4 alkylthio-C2-C4 alkyl; R2, R- and R8 are each hydrogen; and Y is Y-1 or Y-4.
[0015]
15. A compound according to claim 7, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R41 form = 0; R22 together with R13 form = 0; Rg is C4-C4 haloalkyl or C2-C4-alkylthio-C2-C4-alkylthio; R2, R- and R3 are hydrogen; and Y is Y-1 or Y-4.
[0016]
16. A compound according to claim 8, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R41 form = 0, = S or = NR2; Rg is hydrogen, C2-C4 alkyl, C4-C4 haloalkyl or C2-C4 alkylthio-C2-C4 alkyl; R2, R- and Rs are each hydrogen, and Y is Y-1 or Y-4.
[0017]
17. A compound according to claim 9, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R21 form = 0, = S or = NR2; R3 is hydrogen, C1-C4 alkyl, C2-C4 haloalkyl or C1-C4 alkylthio-C4-C4 alkylthio; R2, R7 and R8 are each hydrogen, and Y is Y-1 or Y-4.
[0018]
18. A compound according to claim 8, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R21 form = 0, = S or = NR2; R22 together with R13 form = 0, = S or = NR2 R3 is C2-C4 alkyl, C2-C4 haloalkyl or C4-C4-C4-C4-C4 alkylthio; R2, R7 and R8 are each hydrogen, and Y is Y-1 or Y-4.
[0019]
19. A compound according to claim 9, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R21 form = 0, = S or = NR2; R12 together with R13 form = 0, = S or = NR2; R3 is C2-C4 alkyl, C2-C4 haloalkyl or C2-C4 alkylthio-C2-C4 alkyl; R2, R7 and R8 are each hydrogen; and Y is Y-1 or Y-4.
[0020]
20. Compound according to claim 8, characterized by the fact that: A2 is CH2; Ro is hydrogen; R10 together with R12 form = 0; R22 together with R13 form = 0; R3 is C2-C4 haloalkyl or C2-C4 alkylthio-C4-C4 alkyl; R2, R- and R2 are hydrogen; and Y is Y-1 or Y-4.
[0021]
21. A compound according to claim 9, characterized by the fact that: A2 is CH2; Rg is hydrogen; R10 together with R41 form = 0; R22 together with R13 form = 0; R3 is C4-C4 haloalkyl or C2-C4 alkylthio-C2-C4 alkyl; R2, R- and Rs are hydrogen; and Y is Y-l or Y-4
[0022]
22. A compound according to claim 15, characterized by the fact that: Y is Y-1; and R3 is -CH2CH2SCH3.
[0023]
23. A compound according to claim 15, characterized by the fact that: Y is Y-4; and R3 is -CH2CF3.
[0024]
24. Compound according to claim 1, characterized by the fact that it is selected from the following:
[0025]
25. Compound according to claim 1, characterized by the fact that it is selected from the following:
[0026]
26. Veterinary composition characterized by the fact that it comprises a compound of formula (I) as defined in claim 1 in combination with a vehicle.
[0027]
27. Composition for the protection of crops, plant propagating material, plant or material made from wood against pests characterized by the fact that it comprises a compound of formula (I) as defined in claim 1 in combination with a carrier or diluent .
[0028]
28. Use of a parasitically effective amount of a compound of formula (I) as defined in claim 1 characterized by the fact that it is for the manufacture of a medicament for the treatment or prevention of an infection or parasitic infestation in an animal.
[0029]
29. Method to protect crops and plants that grow from attack or infestation by animal pests characterized by the fact that it comprises the contact of a plant or soil or water in which the plant grows, with a compound of formula (I) as defined in claim 1.
[0030]
30. Method for preventing or controlling infestations of animal pests in a locus characterized by the fact that it comprises the administration of a compound of formula (I) as defined in claim 1 to the locus. haloalkynyl, cycloalkyl, Rio (O) -, R10 (O) 2, R10C (0) - RioC (S) -, RIORIINC (O) -, RioRnNC (S) -RioOC (O) R p> 5 and R6 are, independently, hydrogen 10 haloalkynyl, cycloalkyl, aryl or heteroaryl; R7 and Rs are, independently, hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;

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法律状态:
2017-08-08| B25A| Requested transfer of rights approved|Owner name: MERIAL, INC (US) |

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2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-01-16| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2018-06-19| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|

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2019-01-22| B06G| Technical and formal requirements: other requirements [chapter 6.7 patent gazette]|

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2019-07-09| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-04-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-03| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 16/12/2010, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US28754509P| true| 2009-12-17|2009-12-17|

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US61/287,545|2009-12-17|

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PCT/US2010/060833|WO2011075591A1|2009-12-17|2010-12-16|Anti parasitic dihydroazole compounds and compositions comprising same|

---