NZ613343B2 - Internal parasiticide - Google Patents

Internal parasiticide Download PDF

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Publication number
NZ613343B2
NZ613343B2 NZ613343A NZ61334312A NZ613343B2 NZ 613343 B2 NZ613343 B2 NZ 613343B2 NZ 613343 A NZ613343 A NZ 613343A NZ 61334312 A NZ61334312 A NZ 61334312A NZ 613343 B2 NZ613343 B2 NZ 613343B2
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New Zealand
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group
halogen atom
optionally substituted
atom
group optionally
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NZ613343A
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NZ613343A (en
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Kiyoshi Kita
Akiyuki Suwa
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Nihon Nohyaku Co Ltd
The University Of Tokyo
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Priority claimed from PCT/JP2012/055190 external-priority patent/WO2012118139A1/en
Publication of NZ613343A publication Critical patent/NZ613343A/en
Publication of NZ613343B2 publication Critical patent/NZ613343B2/en

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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
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    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals

Abstract

Disclosed herein is a method for controlling internal endoparasites by orally or parenterally administering to a non-human mammal or bird an effective amount of an endoparasite control agent comprising a carboxamide (i.e. benzamide) derivative represented by the general formula (I), wherein the variables are as defined in the specification. The compositions are suited to administration to humans and domestic animals to control protozoa and helminths. ables are as defined in the specification. The compositions are suited to administration to humans and domestic animals to control protozoa and helminths.

Description

HAS510030NZPR 303864625 DESCRIPTION INTERNAL PARASITICIDE TECHNICAL FIELD The present invention relates an endoparasite control agent comprising a carboxamide tive or a salt thereof as an active ingredient, and a method for controlling endoparasites, comprising orally or parenterally administering the endoparasite control agent.
BACKGROUND ART Certain kinds of carboxamide derivatives have been known to have icidal activity (see Patent Literature 1 to 12).
However, there is no description indicating that these compounds described in the literature are effective against endoparasites in animals such as mammals and birds. Further, it is known that certain kinds of carboxamide tive are effective t nematodes that may damage agricultural products (see Patent Literature 4 or 5), but there is no specific disclosure on any effect against endoparasites in animals.
Furthermore, it has been reported that nds that inhibit succinate-ubiquinone reductase (mitochondrial x II), which is one of the respiratory enzymes of endoparasites, can serve as an rasite control agent (see Non Patent Literature 1).
CITATION LIST Patent Literature Patent Literature 1: JP—A 01—151546 Patent Literature 2: W0 2007/060162 Patent Literature 3: JP~A 53-9739 Patent Literature : Patent Literature : Patent Literature 6: WO 01975 Patent Literature 7: Patent ture 8: Patent Literature 9: Patent Literature 10: Patent Literature 11: Patent Literature 12: W0 2010/106071 Non Patent Literature Non Patent Literature 1: Kiyoshi Kita, “Kansen (Infection)”, Winter 2010, Vol. 40—4, 310-319 SUMMARY OF INVENTION TECHNICAL PROBLEM lly, parasitosis is caused by parasites that have infected and resided in host animals, and examples of the parasites include unicellular protists (protozoa), multioellular helminths and arthropods. It is reported that the incidence of parasitosis in Japan has been remarkably decreased by improvement of nmental hygiene, but on a global scale, particularly in developing ies, parasitosisstillwidelyprevailsandcausestremendousdamage.
In recent years, there has been an increasing trend in the nce of parasitic infection due to introduction of HAS510030NZPR 303864625 infection s via long- or short-term as travelers, ingestion of food imports, ion of raw meat and fish meat that are more available thanks to the advance in freezing and logistics technologies, etc., and also in the incidence of parasitosis from pets etc. Another problem is that immunodeficiency caused by mass administration of immunosuppressants, anticancer drugs, etc. or by AIDS etc. allows usually non-pathogenic or low-pathogenic parasites to express their pathogenicity and to cause opportunistic infection in hosts. Further, tosis in ic animals, such as pigs, horses, cattle, sheep, dogs, cats and domestic fowls, is a universal and serious economic problem. That is, parasitic infection of domestic animals causes anemia, malnutrition, debility, weight loss, and serious damage of intestinal tract walls, tissues and , and may result in decline in feed efficiency and productivity, g to a great economic loss. Therefore, novel endoparasite control agents as a parasiticide, an antiprotozoal or the like have always been desired.
OBJECT It is an object of the present invention to provide a method for controlling endoparasites and/or the use of a carboxamide derivative represented by the general formula (I), or to at least provide the public with a useful .
SOLUTION TO PROBLEM The present inventors conducted extensive research to solve the above-described problems. As a result, the present inventors found that a carboxamide derivative represented by HAS510030NZPR 303864625 the general formula (I) of the present ion, and a salt thereof have a high control effect against endoparasites, and then completed the present invention. That is, the present invention relates to the following.
An endoparasite control agent comprising a carboxamide derivative represented by the general formula (I): (Y)n (X)m GIN A-<Z _ > (I) {wherein A represents a (C1—C8) alkylene group optionally substituted by a halogen atom, a (C1-C5) alkyl group and/or a (C3—C5) cycloalkyl group; a (C1-C8) alkylene group which is optionally substituted by a halogen atom, a (Cl—~06) alkyl group and/or a (C3-C5) lkyl group and is modified by incorporation, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur atom, -SO-, -SOZ~ and -N(R)- (wherein R represents a en atom, a (C1-C6) alkyl group, a (C3~C5) cycloalkyl group, a (C1-C5) alkylcarbonyl group or a (Cl—C5) alkoxycarbonyl group); a (C2-C3) alkenylene group optionally substituted by a halogen atom, a (C1—C6) alkyl group and/or a (C3-C5) cycloalkyl group; a (C2-C3) lene group which is ally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3—C5) cycloalkyl group and is ed by incorporation, into the carbon chain, of at least one atom selected from an oxygen atom, a sulfur atom, ~SO—, -SOz- and —N(R)- (wherein R is as defined above); a ) alkynylene group ally substituted by a halogen atom, a (C1—C6) alkyl group and/or a (C3-C5) cycloalkyl group; or a (C2—C8) alkynylene group which is optionally substituted by a halogen atom, a (Cl-Cs) alkyl group and/or a (C3~C5) cycloalkyl group and is modified by incorporation, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur atom, ~SO-, -SOz~ and —N(R)- (wherein R is as defined above), and in each case, A may form a cyclic structure, where possible, E represents a hydrogen atom; a (Cl-C6) alkyl group; a ) cycloalkyl group; a (C1-C6) alkoxy (C1-C6) alkyl group; a (Cl-Cs) alkylcarbonyl group; or a (C1—C6) alkoxycarbonyl group, each X may be the same or different , and represents a halogen atom; a cyano group; a nitro group; a (C1-C5) alkyl group optionally tuted by a n atom; a (C1—C5) alkoxy group optionally substituted by a halogen atom; a (C1-C5) hio group optionally substituted by a halogen atom; a (C1—C5) alkylsulfinyl group optionally tuted by a halogen atom; or a (C1—C6) alkylsulfonyl group optionally substituted by a halogen atom, m represents an integer of 0 to 5, each Y may be the same or different and ents a halogen atom; a cyano group; a nitro group; a y group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C2-C5) alkenyl group optionally substituted by a halogen atom; a (C2-C5) alkynyl group optionally substituted by a halogen atom; a (C1-C5) alkoxy group optionally substituted by a halogen atom; a (C1—C6) alkoxy (C1~C5) alkoxy group; a (C2-C5) alkenyloxy group optionally substituted by a halogen atom; a ) alkynyloxy group optionally substituted by a halogen atom; a (C1-C6) alkylthio group optionally substituted by a halogen atom; a (C1-C5) alkylsulfinyl group optionally substituted by a n atom; a (Cl—CG) alkylsulfonyl group optionally substituted by a halogen atom; a ) alkoxycarbonyl group; a (C1—C6) alkoxyimino (Cl-C3) alkyl group; a (C3—C30) trialkylsilyl group; a mono(C1-C6) alkylsulfonylamino group optionally substituted by a halogen atom; a phenyl group optionally substituted by one or more substituents selected from group B substituents; a phenoxy group optionally substituted by one or more substituentsselectedfromgroupIBsubstituents;aheterocyclic group optionally substituted by one or more substituents selected from group B substituents; or a heterocycloxy group optionally substituted by one or more substituents ed from group B substituents, the group B substituents are a halogen atom; a cyano group; a nitro group; a (C1-C5) alkyl group ally substituted by a.halogen atom; a ) l group optionally substituted by a halogen atom; a (C2-C5) alkynyl group ally substituted by a halogen atom; a (C1-C6) alkoxy group optionally substituted by a halogen atom; a ) alkenyloxy group optionally substituted by'a halogen atom; a (C2-C5) alkynyloxy group optionally substituted by a halogen atom; a (014k) alkylthio group optionally tuted by a halogen atom; a (C1—C5) alkylsulfinyl group optionally substituted by a halogen atom; a (C1—C6) alkylsulfonyl group optionally tuted by a halogen atom; a (C1-C5) alkoxycarbonyl group; and a (C1—C5) alkoxyimino (C1—C3) alkyl group, n represents an r of O to 5, with the proviso that when n is an integer of 2 to 5, two adjacent Y groups may join together to form a (C3-C5) alkylene group; a (C3-C5) alkenylene group; a (C2-C4) alkyleneoxy group; or a (C1-C3) alkylene dioxy group optionally substituted by a halogen atom, and Z represents a nitrogen atom; CH; or CY (wherein Y is as defined above)}. or a salt thereof as an active ingredient.
The endoparasite control agent according to the above [1] , wherein A represents a (C1-C3) alkylene group optionally tuted by a halogen atom, a (Cy-C6) alkyl group and/or a (C3-C5) cycloalkyl group; or a (Cl—Ca) alkylene group which is optionally substituted by a halogen atom, a ) alkyl group and/or a (C3-C5) cycloalkyl group and is modified by incorporation, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur atom, -SO-, ~SOz- and —N(R)- (wherein R represents a hydrogen atom, a ) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C6) alkylcarbonyl group or a ) alkoxycarbonyl group).
The endoparasite control agent according to the above [1] , wherein A represents a (C1-C3) alkylene group optionally tuted by a (C1-C5) alkyl group and/or a (C3-C5) cycloalkyl group; ~CR1(R2)—CR3(R‘)-Q— (wherein R1, R2, R3 and R4 may be the same or different from each other, and represent a en atom, a (C1-C5) alkyl group or a (C3-C6) cycloalkyl group, or R1, R2, R3 and R‘1 may join together in any combination to form a (C3-C6) cycloalkane, and Q represents an oxygen atom, a sulfur atom, -SO-, -SOz— or -N(R)- (wherein R represents a hydrogen atom, a (C1—C5) alkyl group, a (C3-C5) lkyl group, a (C1-C5) arbonyl group or a (C1—C6) alkoxycarbonyl group”; or -CR1(R2)—CR3(R4)—CR5(R6)-Q— (wherein R1, R2, R3, R4 and Q are as defined above, and R5 and R6 may be the same or different from each other, and ent a hydrogen atom, a (C1—C6) alkyl group or a (C3-C5) cycloalkyl group, or R1, R2, R3, R4, R5 and R6 may join together in any combination to form a (C3—C6) cycloalkane) . [4} The endoparasite control agent according to the above [1] , wherein A represents a (C1~C8) alkylene group optionally substituted by a (C1-C6) alkyl group and/or a (C3-C5) cycloalkyl group; —CR1(R2)-CR3(R4)—Q- (wherein R1, R2, R3 and R4 may be the same or different from each other, and represent a hydrogen atom, a (C1—C5) alkyl group or a (C3-C5) cycloalkyl group, or R1, R2, R3 and R4 may join together in any ation to form a (C3-C6) cycloalkane, and Q represents an oxygen atom, a sulfur atom, ~SO-, -SOz- or -N(R)- (wherein R represents a hydrogen atom, a (C1-C5) alkyl group, a (C3-C5) cycloalkyl group, a (Cl-C5) alkylcarbonyl group or a (C1—C5) carbonyl grouPH; or -CR1(R2)-CR3(R4)~CR5(R6)-Q~ (wherein R1, R2, R3, R4 and Q are as defined above, and R5 and R6 may be the same or different from each other, and represent a en atom, a (C1-C6) alkyl group or a (C3-C6) cycloalkyl group, or R1, R2, R3, R“, R5 and R6 may join together in any combination to form a (C3-C5) cycloalkane) , E ents a hydrogen atom; a (C1-C5) alkyl group; a (C1-C6) alkylcarbonyl group; or a (C1—C5) alkoxycarbonyl group, each X may be the same or different and represents a halogen atom; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C1—C5) alkoxy group optionally substituted by a halogen atom; or a (C1—C5) alkylthio group optionally substituted by a halogen atom, m represents 1 or 2, each Y may be the same or ent , and represents a halogen atom: a hydroxy group; a (C1‘”C6) alkyl group optionally substituted by a halogen atom; a (C1—C6) alkoxy group optionally substituted by a halogen atom; a (C1-C5) alkoxy (C1—C6) alkoxy group; a ) loxy group optionally substituted by a halogen atom; a mono(C1-C5) alkylsulfonylamino group optionally substituted by a n atom; a phenyl group optionally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (C1—C5) alkyl group optionally tuted by a halogen atom, and a ) alkoxy group ally substituted by a halogen atom; a phenoxy group optionally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (Cl—C5) alkyl group optionally substituted by a halogen atom, and a ) alkoxy group optionally substituted by a halogen atom; a heterocyclic group ally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (C1—C5) alkyl group optionally substituted by a halogen atom, and a (C1-C5) alkoxy group optionally tuted by a halogen atom,- or a heterocycloxy group optionally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a ) alkyl group optionally substituted by a halogen atom, and a (C1-C6) alkoxy group optionally substituted by a halogen atom, n ents an r of 0 to 3, with the proviso that when n is 2 or 3, two adjacent Y groups may join together to 2O form a (C2-C4) alkyleneoxy group or a (C1-C3) alkylene dioxy group optionally substituted by a halogen atom, and Z represents a nitrogen atom; CH; or CY (wherein Y is as defined above). {5] The endoparasite control agent according to the above [1] , wherein A represents a (C1-C5) alkylene group optionally substituted by a (C1"C5) alkyl group and/or a (C3-C6) cycloalkyl group; —CR1(R2)—CR3(R4)—Q- (wherein R1, R2, R3 and R4 may be the same or different from each other, and represent a hydrogen atom, a (C1-C5) alkyl group or a (C3-C5) cycloalkyl group, and Q HAS510030NZPR 303864625 represents an oxygen atom or a sulfur atom); or -CR1(R2)-CR3(R4)-CR5(R6)-Q- in R1, R2, R3, R4 and Q are as defined above, and R5 and R6 may be the same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group or a ) cycloalkyl group), E represents a hydrogen atom, each X may be the same or ent, and represents a halogen atom or a (C1-C6) alkyl group optionally substituted by a halogen atom, m represents 1, each Y may be the same or ent, and represents a halogen atom or a (C1-C6) alkyl group optionally substituted by a halogen atom, n ents an integer of 1 to 3, and Z represents a en atom; CH; or CY (wherein Y is as defined above).
A method for controlling endoparasites, comprising orally or parenterally administering an effective amount of the endoparasite control agent according to any one of the above [1] to [5] to a non-human mammal or a bird.
A method for controlling endoparasites, comprising orally or parenterally administering an effective amount of the endoparasite control agent according to any one of the above to [5] to a non-human mammal. [8] The method according to the above [7], wherein the non-human mammal is a domestic animal.
A method for controlling endoparasites, comprising orally or erally administering to a non-human mammal or bird an effective amount of an endoparasite HAS510030NZPR 303864625 control agent comprising a carboxamide tive represented by the general a (I): wherein A represents a (C1-C8) alkylene group optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group; a (C1-C8) alkylene group which is optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a ) cycloalkyl group and is modified by incorporation, into the carbon chain, of at least one atom selected from an oxygen atom, a sulfur atom, -SO-, -SO2- and -N(R)- (wherein R represents a hydrogen atom, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C6) alkylcarbonyl group or a (C1-C6) alkoxycarbonyl group); a (C2-C8) alkenylene group optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a ) cycloalkyl group; a (C2-C8) alkenylene group which is optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group and is modified by oration, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur atom, -SO-, -SO2- and -N(R)- (wherein R is as defined above); a (C2-C8) alkynylene group optionally substituted by a n atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group; or a (C2-C8) alkynylene group which is optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) lkyl group and is modified by incorporation, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur HAS510030NZPR 303864625 atom, -SO-, -SO2- and -N(R)- (wherein R is as defined above), and in each case, A may form a cyclic structure, where possible, E represents a hydrogen atom; a (C1-C6) alkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy (C1-C6) alkyl group; a (C1-C6) alkylcarbonyl group; or a (C1-C6) alkoxycarbonyl group, each X may be the same or different, and represents a halogen atom; a cyano group; a nitro group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C1-C6) alkoxy group optionally substituted by a halogen atom; a ) hio group optionally substituted by a halogen atom; a (C1-C6) alkylsulfinyl group optionally substituted by a n atom; or a (C1-C6) ulfonyl group optionally substituted by a halogen atom, m represents an integer of 0 to 5, each Y may be the same or different, and represents a halogen atom; a cyano group; a nitro group; a hydroxy group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C2-C6) alkenyl group optionally substituted by a halogen atom; a (C2-C6) alkynyl group optionally substituted by a halogen atom; a (C1-C6) alkoxy group optionally substituted by a halogen atom; a (C1-C6) alkoxy (C1-C6) alkoxy group; a (C2-C6) alkenyloxy group optionally substituted by a halogen atom; a (C2-C6) alkynyloxy group ally substituted by a halogen atom; a (C1-C6) alkylthio group optionally substituted by a halogen atom; a (C1-C6) alkylsulfinyl group optionally substituted by a halogen atom; a (C1-C6) alkylsulfonyl group optionally tuted by a n atom; a ) alkoxycarbonyl group; a (C1-C6) alkoxyimino (C1-C3) alkyl group; a 0) trialkylsilyl group; a mono(C1-C6) alkylsulfonylamino group ally substituted HAS510030NZPR 303864625 by a halogen atom; a phenyl group optionally substituted by one or more tuents selected from group B substituents; a phenoxy group optionally substituted by one or more substituents selected from group B substituents; a heterocyclic group optionally substituted by one or more substituents selected from group B tuents; or a heterocycloxy group optionally substituted by one or more substituents selected from group B substituents, the group B substituents are a n atom; a cyano group; a nitro group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C2-C6) alkenyl group optionally substituted by a halogen atom; a (C2-C6) alkynyl group optionally substituted by a halogen atom; a (C1-C6) alkoxy group optionally tuted by a halogen atom; a (C2-C6) alkenyloxy group optionally tuted by a halogen atom; a (C2-C6) alkynyloxy group optionally substituted by a halogen atom; a (C1-C6) alkylthio group optionally substituted by a halogen atom; a ) alkylsulfinyl group optionally substituted by a halogen atom; a (C1-C6) alkylsulfonyl group optionally substituted by a halogen atom; a (C1-C6) alkoxycarbonyl group; and a (C1-C6) imino (C1-C3) alkyl group, n represents an r of 0 to 5, with the proviso that when n is an integer of 2 to 5, two adjacent Y groups may join together to form a ) alkylene group; a (C3-C5) alkenylene group; a (C2-C4) alkyleneoxy group; or a (C1-C3) alkylene dioxy group optionally substituted by a halogen atom, and Z represents CH or CY (wherein Y is as defined above), or a salt thereof as an active ingredient.
A method for controlling endoparasites, comprising orally HAS510030NZPR or parenterally administering an effective amount of the non-human mammal or bird endoparasite control agent as defined in [9] to a non-human mammal.
ADVANTAGEOUS EFFECTS OF INVENTION The present invention provides a compound useful as an endoparasite control agent which excels in performance as ed with the tional art.
DESCRIPTION OF EMBODIMENTS The definitions in the general formula (I) representing the carboxamide derivative of the present ion are bed below.
The “(Cl—Ca) alkylene group” refers to a straight C1-C3 alkylene group, for example, a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a.hexamethylene group, a.heptamethylene group, an octamethylene group or the like. In the “(Cl—Cg) alkylene group optionally substituted by a halogen atom, a (C1-C6) alkyl group or a (C3-C5) cycloalkyl group,” each substituent may be bound to any carbon atom in the alkylene group.
The “(Cl—Ca) ne group which is optionally substituted by a halogen atom, a (C1~C5) alkyl group or a (C3—C5) cycloalkyl group and.is modified.by incorporation, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur atom, -SO-, —SOz— and —N(R)—” refers to a group which is the same as the above-mentioned optionally substituted straight (C1-C3) alkylene group except for having such a heteroatom attached to a terminal carbon atom or inserted between carbon atoms in the alkylene group. The specific examples include an ethyleneoxy'group, an.ethylenethio group, an.ethylene sulfinyl group, an ethylene sulfonyl group, an ethylene amino group, a eneoxy group, a propylenethio group , a propylene sulfinyl group, a propylene sulfonyl group, a propylene amino group, ~CH2-CH2-O-CH2—, ~CH2~CH2—S-CH2- and -CH2-CH2-NH-CH2-.
The “(Cg—Cg) alkenylene group” refers to a straight (CZ-Ca) lene group having one or more double bonds therein, for example, a vinylene group, a propenylene group, a butenylene group, a butadienylene group, a pentenylene group, a pentadienylene group , a hexenylene group , a hexadienylene group, a heptenylene group, a heptadienylene group, an octenylene group, an octadienylene group or the like. In the “(C2-C3) lene group optionally substituted by a halogen atom, a (Cl-C5) alkyl group or a (C3-C5) cycloalkyl group,” each substituent may be bound to any carbon atom in the alkenylene group. The ) alkenylene group which is optionally tuted by a halogen atom, a (Cl-C6) alkyl group or a (C3-C5) cycloalkyl group and is modified by incorporation, into the carbon chain of at least one heteroatom selected from an oxygen atom, a sulfur atom, -SO-, -SOr-and ~N(R)w” refers to a group which is the same as the above-mentioned optionally substituted straight (CZ—C8) alkenylene group except for having such a heteroatom ed to a terminal carbon atom or inserted between carbon atoms in the alkenylene group. The specific examples include a vinyleneoxy group, a nethio group, a vinylene sulfinyl group, a‘vinylene sulfonyl group, a vinylene amino group, a propenyleneoxy group, a propenylenethio group, a propenylene sulfinyl group, a propenylene yl group, a propenylene amino group, -CH=CH~CH¢O~CHz-, -CH=CH—CH2-S-CH2- and —CH=CH-CH2-NH-CH2-.
The “(CZ—Cg) alkynylene group” refers to a straight C2-C8 alkynylene group having one or more triple bonds therein, for example, an ethynylene group, a propynylene group, a butynylene group, a butadiynylene group, a pentynylene group, a pentadiynylene group , a hexynylene group, a hexadiynylene group , a heptynylene group, a heptadiynylene group, an ootynylene group, an octadiynylene group or the like. In the “(CZ-Ca) alkynylene group optionally tuted by a halogen atom, a (C1—C5) alkyl group or a (C3—C5) cycloalkyl group,” each substituent may be bound to any carbon atom in the alkynylene group. The “(CZ—Ca) alkynylene group which is ally substituted by a halogen atom, a ) alkyl group or a (C3-C5) cycloalkyl group and is modified by incorporation, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur atom, —SO—, —SOz- and -N(R)-” refers to a group which is the same as the mentioned optionally substituted straight (C2-C3) alkynylene group except for having such a heteroatom attached to a terminal carbon atom or inserted between carbon atoms in the alkynylene group. The specific examples include an ethynyleneoxy group, an ethynylenethio group, an ethynylene sulfinyl group, an ethynylene sulfonyl group, an ethynylene amino group, a yleneoxy group, a propynylenethio group, a propynylene sulfinyl group, a ylene sulfonyl group, a propynylene amino group, H2-O-CH2-, -CEC-CHz-S-CH2- and ~CECwCH2—NH-CH2-.
The “halogen atom” refers to a chlorine atom, a bromine atom, an iodine atom or a fluorine atom. The “(C1-C5) alkyl group” refers to a straight or ed alkyl group of l to 6 carbon atoms, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n—butyl group, an isobutyl group, a sec—butyl group, a tert-butyl group, a n-pentyl group, a neopentyl group, a n—hexyl group or the like.
The “ ) alkyl group optionally substituted by a halogen atom” refers to a straight or branched alkyl group of 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a n-propylgroup,anisopropylgroup,arrbutylgroup,anisobutyl group, a sec-butyl.group, a tert—butyfl.group, a11-pentyl.group, entyl group, a.n~hexyl group or‘the like; and.also refers to a ht or branched alkyl group of l to 6 carbon atoms substituted by one or more halogen atoms which.may be the same or different from each other, for example, a trifluoromethyl group, a romethyl group, a perfluoroethyl group, a hexafluoroisopropyl group, a perfluoroisopropyl group, a chloromethyl group, a bromomethyl group, a oethyl group, a 2,3—dibromopropyl group or the like.
The “(CZ-Ca) alkenyl group optionally substituted by a halogen atom” refers to a straight or branched alkenyl group of 2 to 6 carbon atoms, for example, a.vinyl group, a propenyl group, a butenyl group or the like; and also refers to a straight or branched alkenyl group of 2 to 6 carbon atoms substituted by one or~more halogen atoms whichlnay be the same or different from each other, for example, a fluorovinyl group, a difluorovinyl group, a orovinyl group, a 3 , 3 ~dichloropropenyl group , a 4 , 4 —difluoro— 3 ~butenyl group or the like.
The “(CZ—Cs) alkynyl group optionally substituted by a halogen atom” refers to a ht or branched alkynyl group of 2 to 6 carbon atoms, for example, an ethynyl group, a propynyl group, a butynyl group or the like; and also refers to a straight or branched alkynyl group of 2 to 6 carbon atoms substituted by one or more n atoms which may be the same or different from each other, for example, a fluoroethynyl group, a perfluoropropynyl group, a 4 , 4, 4-trifluoro-2—butynyl group or the like.
The “(Cl-Ce) alkoxy group ally substituted by a halogen atom” refers to a straight or branched alkoxy group of l to 6 carbon atoms, for example, a methoxy group, an ethoxy group , a oxy group , an isopropoxy group, a n—butoxy group , a sec-butoxy group, a tert-butoxy group, a n—pentyloxy group, an isopentyloxy group , a neopentyloxy group, a n~hexyloxy group or the like ; and also refers to a ht or branched alkoxy group of l to 6 carbon atoms substituted by one or more halogen atoms which may be the same or different from each other, for example, a trifluoromethoxy group, a difluoromethoxy group, a perfluoroethoxy group, a perfluoroisopropoxy group, a chloromethoxy group, a ethoxy group, a l—bromoethoxy group, a 2,3-dibromopropoxy group or the like.
The “(C1~C5) alkoxy (C1-C6) alkoxy group” refers to a straight or branched alkoxy group of l to 6 carbon atoms having a straight or branched alkoxy group of 1 to 6 carbon atoms as a substituent at a substitutable position, for example, a methoxymethoxy group , an ethoxymethoxy group , a l-methoxyethoxy group, a 2-methoxyethoxy group, a l-ethoxyethoxy group, a 2~ethoxyethoxy group or the like.
The “ (C1-C5) alkoxy (C1—C5) alkyl group” refers to a straight or branched alkyl group of 1 to 6 carbon atoms having a straight or branched alkoxy group of 1 to 6 carbon atoms as a substituent at a substitutable position, for example, a methoxymethyl group, an methyl group, a l—methoxyethyl group, a 2-methoxyethyl group , a l~ethoxyethyl group , a 2-ethoxyethyl group or the like.
The “(CZ-Ca) alkenyloxy group optionally tuted by a halogen atom” refers to a ht or branched loxy group of 2 to 6 carbon atoms, for example, a propenyloxy group, a loxy group, a pentenyloxy group or the like; and also refers to a straight or branched alkenyloxy group of 2 to 6 carbon atoms substituted by one or more halogen atoms which may be the same or different from each other, for example , a fluorovinyloxy group, a difluorovinyloxy group, a perfluorovinyloxy group, a 3,3-dichloropropenyloxy group, a 4 , 4 oro- 3 ~butenyloxy group or the like .
The “(CZ—Cs) alkynyloxy group optionally substituted by a halogen atom” refers to a straight or branched alkynyloxy group of 2 to 6 carbon atoms, for example, a propynyloxy group, a butynyloxy group, a pentynyloxy group or the like; and also refers to a straight or branched alkynyloxy group of 2 to 6 carbon atoms substituted by one or more halogen atoms which may be the same or different from each other, for example, a fluoroethynyloxy group, a perfluoropropynyloxy group, a 4,4,4~trifluoro-2—butynyloxy group or the like.
The “(Cl-Cs) alkylthio group optionally substituted by a halogen atom” refers to a straight or branched alkylthio group of 1 to 6 carbon atoms, for example, a methylthio group, an hio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, a sec-butylthio group, a tert—butylthio group, a n-pentylthio group, an isopentylthio group, a n—hexylthio group or the like; and also refers to a straight or branched alkylthio group of l to 6 carbon atoms substituted by one or more halogen atoms which may be the same or different from each other, for example, a trifluoromethylthio group, a romethylthio group, a perfluoroethylthio group, a perfluoroisopropylthio group, a chloromethylthio group, a bromomethylthio group a l - bromoethylthio , group, 2,3-dibromopropylthio group or the like.
The “(C1~C5) alkylsulfinyl group optionally substituted by a halogen atom” refers to a straight or branched alkylsulfinyl group of l to 6 carbon atoms , for example, a methylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl group, an pylsulfinyl group, a n-butylsulfinyl group, a sec—butylsulfinyl group, a tert-butylsulfinyl group, a n-pentylsulfinyl group, an isopentylsulfinyl group, a n~hexylsulfinyl group or the like; and also refers to a ht or branched alkylsulfinyl group of l to 6 carbon atoms substituted by one or more halogen atoms which may be the same or ent from each other , for example , a trifluoromethylsulfinyl group , a difluoromethylsulfinyl group, a perfluoroethylsulfinyl group, a perfluoroisopropylsulfinyl group, a methylsulfinyl group, a bromomethylsulfinyl group, a 1 ~ bromoethylsulfinyl group, a 2,3-dibromopropylsulfinyl group or the like.
The “(Cy-C5) alkylsulfonyl group optionally substituted by a halogen.atom” refers to a straight or branched ulfonyl group of l to 6 carbon atoms , for example, a methylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group, an isopropylsulfonyl group, a n-butylsulfonyl group, a sec~butylsulfonyl group, a tert-butylsulfonyl group, a ylsulfonyl group, an isopentylsulfonyl group, a n-hexylsulfonyl group or the like; and also refers to a straight or branched alkylsulfonyl group of l to 6 carbon atoms substituted by one or more halogen atoms which may be the same or different from each other , for example , a trifluoromethylsulfonyfl.group,21difluoromethylsulfonyfl.group, a perfluoroethylsulfonyl group, a oroisopropylsulfonyl group, a chloromethylsulfonyl group, a bromomethylsulfonyl group , a 1 - bromoethylsulfonyl group, a 2,3-dibromopropylsulfonyl group or the like.
The “(Cl-Cs) alkylcarbonyl group” refers to a straight or branched alkyl group of l to 6 carbon atoms bound to a carbonyl group, for e, a methylcarbonyl group, an ethylcarbonyl group, a n—propylcarbonyl group, an isopropylcarbonyl group, a n-butylcarbonyl group, a tert—butylcarbonyl group or the like.
The “( C1-C5) alkoxycarbonyl group" refers to a straight or branched alkoxy group of l to 6 carbon atoms bound to a carbonyl group, for example, a methoxycarbonyl group, an ethoxycarbonyl group , a n—propoxycarbonyl group , an isopropoxycarbonyl group, a n~butoxycarbonyl group, a tert-butoxycarbonyl group or the like .
The “(Cl-c5) alkoxyimino (C1~C3) alkyl group” refers to a straight or branched alkoxy group of 1 to 6 carbon atoms bound to an imino ) alkyl group, for example, a methoxyimino methyl group, an ethoxyimino methyl group, a n-propoxyimino methyl group, an isopropoxyimino ethyl group or the like.
The “(C3-C3o) trialkylsilyl group” refers to a ht or branched alkylsilyl group of 3 to 30 carbon atoms in total, for example, a trimethylsilyl group, a triethylsilyl group or the like .
The “mono(C1-C5) alkylsulfonylamino group optionally substituted by a halogen atom” refers to a straight or branched kylsulfonylamino group of 1 to 6 carbon atoms , for example, a methylsulfonylamino group, an ethylsulfonylamino group, an isopropylsulfonylamino group or the like ; and also refers to a straight or branched monoalkylsulfonylamino group of l to 6 carbon atoms substituted by one or more halogen atoms which may be the same or different from each other, for e, a oromethylsulfonylamino group or the like.
The “(c3—c6) cycloalkane” that R1, R2, R3 and R4 may join together in any combination to form and the “(Ca—Cs) lkane” that R1, R2, R3, R4, R5 and R6 may join together in any combination to form are, for example, cyclopropane, utane, cyclopentane, cyclohexane or the like.
Examples of the “ (C2 -C4) alkyleneoxy group” include "CH2'CH2‘O', 'CH2“C(CH3)2-O-, -CH2-CH2-CH2-O* and H2-CH2-CH2~O~ .
The “ (C1~C3) alkylene dioxy group optionally tuted by a halogen atom” refers to an alkylene dioxy group of 1 to 3 carbon atoms, for example, ~O-CH2-O-, -O-CH2-CH2-O~, ~O~CH2~CH2—CHz-O- or the like; and also refers to an alkylene dioxy group of 1 to 3 carbon atoms substituted by one or more halogen atoms which may be the same or different from each other, for example, ~0~CF2-O—, ~O-CF2-CF2-O-, -O-CC12~O— or the like.
The “heterocyclic group" refers to a 5— or 6—membered monocyclic aromatic or 3- or 6-membered monocyclic non—aromatic heterocyclic group containing, as ring atoms , a carbon atom(s) and 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom; and also refers to a condensed heterocyclic group formed by condensation of such a monocyclic aromatic or non-aromatic cycle with a benzene ring or by condensation of such monocyclic aromatic or non-aromatic heterocycles (the heterocycles may be different from each other).
Examples of the “aromatic cyclic group” e monocyclic aromatic heterocyclic groups , such as furyl , thienyl , pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, yl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl andtriazinyl;andaromaticcondensedheterocyclicgroups,such as quinolyl, isoquinolyl, olyl, quinoxalyl, benzofuranyl, benzothienyl, azolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, l, lyl, opyrazinyl, imidazopyridinyl, imidazopyrazinyl, pyrazolopyridinyl, pyrazolothienyl and pyrazolotriazinyl.
Examples of the “non-aromatic heterocyclic group” include monocyclic non-aromatic heterocyclic groups , such as oxiranyl, thiiranyl, aziridinyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, piperidinyl, linyl, thiomorpholinyl, piperazinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl, imidazolinyl, dioxolyl, dioxolanyl, dihydrooxadiazolyl, 2—oxo~1,3—oxazolidin~5—yl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, l-oxide tetrahydrothiopyranyl, 1,1~dioxide tetrahydrothiopyranyl, tetrahydrofuryl, dioxanyl, pyrazolidinyl, pyrazolinyl, tetrahydropyrimidinyl, dihydrotriazolyl and tetrahydrotriazolyl; and non-aromatic condensed.heterocyclic groups, such as oindolyl, dihydroisoindolyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, obenzodioxepinyl, tetrahydrobenzofuranyl, chromenyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl and dihydrophthalazinyl.
Examples of a salt of the carboxamide derivative ented by the general formula (I) of the present invention include inorganic acid salts , such as hydrochlorides, sulfates , nitrates and phosphates; organic acid salts, such as acetates, fumarates , maleates , oxalates , methanesulfonates benzenesulfonates and p-toluenesulfonates; and salts with an inorganic or organic base such as a sodium ion, a potassium ion, a m ion and a trimethylammonium ion.
As the carboxamide derivative of the present invention, preferred is a compound of the general a (I) wherein A represents a (C1—C8) alkylene group optionally substituted by a (Cl—Ca) alkyl group and/or a (C3~C6) cycloalkyl group; —CR1(R2)—CR3(R4)—Q— (wherein R1, R2, R3 and R4 may be the same or different from each other, and represent a hydrogen atom, a (Cl-C5) alkyl group or a (C3-C5) cycloalkyl group, or R1, R2, R3 and R‘1 may join together in any combination to form a (C3~C6) cycloalkane, and Q represents an oxygen atom, a sulfur atom, -SO-, -SO;- or —N(R)- (wherein R represents a hydrogen atom, a (C1—C6) alkyl group, a (C3-C5) cycloalkyl group, a (C1-C5) arbonyl group or a (C1-C5) alkoxycarbonyl ; or 2)-CR3(R4)-CR5(R6)-Q- (wherein R1, R2, R3, R‘ and Q are as defined above, and R5 and R6 may be the same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group or a (C3-C6) cycloalkyl group, or R1, R2, R3, R4, R5 and R6 may join together in any ation to form a (C3-C5) cycloalkane) , E represents a hydrogen atom; a (C1-C5) alkyl group; a (C1-C6) alkylcarbonyl group; or a (Cl-C6) alkoxycarbonyl group, each X may be the same or ent , and represents a halogen atom; a (Cl-C5) alkyl group optionally substituted by a halogen atom; a (C1-C5) alkoxy group optionally substituted by a halogen atom; or a (C1-C6) alkylthio group ally substituted by a n atom. m ents 1 or 2, each Y may be the same or different , and represents a halogen atonn a. hydroxy group; a (C1-C5) alkyl group optionally substituted by a halogen atom; a (Cl-C5) alkoxy group optionally substituted by a n atom; a (C1-C5) alkoxy (C1—C5) alkoxy group; a (C2-C6) alkenyloxy group optionally substituted by a halogen atom; a mono( C1-C5) alkylsulfonylamino group optionally substituted by a halogen atom; a phenyl group optionally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (C1-C6) alkyl group optionally substituted by a halogen atom, and a (C1—C5) alkoxy group optionally tuted by a halogen atom; a phenoxy group optionally substituted by one or more substituents selected 2O from a halogen atom, a cyano group, a nitro group, a (C1-C6) alkyl group optionally substituted by a n atom, and a (C1—C5) alkoxy group ally substituted.by a.halogen atom; a heterocyclic group optionally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (C1—C6) alkyl group optionally substituted by a halogen atom, and a (C1~C6) alkoxy group optionally substituted by a halogen atom; or a heterocycloxy group optionally tuted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (Cl-Ce) alkyl group optionally substituted by a halogen atom, and a (Cl—Cs) alkoxy group optionally substituted by a halogen atom, n represents an integer of O to 3, with the proviso that when n is 2 or 3, two nt Y groups may join together to form a (C2—C4) alkyleneoxy group or a (C1-C3) alkylene dioxy group optionally substituted by a halogen atom, and 2 ents a nitrogen atom; CH,- or CY (wherein Y is as defined above).
More preferred is a compound of the general formula (I) wherein A represents a (C1—C5) alkylene group optionally substituted by a (C1-C6) alkyl group and/or a ) cycloalkyl group; -CR1(R2)-CR3(R‘)~Q~ (wherein R1, R2, R3 and IR4 may be the same or ent from each other, and represent a hydrogen atom, a (C1-C5) alkyl group or a (C3—C5) cycloalkyl group, and Q represents an oxygen atom or a sulfur atom); or -CR1(R2)-CR3(R4)-CR5(R6)-Q- (wherein R1, R2, R3, R4 and Q are as defined above, and R5 and R6 may be the same or different from each other, and represent a hydrogen atom, a (C1~C6) alkyl group or a (C3-C5) lkyl group), E represents a hydrogen atom, each X may be the same or different , and represents a halogen atom or a (Cl-Cs) alkyl group optionally substituted by a halogen atom, m ents 1, each Y may be the same or different , and represents a halogen atom or a (C1—C6) alkyl group optionally tuted by a halogen atom , n represents an integer of 1 to 3, and Z represents a nitrogen atom; CH; or CY (wherein Y is as defined above) .
The nd represented by the general formula (I) of the present invention is a known compound, and can be produced by the production method described in JP—A 01-151546, WO 2007/060162, JP-A 53—9739, , W0 2008/101975, WO 2008/101976, , , , W0 2009/127718 or WO 06071, the method described in Shin—Jikken Kagaku Kouza 14 (Maruzen, December 20, 1977), a ed method of the foregoing, or the like.
Representative examples of the carboxamide derivative represented by the general formula (I) of the t invention are shown in Table l, but the present invention is not limited thereto. In Table 1, “Me” represents a methyl group, “Et” represents an ethyl group, “Pr" represents a propyl group, “Bu” represents a butyl group, “Ph” represents a phenyl group, “0-” represents cyclo, “i-” represents iso , “t-” represents ry, and the physical property refers to a melting point (°C) .
Regarding the compounds shown with the note ” in the column “Physical property” in Table l , their 1HNMR spectrum data are shown in Table 5. Q1 to Q7 represent the following structures.
C1 fie; Q19 0 l‘v—/ CF3 23 O 1\‘J/ CF3 Q3, 0 Cl 3 s (27, 0—(N'/ (X) -- H R3 R4 m N (1—1) () 111112 “-(an Table 1 ---flflfl_- “mu—— --nnnn—— —---——n -n-m-_n ”mum mama _--fl--—— -—-——nun “mun —-n--—_n 1-13 2—I H H Me Et 4-Cl Paste —--——nn “nun—- —----——n manna --nnnn—— “mun manna—— -—-_—nnu --—-nnn “unn-—_ --n-n-— ”mama “I—flflfl —-nnnn_ mun“ Table 1 (Continued) --Iflflfl “nun“ - “III—H “man—- ”——— “nu—— —-_—nnu -I-—_ mun—— mun—— "mun —m:flflfl__144 2, 4--Clz 124- 126 “—flflflfl— —-IIII—- -———IIII —IIII—_ I—--I-—— _-——IIII ——IIII—— —_Il——II —-IIII—— --I_II— —-IIII—- ————IIII —-lI——II —-IIII—— Table 1 (Continued) --"-- -II—I_ ”IIII- “II—mn— ——IIII——.
——IIII——.
————IIII -IIII—— --II__II —-II—-II —-IIII—— —-I—III- “II—flu- ——n:n-n——1-74 2CF3 2---Cl4Q5 “mu-n” mann— Emu—n— manna—— “mama—— “mama—— ---mnn—— “m-nn—— “man—— “an— mann— “MIME—— —-mmnu—- ”mn_— Table 1 (Continued) “HIE-u man- “In—— ---_- —-n-—nu— mun— —-----n_ ”ma— -—--—nn— ”unan— mu--—_ “Inna—— 1—- 104 2--CF;, 2-Cl- 4- SOMe 128. 9- 129. 6 unnu— ——n-nn—— -fl-fl— “-nnn" --n-n-—_ “Inna—- “n-mm—_ mm—(erHYO‘)“ <12) 0R1 R2 Table 2 -”-- ”nu— ———-nn _n”—- “nu—— -—-—-n —-—_nn —-———n (X)m-O\K§ Y1 ”a (1—3) 0 N Table 3 (X)m Y Y property value —u-— --——n x m— H R3 R4 -m1] 0 R1 R2 Table 4 "Iflflfl—n "II-“l- nnll “nun—— lama m-mnn “mu-u ----—_nn mum—— ul-nn-mn—— "annual-— Table 5 Com 0 nd 7.65(dd, 1H), 7.51(m, 2H), 7.32(dd, 1H), 7.30(d, 2H), 7.14(d, 2H), 5.58(br, 1H), 3.92(m, 1H), , 1H), 2.80(m, 1H), l.79(m,1H), 1.60(m, 1H), 0.83(t, 3H) 7.65(d, 1H), 7.51(m, 2H), 7.25-7.36(m, 5H), 5.40(br, 1H), d, 1H), 3.59(dd, 1H), l.80(m, 1H), 1.66(m, 1H), 1.37(s, 3H), 0.74(t, 3H) 7.65(dd, 1H), 7.51(m, 2H), 7.26-7.37(m, 5H), 5.31(br, 1H), , 2H), l.75(m, 4H), 0.79(t, 6H) 7.65(dd, 1H), 7.51(m, 2H), 7.32(dd, 1H), 7.29(d, 2H), , 2H), 5.56(br, 1H), 3.87(m, 1H), 3.33(m, 1H), 2.98(m, 1H), 1.53(m, 2H), l.40(m, 1H), 0.87(t, 6H) 7.81(dd, 1H), 7.27-7.34(m, 5H), 7.22(dd, 1H), 7.05(dt, 1H), .43(br, 1H), 3.76(dd, 1H), 3.61(dd, 1H), , 1H), l.68(m, 1H), l.4l(S, 3H), , 3H) 7.81(dd, 1H), 7.30~7.35(m, 5H), 7.22(dd, 1H), 7.06(dt, 1H), .34(br, 1H), 3.75(d, 2H), l.78(m, 4H), O.81(t, 6H) 7.70(d, 1H), , 1H), 7.53(t, 1H), 7.46(d, 1H), 7.4D(s, 1H), 7.39(d, 1H), 7.30(d, 1H), 5.86(br, 1H), 3.7l(dd, 2H), 3.00(t, 2H), 2.44(S, 3H) 7.69(d, 1H), 7.47-7.60(m, 3H), 7.36(t, 2H), 7.24(d, 1H), 7.15(t, 1H), 7.00—7.03(m, 3H), 6.88(dd, 1H), 5.85(br, 1H), 3.73(q, 2H), 3.05(t, 2H) The endoparasite control agent of the t invention has excellent anti-endoparasite effect, and exerts appropriate controleffectagainstendoparasites. Theanimalforwhichthe endoparasite control agent of the present invention can be used is a human and an animal of non-human mammalian or avian species . ary members of the non-human mammalian species include ic animals, such as pigs, horses, cattle, sheep, goats, rabbits, camels, water buffalos, deer, mink and chinchillas; pet s, such as dogs, cats, little birds and.monkeys; and experimental animals, such as rats, mice, golden hamsters and guinea pigs. Exemplary members of the avian species include domestic fowls, such as chickens, ducks, aigamo ducks (crossbreeds of wild and domestic ducks), quails, domestic ducks, geese and s.
Human rasites against which the rasite l agent of the present invention is effective are roughly classified into protozoa and helminths. Examples of the protozoa include, but are not limited.thereto, Rhizopoda, such as Entamoeba histolytica; Mastigophora, such as ania, Trypanosoma and Trichomonas; oea, such as Plasmodium and Toxoplasma; and Ciliophora, such as Balantidium coli.
Examples of the helminths include, but are not limited thereto, Nematoda, such as Ascaris lumbricoides, Anisakis, Toxocara canis, Trichostrongylus spp., Enterobius vermicularis, hookworms (for example, Ancylostoma ale, Necator americanus, Ancylostoma braziliense, etc.), Angiostrongylus spp., Gnathostoma spp., filarial worms (filaria, Wuchereria bancrofti. Brugia malayi , etc. ) , Onchocerca volvulus , Dracunculus nsis, Trichinella spiralis and Strongyloides stercoralis ; Acanthocephala , such as Macracan thorhynchus hirudinaceus; Gordiacea, such as Gordioidea; Hirudinea, such as Hirudo nipponia; Trematoda, such as Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium, chis sinensis, Heterophyes heterophyes, Fasciola spp. and Paragonimus spp.; and Cestoda, such as Diphyllobothrium latum, Sparganum mansoni, Sparganum proliferum, Diplogonoporus grandis, Taeniidae (for example, Taeniarhynchus saginatus, Taenia solium, Echinococcus, etc. ) , Hymenolepis spp., diunzcaninum, Mesocestoides.lineatus, Bertiella spp. and nia surmenicola.
Non-human mammalian or avian endoparasites against which the rasite control agent of the present invention is effective are roughly classified into protozoa and.helminths.
Examples of the protozoa include, but are not limited thereto, Apicomplexa, such.as Coccidia (for‘example, Eimeria, ra, Toxoplasma, Neospora, Sarcocystis, Besnoitia, Hammondia, Cryptosporidium, Caryospora, etc.), Haemosporina (for example, Leucocytozoon, dium, etc.), Piroplasma (for example, Theileria, Anaplasma, Eperythrozoon, Haemobartonella, Ehrlichia, etc.), and others (for example, Hepatozoon, Haemogregarina , etc. ) ; Microspora, such as Encephalitozoon and NOsema; Mastigophora, such as Trypanosomatina (for example, Trypanosoma, Leishmania, etc.), Trichomonadida (for example, Chilomastix, Trichomonas, Monocercomonas, Histomonas, etc.), and onadida (for example, Hexamita, Giardia, etc.); Sarcodina , such as Amoebida (for example , Entamoeba histolytica (Entamoeba) etc.); and Ciliophora, such as Balantidium coli (Balantidium), Buxtonella and Entodinium.
Examples of the helminths include, but are not limited thereto, de, such as Ascaridida (for e, Ascaris suum (Ascaris), Toxocara canis and Toxocara cati (Toxocara), Toxascaris leonina (Toxascaris), Parascaris equorum (Parascaris), Ascaridia galli (Ascaridia), Heterakis gallinarwn(Heterakis),Anisakis,etc.),Oxyurida(forexample, Oxyuris equi (Oxyuris), Passalurus ambiguus (Passalurus), etc.), Strongylida (for example, Strongylus vulgaris (Strongyflus), Haemonchus contortus (Haemonchus), agia ostertagi (Ostertagia), Trichostrongylus colubriformis (Trichostrongylus) , Cooperia punctata (Cooperia) , Nematodirus filicollis (Nematodirus), Hyostrongylus rubidus (Hyostrongylus), agostomum.radiatum (Oesophagostomum), Chabertia ovina (Chabertia), Ancylostoma caninum (Ancylostoma), Uhcinaria stenocephala (Uhcinaria), Nacator americanus (Nantor), omum tomum (Bunostomum), Dictyocaulus Viviparus (Dictyocaulus), Metastrongylus elongatus (Metastrongylus), Filaroides hirthi (Filaroides), strongylus abstrusus (Aelurostrongylus), Angiostrongylus cantonensis (Angiostrongylus), Syngamus trachea (Syngamus), Stephanurus dentatus (Stephanurus), etc.), Rhabditida (for example, Strongyloides stercoralis (Strongyloides), Micronema, etc.), Spirurida (for example, Thelazia.rhodesi (Thelazia), OxyspiruraJnansoni (Oxyspirura), erca lupi (Spirocerca), onema pulchrum (Gongyionema), Draschia megastama (Draschia), ema 2O microstoma (Habronema), ps strongylina (Ascarops), Physaloptera tialis (Physaloptera), Gnathostoma spinigerum (Gnathostoma), etc.), Filariida (for example, Dirofilaria immitis ilaria), Setaria equina (Setaria), Dipetalonema, laria multipapillosa (Parafilaria), Onchocerca cervicalis (Onchocerca), etc.), and Enoplida (for example, Parafilaria bovicola (Parafilaria), Stephanofilaria okinawaensis (Stephanofilaria), Trichuris vulpis (Trichuris), Capillaria bovis (Capillaria), Trichosomoides crassicauda (Trichosomoides), Trichinella spiralis (Trichinella), Dioctophyma renale (Dioctophyma), etc.); Trematoda, such as Fasciolata (for example, Fasciola hepatica (Fasciola), Fasciolopsis buski (Fasciolopsis), etc.), Paramphistomatidae (for example, gaster paloniae (Hbmalogaster), etc.), Dicrocoelata (for e, Eurytrema pancreaticum (Eurytrema) oelium dendritioum (Dicrocoelium), etc.), Diplostomata (for example, Pharyngostomum cordatum (Pharyngostomum), Alaria, etc.), Echinostomata (for e, Echinostoma hortense (Echinostoma), Echinochasmus, etc.), Troglotrematoidea (for example, lung flukes (Paragonimus), yetus salmincola (Nanophyetus), etc.), Opisthorchiida (for example, Clonorchis sinensis rchis) etc.), Heterophyida (for example, Heterophyes heterqphyes (Heterophyes), nimus yokogawai (Metagonimus), etc.), Plagiorchiida (for example, Prosthogonimus ovatus (Prosthogonimus) etc.), and Schistosomatidae (for example, Schistosoma japonicum (Schistosoma) etc.); a, such as Pseudophylidea (for example, Diphyllobothrium nihonkaiense (Diphyllobothrium), Spirometra erinacei (Spirometra), etc.), and Cyclophyllidea (for example, Anoplocephala perfoliata (Anoplocephala), Paranoplocephala mamillana (Paranoplocephala), Mbniezia benedeni (Mbniezia), Dipylidium caninum(Dipylidiwn),Mesocestoideslineatus(Mbsocestoides), Taenia pisiformis and Taenia hydatigena (Taenia), Hydatigera taeniaeformis (Hydatigera), MUlticeps eps (Multiceps), Echinococcus granulosus (Echinococcus), Echinococcus multilocularis (Echinococcus), ibenia solium (Taenia), Taeniarhynchus saginatus (Taeniarhynchus), Hymenolepis diminuta (Hymenolepis), vampirolepis nana (vampirolepis), Raillietina tetragona (Raillietina) , Amoebotaenia sphenoides (Amoebotaenia) , etc. ) ; Acanthocephala, such as Macracanthorhynchus hirudinaceus (Macracanthorhynchus) and formis moniliformis (Moniliformis); Linguatulida, such as Linguatula serrata (Linguatula): and other various parasites.
In different designations, examples of the helminths include, but are not limited to, Nematode, such as da (for example,Ziichurisspp.,capillariaspp.,Trichomosoidesspp., ikichinellaspp.,etc.),Rhabditia(forexample,Micronemaspp., Strongyloides spp., etc.), ylida (for example, Strongylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., nurus spp., Ancylostoma spp., Uhcinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Mnellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., ParelaphostrongleS'spp., Crenosoma spp., Paracrenosoma spp., Angiostrongyius spp.,.Aelurostrongylus spp., Filaroides spp., laroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., nus spp., etc.), Oxyurida (for e, Oxyuris spp., Enterobius spp., Passalurus spp. , Syphacia spp. , Aspiculuris spp. , Heterakis spp. , etc. ) , Ascaridia (for example, Ascaris spp. , aris spp. , Toxocara spp. , Parascaris spp. , Anisakis spp. , dia spp. , etc. ) , Spirurida (for example, Gnathostoma spp. , Physaloptera spp. , Thelazia spp. , Gongylonema spp. , Habronema spp. , Parabronema spp. , Draschia spp . , Dracunculus spp. , etc. ) , and Filariida (for example, Stephanofilaria spp. , Parafilaria spp. , Setaria spp. , Loa spp. , Dirofilaria spp. , Litomosoides spp., Brugia spp. , Wuchereria spp. , Onchocerca spp., etc.); Acanthocephala (for example, Filicollis spp. , Moniliformis spp. , Macracanthorhynchus spp. , Prosthenorchis spp. , etc. ) ; Trematoda including subclasses , such as Monogenea (for example , Gyrodactylus spp. , Dactylogyrus spp. , Polystoma spp. , etc. ) and a (for example, Diplostomum spp . , Posthodiplostomum spp. , Schistosoma spp. , Trichobilharzia spp . , Ornithbilharzia spp. , Austrobilharzia spp. , Gigantobilharzia spp.
, Leucochloridium spp. , Brachylaima spp. , Echinostoma spp. , Echinoparyphium spp . , Echinochasmus spp. , Hypoderaeum spp. , Fasciola spp. , Fasciolides spp. , Fasciolopsis spp. , oelum spp. , coelum spp. , Paramphistomum spp. , phoron spp. , Cotylophoron spp. , Gigantoctyle spp. , Fischoederius spp. , Gastrothylacus spp. , Notocotylus spp. , Catatropis spp. , Plagiorchis spp. , Prosthogonimus spp. , Dicrocoelium spp. , Eurytema spp. , Troglotrema spp. , nimus spp. , Collyriclum spp. , Nanophyetus spp. , Opisthorchis spp. , Clonorchis spp. , Metorchis spp. , Heterophyes spp. , Metagonimus spp. , etc. ) ; Cestoda , such as Pseudophyllidea (for example , Diphyllobothrium spp. , Spirometra spp. , Schistocephalus spp. , Ligula spp. , Bothridium spp. , Diplogonoporus spp. , etc. ) , and Cyclophyllidea (for example, Mesocestoides spp. , Anoplocephala spp. , Paranoplocehala spp. , Moniezia spp. , osomsa spp. , Thysaniezia spp. , lina spp. , ia spp. , Cittotaenia spp . , Andyra spp. , Bertiella spp. , Taenia spp. , Echinococcus spp. , Hydatigera spp. , Davainea spp. , Raillietina spp. , Hymenolepis spp. , Echinolepis spp. , Echinocotyle spp. , Diorchis spp. , Dipylidium spp. , Joyeuxiella spp. , Diplopylidium spp. , etc . ) ; and others including parasites belonging to Acanthocephala and Linguatulida.
The endoparasite control agent of the present invention is effective against not only parasites that live in the body of an intermediate or final host, but also parasites that live in the body of a reservoir host . The compound ented by the general a (I) of the present invention is effective at every developmental stage of tes. For example, in the case of protozoa, the compound is effective against their cysts precystic forms and trophozoites; schizonts and amoeboid forms at the l stage; gametocytes, gametes and zygotes at the sexual stage; sporozoites; etc. In the case of nematodes, the compound is effective against their eggs, larvae, and adults.
The compound of the present invention is capable of not only combating parasites in the living body, but also even preventing parasitic infection by application to the environment as a route of infection. For example, soil-borne infection, i.e. infection from soil of crop fields and parks; percutaneous infection from water in rivers, lakes, s, paddy fields, etc. ; oral infection from feces of animals such as dogs and cats; oral infection from saltwater fish, freshwater fish, crustaceans, shellfish, raw meat of domestic animals, etc.; infection from mosquitoes , gadflies , flies , cockroaches , mites , fleas, lice, assassin bugs, trombiculid mites, etc.; and the like can be prevented from occurring.
The endoparasite control agent of the present invention can be administered as a pharmaceutical for treatment or prevention of'parasitosis in humans and animals of non~human1nammalian or avian species. The mode of administration may be oral or parenteral administration. In the case of oral administration, the endoparasite control agent of the present invention can be stered, for example, as a capsule, a tablet, a pill, a powder, a granule, a fine granule, a powder, a syrup, an c-coated preparation, a suspension or a paste, or after blended in a liquid drink or feed for animals. In the case of parenteral administration, the endoparasite control agent of the present invention can be stered in a dosage form which allows sustained mucosal or percutaneous absorption, for example, as an injection, an infusion, a suppository, an emulsion, a suspension, a drop, an nt a cream, a solution, a lotion, a spray, an aerosol, a cataplasm or a tape.
In the case where the rasite control agent of the present invention is used as a pharmaceutical for humans and animals of man mammalian or avian s, the optimum amount (effective amount) of the active ingredient varies with the purpose (treatment or prevention), the kind of infectious parasite, the type and severity of infection, the dosage form, etc., but in general, the oral daily dose is in the range of about 0 . 0001 to 10000 mg/kg body weight and the parenteral daily dose is in the range of about 0.0001 to 10000 mg/kg body weight, and such a dose may be administered as a single dose or d doses.
The concentration of the active ingredient in the endoparasite control agent of the t invention is generally about 0.001 to 100% by mass, preferably about 0.001 to 99% by mass , and more ably about 0 . 005 to 20% by mass.
The endoparasite control agent of the present invention may be a composition that can be ly administered, or a highly concentrated composition that is used for administration after diluted to a suitable concentration.
For the purpose of reinforcing or complementing the effect of the endoparasite control agent of the present invention, a ed use with any existing endoparasite control agent is possible. In such a combined use, two or more active ingredients may be mixed and formulated into a preparation before administration, or two or more different preparations may be administered separately.
EXAMPLES Next, the present invention will be illustrated in detail by formulation examples and test examples of the endoparasite control agent of the present invention, but the scope of the present invention is not limited by the following formulation examples and test examples.
Formulation e 1 (emulsion) Ten parts of the carboxamide derivative represented.by the general formula (I) of the present invention, 6 parts of Sorpol 3555 (surfactant, manufactured by Toho Chemical ry) , and 84 parts of Solvesso 150 (manufactured.by Exxon) are uniformly mixed with stirring to give an emulsion.
Formulation Example 2 (ointment) One part of the carboxamide derivative represented by the general formula (I) of the present ion, 50 parts of white beeswax, and 49 parts of white petrolatum are well mixed to give an ointment.
Formulation Example 3 (tablet) Two parts of the carboxamide tive represented.by the general formula (I) of the present invention, 10 parts of vegetable oil (olive oil), 3 parts of crystalline cellulose, 20 parts of white carbon, and 65 parts of kaolin are well mixed and compressed into a tablet.
Formulation Example 4 (injection) Ten.parts of the carboxamide derivative represented.by the general formula (I) of the present ion, 10 parts of propylene glycol for use as a food additive, and 80 parts of vegetable oil (corn oil) are mixed to give an injection.
Formulation e 5 (solution) Five parts of the carboxamide derivative represented by the general formula (I) of the present invention, 20 parts of surfactant, and 75 parts of ion exchanged water are well mixed to give a solution.
Test Example 1 (in vitro measurement of inhibitory activity on Ascaris suum succinate—ubiquinone reductase (mitochondrial complex 11)) To a solution containing 50 mM potassium phosphate (pH 7 .4) and 0.1% (w/v) sucrose monolaurate, an electron acceptor ubiquinone-z (UQz) was added at a final concentration of 60 MM, and the mixture was allowed to stand at 25°C for 20 s.
To this, potassium cyanide (final concentration: 2 mM) and mitochondria prepared from adult Ascaris suum muscle were added, and thorough mixing was done. To aliquots of the mixture, an inhibitor to be tested was added at various concentrations, and the mixtures were allowed to stand at 25°C for 3 minutes. The enzymatic on was ted by addition of potassium succinate (final concentration: 10 mM) . The enzymatic activity was calculated based on the measurement of change in the absorbance at 278 nm of UQz (a = 1.5x104 l), and ICso was determined from the plot of the inhibition percentage t the inhibitor tration.
Test Example 2 (in vitro ement of inhibitory activity on porcine succinate—ubiquinone reductase (mitochondrial complex II)) To a solution containing 50 mM potassium phosphate (pH 7 .4) and 0.1% (w/v) sucrose monolaurate, an electron acceptor ubiquinone-2 (UQZ) was added at a final concentration of 60 MM, and the e was allowed to stand at 25°C for 20 minutes.
To this, potassium e (final concentration: 2 mM) and mitochondria prepared from porcine heart muscle were added, and thorough mixing was done. To aliquots of the mixture, an inhibitor to be tested was added at various concentrations , and the es were allowed to stand at 25°C for 3 s. The enzymatic reaction was initiated by on of potassium succinate (final concentration: 10 mM). The enzymatic activity was calculated based on the measurement of change in the absorbance at 278 nm of U02 (8 1.5x10“ M‘lcm'l), and Ic50 was determined from the plot of the inhibition percentage against the inhibitor concentration.
The results are shown in Table 5. In the table, “-” tes “not tested,” and “Ascaris suum ICso value (A)” indicates an Icw value (50% inhibitory concentration) for inhibition of succinate-ubiquinone reductase (mitochondrial complex II) of s suum. From the extent of inhibition of this respiratory enzyme, the parasite control activity can be estimated. “Porcine mitochondria ICm,value (8)” indicates an Icm value for inhibition of succinate-ubiquinone reductase (mitochondrial complex II) of the host pig. From the extent of inhibition of this respiratory enzyme, the influence on the host can be estimated. A greater selectivity index B/A indicates a higher safety for the host.
Table 6 Ascaris suum Porcine ondria Selectivity No. ICsovalue(A) ICsovalue(B) B/A iii nn no inhibition at 90 MM no inhibition at 90 pM iii ii no inhibition at 90 [.LM iii in no inhibition at 9 pM no inhibition at 9 MM 1~llO 4.07 nM no inhibition at 10 1114 iii in no inninininn ii in in iii ii no inhibition at 90 pm ii iii in mm no inhibition at 90 [.LM 70.5 nM no inhibition at 90 [AM inn nn no inhibition at 9 uM _N-\I 14 nM no inhibition at 90 11M no inhibition at 90 uM 3-7 90 w 4-1 3.44 nM 3% I N 5.15 nM #h I L0 1.98 nM 8.36 nM 6.07 nM Ih l 0‘ 8.34 nM no inhibition at 9 pM #8 I \l 1.78 nM w 2.61 nM As is clear from the results in Table 5, the carboxamide derivatives represented by the general a (I) of the present invention and salts thereof showed a strong inhibitory activity on the parasitic succinate—ubiquinone reductase (mitochondrial complex II) (ICso values: 1.21 to 127 nM) , but hardly affected the ty of succinate—ubiquinone reductase hondrial complex II) of the host pig (more than 1 , GOO-fold selectivity) . Therefore, the endoparasite control agent of the present invention is not only highly active in parasite control, but also highly safe for the host.
Test Example 3 (in vivo activity on Haemonchus contortus) The test was conducted according to the larval migration inhibition assay (LMIA: Demeler et al., 2010). A larval suspension was prepared so as to contain 100 to 120 third-stage larvae of Haemonchus contortus per 20 uL, and then 20 p21. of the larval suspension was added to each well on a breeding plate to which compound solutions ed to predetermined concentrations were usly added at 1780 uL/well each. The breeding plate was maintained for breeding at 28°C for 24 hours .
Meanwhile, to a plate for larval migration observation, 400 uL of a 1.5% agar solution was added and left to stand until coagulation. Then, the larvae were allowed to migrate through a sieve from the breeding plate to the plate for larval migration observation , and the plates were maintained for breeding at 28°C for another 24 hours. The larvae which had migrated, and the larvae which had not migrated were counted, the percentage of migration inhibition was calculated, and the activity was graded based on the following ion. All samples were tested in duplicate, and the results are shown in Table 7. In the table, “-” indicates “not tested.” tage of migration inhibition 70 to 100%: A 40 to 69%: B HAS510030NZPR 303788177 to 39%: C lower than 10%: D Table 7 Compound Concentration (ppm) No. 100 10 1 0.1 1-16 B C C C 1-32 - B C C 2-1 - - B C 2-6 - C C C 3-7 B C C C 4-1 - C C C 4-7 B C C C As is clear from the results in Table 7, the compounds proven in the described in vitro test to have a strong activity showed a strong activity in the in vivo test as well, and thus the compound of the present invention is effective as an endoparasite control agent.
Unless the context clearly requires otherwise, throughout the ption and the claims, the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of “including, but not limited to”.
The reference to any prior art in the specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in New Zealand.
HAS510030NZPR 303864629

Claims (8)

1. A method for controlling endoparasites, comprising orally or parenterally stering to a non-human mammal or bird an 5 effective amount of an rasite control agent comprising a carboxamide derivative represented by the general formula (I): wherein A represents a (C1-C8) alkylene group optionally 10 substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group; a (C1-C8) alkylene group which is optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group and is modified by incorporation, into the carbon chain, of at least one heteroatom 15 selected from an oxygen atom, a sulfur atom, -SO-, -SO2- and -N(R)- in R represents a hydrogen atom, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C6) alkylcarbonyl group or a (C1-C6) alkoxycarbonyl group); a (C2-C8) alkenylene group optionally substituted by a halogen atom, a (C1-C6) alkyl group 20 and/or a (C3-C6) cycloalkyl group; a (C2-C8) alkenylene group which is optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group and is modified by incorporation, into the carbon chain, of at least one atom selected from an oxygen atom, a sulfur atom, -SO-, 25 -SO2- and -N(R)- (wherein R is as d above); a ) lene group optionally substituted by a halogen atom, a HAS510030NZPR 303864629 (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group; or a (C2-C8) alkynylene group which is optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group and is ed by incorporation, into the carbon chain, 5 of at least one atom selected from an oxygen atom, a sulfur atom, -SO-, -SO2- and -N(R)- in R is as defined above), and in each case, A may form a cyclic structure, where le, E represents a hydrogen atom; a (C1-C6) alkyl group; a (C3-C6) cycloalkyl group; a (C1-C6) alkoxy (C1-C6) alkyl group; a (C1-C6) 10 arbonyl group; or a (C1-C6) alkoxycarbonyl group, each X may be the same or different, and represents a halogen atom; a cyano group; a nitro group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C1-C6) alkoxy group optionally substituted by a halogen atom; a ) alkylthio 15 group optionally substituted by a halogen atom; a (C1-C6) alkylsulfinyl group optionally substituted by a halogen atom; or a (C1-C6) alkylsulfonyl group optionally substituted by a halogen atom, m represents an integer of 0 to 5, 20 each Y may be the same or different, and represents a halogen atom; a cyano group; a nitro group; a hydroxy group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C2-C6) alkenyl group optionally tuted by a n atom; a (C2-C6) alkynyl group optionally tuted by a halogen atom; 25 a (C1-C6) alkoxy group optionally substituted by a halogen atom; a (C1-C6) alkoxy (C1-C6) alkoxy group; a (C2-C6) alkenyloxy group optionally substituted by a halogen atom; a (C2-C6) alkynyloxy group optionally substituted by a halogen atom; a (C1-C6) alkylthio group optionally tuted by a halogen atom; a HAS510030NZPR 303864629 (C1-C6) alkylsulfinyl group optionally substituted by a halogen atom; a ) alkylsulfonyl group optionally substituted by a halogen atom; a (C1-C6) alkoxycarbonyl group; a (C1-C6) alkoxyimino (C1-C3) alkyl group; a (C3-C30) trialkylsilyl group; 5 a mono(C1-C6) alkylsulfonylamino group optionally substituted by a halogen atom; a phenyl group optionally tuted by one or more substituents selected from group B substituents; a phenoxy group optionally substituted by one or more substituents selected from group B substituents; a heterocyclic 10 group optionally substituted by one or more substituents selected from group B substituents; or a heterocycloxy group optionally substituted by one or more substituents selected from group B substituents, the group B substituents are a n atom; a cyano group; 15 a nitro group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C2-C6) alkenyl group optionally substituted by a halogen atom; a (C2-C6) alkynyl group optionally substituted by a halogen atom; a (C1-C6) alkoxy group ally substituted by a halogen atom; a ) alkenyloxy group 20 optionally substituted by a halogen atom; a (C2-C6) alkynyloxy group optionally substituted by a halogen atom; a ) hio group optionally substituted by a n atom; a (C1-C6) alkylsulfinyl group optionally substituted by a halogen atom; a (C1-C6) ulfonyl group optionally substituted by 25 a halogen atom; a (C1-C6) alkoxycarbonyl group; and a (C1-C6) alkoxyimino (C1-C3) alkyl group, n represents an integer of 0 to 5, with the proviso that when n is an integer of 2 to 5, two adjacent Y groups may join together to form a ) alkylene group; a (C3-C5) alkenylene HAS510030NZPR 303864629 group; a (C2-C4) alkyleneoxy group; or a (C1-C3) alkylene dioxy group optionally substituted by a halogen atom, and Z represents CH or CY in Y is as defined above), or a salt thereof as an active ingredient.
2. The method according to claim 1, wherein A represents a (C1-C8) ne group optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group; or a (C1-C8) ne group which is 10 optionally substituted by a halogen atom, a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group and is modified by incorporation, into the carbon chain, of at least one heteroatom selected from an oxygen atom, a sulfur atom, -SO-, -SO2- and -N(R)- (wherein R represents a hydrogen atom, a (C1-C6) alkyl 15 group, a (C3-C6) cycloalkyl group, a (C1-C6) alkylcarbonyl group or a (C1-C6) alkoxycarbonyl group).
3. The method according to claim 1, wherein A represents a (C1-C8) alkylene group optionally 20 substituted by a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group; -CR1(R2)-CR3(R4)-Q- in R1, R2, R3 and R4 may be the same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group or a (C3-C6) cycloalkyl group, or R1, R2, R3 and R4 may join together in any combination to form 25 a (C3-C6) lkane, and Q represents an oxygen atom, a sulfur atom, -SO-, -SO2- or -N(R)- (wherein R represents a hydrogen atom, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a ) alkylcarbonyl group or a ) alkoxycarbonyl group)); or -CR1(R2)-CR3(R4)-CR5(R6)-Q- (wherein R1, R2, R3, R4 and Q are as HAS510030NZPR 303864629 d above, and R5 and R6 may be the same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group or a (C3-C6) cycloalkyl group, or R1, R2, R3, R4, R5 and R6 may join together in any combination to form a (C3-C6) cycloalkane).
4. The method according to claim 1, wherein A represents a (C1-C8) alkylene group optionally substituted by a (C1-C6) alkyl group and/or a (C3-C6) cycloalkyl group; -CR1(R2)-CR3(R4)-Q- (wherein R1, R2, R3 and R4 may be the 10 same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group or a (C3-C6) cycloalkyl group, or R1, R2, R3 and R4 may join together in any combination to form a (C3-C6) cycloalkane, and Q ents an oxygen atom, a sulfur atom, -SO-, -SO2- or -N(R)- (wherein R represents a hydrogen 15 atom, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C6) alkylcarbonyl group or a (C1-C6) alkoxycarbonyl group)); or -CR1(R2)-CR3(R4)-CR5(R6)-Q- (wherein R1, R2, R3, R4 and Q are as defined above, and R5 and R6 may be the same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group 20 or a (C3-C6) cycloalkyl group, or R1, R2, R3, R4, R5 and R6 may join together in any combination to form a (C3-C6) lkane), E represents a hydrogen atom; a (C1-C6) alkyl group; a (C1-C6) alkylcarbonyl group; or a ) alkoxycarbonyl group, each X may be the same or different, and represents a n 25 atom; a ) alkyl group optionally tuted by a halogen atom; a (C1-C6) alkoxy group optionally substituted by a halogen atom; or a (C1-C6) alkylthio group optionally substituted by a halogen atom, m represents 1 or 2, HAS510030NZPR 303864629 each Y may be the same or different, and represents a halogen atom; a hydroxy group; a (C1-C6) alkyl group optionally substituted by a halogen atom; a (C1-C6) alkoxy group optionally substituted by a halogen atom; a (C1-C6) alkoxy ) alkoxy 5 group; a ) loxy group optionally substituted by a halogen atom; a mono(C1-C6) alkylsulfonylamino group optionally substituted by a halogen atom; a phenyl group optionally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (C1-C6) alkyl group 10 optionally substituted by a halogen atom, and a (C1-C6) alkoxy group optionally tuted by a halogen atom; a phenoxy group ally substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, a (C1-C6) alkyl group optionally substituted by a halogen atom, and a 15 (C1-C6) alkoxy group optionally substituted by a halogen atom; a heterocyclic group optionally substituted by one or more substituents ed from a halogen atom, a cyano group, a nitro group, a (C1-C6) alkyl group optionally substituted by a halogen atom, and a (C1-C6) alkoxy group ally 20 substituted by a halogen atom; or a heterocycloxy group optionally substituted by one or more substituents ed from a halogen atom, a cyano group, a nitro group, a (C1-C6) alkyl group optionally substituted by a halogen atom, and a (C1-C6) alkoxy group optionally substituted by a halogen atom, 25 n represents an integer of 0 to 3, with the proviso that when n is 2 or 3, two adjacent Y groups may join together to form a (C2-C4) alkyleneoxy group or a (C1-C3) ne dioxy group optionally substituted by a halogen atom, and Z represents CH or CY (wherein Y is as defined above). HAS510030NZPR 303864629
5. The method according to claim 1, wherein A represents a (C1-C5) alkylene group optionally substituted by a (C1-C6) alkyl group and/or a (C3-C6) lkyl 5 group; -CR1(R2)-CR3(R4)-Q- (wherein R1, R2, R3 and R4 may be the same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group or a (C3-C6) lkyl group, and Q represents an oxygen atom or a sulfur atom); or -CR1(R2)-CR3(R4)-CR5(R6)-Q- (wherein R1, R2, R3, R4 and Q are as 10 defined above, and R5 and R6 may be the same or different from each other, and represent a hydrogen atom, a (C1-C6) alkyl group or a (C3-C6) cycloalkyl group), E represents a en atom, each X may be the same or different, and represents a n 15 atom or a (C1-C6) alkyl group optionally substituted by a halogen atom, m represents 1, each Y may be the same or different, and represents a halogen atom or a (C1-C6) alkyl group optionally substituted by a halogen 20 atom, n represents an integer of 1 to 3, and Z represents CH or CY (wherein Y is as defined above).
6. A method for controlling endoparasites, sing orally 25 or parenterally administering an effective amount of the non-human mammal or bird endoparasite control agent as defined in any one of claims 1 to 5 to a man mammal.
7. The method according to claim 6, wherein the non-human mammal HAS510030NZPR 303908001 is a domestic animal.
8. A method for controlling endoparasites as claimed in any one of claims 1 to 7, substantially as hereinbefore described with 5 particular nce to any one or more of the examples.
NZ613343A 2011-03-02 2012-03-01 Internal parasiticide NZ613343B2 (en)

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JP2011-045042 2011-03-02
JP2011045042 2011-03-02
PCT/JP2012/055190 WO2012118139A1 (en) 2011-03-02 2012-03-01 Internal parasiticide

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NZ613343B2 true NZ613343B2 (en) 2016-01-06

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