CA2054430A1 - 3-oxy-substituted isoxazolines, process for their preparation and their use for combating endoparasites - Google Patents

3-oxy-substituted isoxazolines, process for their preparation and their use for combating endoparasites

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Publication number
CA2054430A1
CA2054430A1 CA002054430A CA2054430A CA2054430A1 CA 2054430 A1 CA2054430 A1 CA 2054430A1 CA 002054430 A CA002054430 A CA 002054430A CA 2054430 A CA2054430 A CA 2054430A CA 2054430 A1 CA2054430 A1 CA 2054430A1
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Canada
Prior art keywords
formula
spp
alkyl
oxy
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA002054430A
Other languages
French (fr)
Inventor
Gerald Dyker
Werner Lindner
Achim Harder
Norbert Mencke
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Bayer AG
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Individual
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Publication of CA2054430A1 publication Critical patent/CA2054430A1/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members 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
    • C07D261/12—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

3-Oxy-substituted isoxazolines, processes for their preparation, and their use for combating endoparasites A b s t r a c t The present invention relates to novel 3-oxy-substituted isoxazolines of the formula

Description

The present invention relates to novel 3-oxy-sub~tituted isoxazolines, processes for their preparation, and their use for combating endoparasites.

3-Chlorosubstituted isoxazolines and ~heir use against endoparasites have already been disclosed (US Patent Specification 4,694,016, US-P 4,593,024). 3-Tolyl~hio-isoxazolines and their use against endoparasites have already been disclosed (US-P 4,636,517).

However, the action of the known compounds is not sati~-factory in every case.

The present invention relates to 1. Novel 3-oxy-substituted isoxazolines of the formula Rl- R2~3 (I) N~
in which Rl represents hydrogen or op~ionally sub~tituted alkyl, R2 represents hydrogen, acyl, alkyl or aryl, R3 repre ent~ hydrogen, acyl, alkyl or aryl Le A 27 929 - 1 --` ~ - ' ' . ' ' `':
, .
' .; . ' , .. .

-, :

. ~d~3~

R2 and R3 together with the ad~acent N a~om represent a ~a~urated heterocycle, where Rl, R2 and R3 must not sLmultaneously represent hydrogen, S and ~he corresponding ~automer~ and stereoisomers of these compounds.
2. Process for the preparation of the 3-oxy-substituted isoxazolines of the formula I
R1- ~ R2R3 (I) in which R1 represents hydrogen or optionally sub-stituted alkyl, R2 repre~ent~ hydrogen, aoyl, alkyl or aryl, R3 repxesent~ hydrogen, acyl, alkyl or aryl R2 and R3 together with the ad~acent N atom represent a saturated hetexocycle, where Rl, R2 a~d R3 must not sLmultaneou~ly represent hydrogen, characteri~ed in that Le A 27 929 - 2 -- . : . : ..... . .
. . ~,~ . . .
. .
- . '. ' . . . , , . . . . . . . .

2 ~ 3 a~ 3-0xy-4~amino-substi~uted isoxazolin~s of the formula II

~1_ ~ H2 (II~
in which R1 has the abovementioned meaning are reac~ed wi~h mono- or bifunc~ional acylating, alkylating or arylating agents, b) in the e~ent that, in formula I, R2 represen~ the phthaloyl radical and R3 repre~ents hydrogen.
Compounds of the formula III

Hal ~ (IIX) in which Hal repre~ents halogen, are rea~ted with alcoholates of the formula IV
(R-0-)nM (IV) Le A 27 929 3 -`; . . ' ' ~ Q ?~ ~ ~ r in which R represents optionally substituted alkyl, M represents a mono- or polyvalent metal cation, n represents integers from 1-3~

c) in the event that~ in formula I, R2 and ~3 repres-ent hydrogen~ compounds of the formula V

R
Rl_o~N ~ (~) Il in which o Rl has the abovementioned meaning, are reacted with alkylhydrazines of the formula VI
H2N~ R4 in which R4 represent~ Cl4-alkyl.
3. Novel compounds of the formula V

Le A 27 929 - 4 -, "

- : .,. - ,..

,, , R 1 _ o~, ( Y ) in which Rl has the meaning given undex 1.
4. Process for the pxeparation of the compounds of the formula V
R

Il (v) .in which R1 has the meaning given under 1, characterised in that compounds of the formula Il .
Hal ~ O (III) in which Le A 27 929 - 5 -"
-.f ~

~al represents halogen, are reacted with alcoholates of the formula IV

(R)nM
in which R, M and n have the meaning given under 1.

Preferred compounds of the formula I are those in which the C atom 4 of ~he isoxazoline ring is in the R con-figuration.

Preferred compound~ of the ormula I are those in which 10 Rl rPpre~ents hydrogen or Cll2-alkyl which is optionally substituted by OH, CN, halogen, in paxticular fluorine or chlorine, Cl-C4-alkoxy, Cl4 alkylthio, C36-cycloalkyl, 5 6-membered ~aturated or unsatura-ted he~erocyclic rings which can contain N,O or 5 a~
hetero atoms ~uch as, for example, furan, tetra-hydrofuran, tetrahydro~uran, thiophene, pyrrole, pyridine or pyrimidine; furthermore by phenyl which in turn can be sub~tituted by Cl4-alkyl, C14-alkoxy, Cl"-alkylthio~ Cl4-halogenoalkyl, Cl4-halogenoalkoxy, C14-halogenoalkylthio9 C,4-alkylenedioxy, Cl4-halo-genoalkylenedioxy, OH, CN, halogen, carbo~yl, Cl4-alkoxycarbonyl, C14-alkoxy-C14-alkyl, hydroxy-Cl4-Le A 27 929 - 6 --~ .

:
, ~ - . . . . .

~ ,5 alkyl, hydroxy Cl4-alkoxy, phenoxy, phenylthio, R2 represents hydrogen, optionally substituted C1a-alkyl, optionally substituted phenyl, acyl radicals such as Cla-alkyl carbonyl which is op~ionally substituted, Cla-alkylsulphonyl which i8 optionally substituted, Cl~-alkylsulphonyl which i3 optionally substituted, arylcarbonyl, in particular benzoyl, which i~ optionally substituted, arylsulphonyl i~
particular phenylsulphonyl which i8 optionally substituted, aminocarbonyl, mono- or di-Cl4-alkyl-aminocarbonyl, Cl4 alkylarylaminocarbonyl, mono- or -diarylaminocarbonyl (where phenyl may be mentioned in p~rticular a~ aryl radical and where the alkyl or aryl radical~ can optionally be 3ub~tituted), Ca4~
alkoxycarbonyl which is optionally substituted, aryloxycarbonyl, in particular phenoxycarbonyl, which i8 optionally sub~tituted, Cl4-alkyl- or aryl-amino-carbonyliminoalkyl or -aryl which i~ option-ally substituted in the al~yl or aryl moieties and where aryl represents, in particular, phsnyl.
Suitable ~ubstituent~ ~re the ~ub~tituent~ of the alkyl radical which have been mentioned in the ca3e o~ R1, R3 represents the radicals men~ioned in the case of R2, R2 and R3 together with the ad~acent N atom repre~ent a 5-6-membered, ~aturated or unsaturated hetero cycle such as, for example, pyrrole, :Le A 27 929 - 7 -. . : , . ~.'. ~ " ' ,' ,' ', ' , .
. ~
.
.
. . ~ .

~. r~ ~ j7 ,~

pyrrolidinel piperidine or morpholine.

Particularly preferred compounds of the formula I are those in which Rl xepresents h~drogen, Cl8-alkyl which is optionally substituted by halogen, in particular fluorine or chlorine, C~4-alkoxy, in par~icular methoxy, cyclo-propyl, tetrahydrofuran, furan, t0trahydrofuranone, pyrrole, thiophene, pyridine, phenyl, furthermore represents benzyl which is optionally substituted by halogen such as fluorina or chlorine, C14-alkoxy such as methoxy, ethoxy, methylenedioxy, ethylene-dioxy, Cl4~alkyl such as methyl, ethyl, Cl4-halo~enoalkyl such as trifllloromethyl, carbonyl-Cl4-alkoxy such as me~hoxycarbonyl, Cl4-halogeno-alkylthio in particular trifluoromethylthio, Cl_4-halogenoalkoxy in par$icular trifluoromethoxy.

R2 represents hydrogen or optionally ~ubstituted benzoyl, where suitable substituents are those mentioned in the case of R1 and where carboxyl (COOH) may be mentioned in particular.

The followin~ compounds of the formula I m~y be mentioned individually:
-Le A 27 929 - ~

- . - - . ~ - , , .

.
. ~ ' ,~, ' ' . .
. . .
, ~ ~3 ~ i i 3 H

11 - ~NR2 ~ . , o Il C(CH2)6CH3 ~C phenyl ,C-4-Cl-- phen ~C-4 CH3-PhenY

-C-3-~ phenyl --C-2-Cl-phenyl _ g _ :
:. . .. .

..
:. ', ~ . : , .

~, ' ` . ' ` ' ` .
.
.

-CO-3-CH3-PhenY
-CO-2-CH3-PhenY
-CO-4-SCF3-PhenY
-CO-4-CF3-PhenYl ~CO-4-OCF3- phenyl -CO-3,4-C12-phenyl -CO-2,4-C12-phenyl -CO-4-OCH3- phenyl -CO-3-OCH3- phenyl ~0-2-OCH3- phenyl ~CO-4-SCH3- phenyl -~0-4-S020H3- phenyl SO~ C~3 -S02- phenyl -S02-~-CH3- phenyl -S02-4-Cl- phenyl -CO-OC:2H5 -CO-O-phenyl ~0-0-4-Cl- phenyl ~CO-O-I:H2- PhenY
-CO~NHCH3 -CO^N~IC2H5 -CO-NHtG~2~6CH3 -CO-NH-phenyl -CO-NH-4-Cl- phenyl -CO-NH-3-~1_phenyl -CO-NH~2-Cl-phenyl -CO-NH-4-CH3- phenyl Le A 27 929 - 10 -, .~ : ' . ..
: ~ : . , . ::.
~ ~ ' ~. ', "' ,' " ' ':

,h, ~ r;~

-CO-NH-3-CH3- phenyl -CO-NH-2-CH3- phenyl -CO-NH-3,4-C12- phenyl -CO-NH-2~4-C12- phenyl -CO-NH-4-SCF3- phenyl -CO-NH-4-OCF3- ph~nyl -CO-N~-2~3-(CH3)2- phenyl -CO-NH-3-Cl, 4 CF3- phenyl -CO-NH-4-5C~3- phenyl -CO-NH-4 502CH3- phenyl -CO-NH-4-tJ02-PhenYl ~co-NH-(4-ph~no~y)- phenyl CNCH3 N~CH3 -i-C3H7 -CH2- phenyl -C~J2-4-cl- phen If 3-msthoxy-4~amino-4,5-dihydroisoxazole, i8 cet for the prepaxation of the compou~ds of the formula I by process 2a, the process can be xeproduc~d by the following diagrammatic repre~entation~ of formulae7 depending on the acylating, alkylating or arylating agents used:

Le A 27 929 : ' . .
.
, - . . ~ : , .

0= ~ . O
:r:

0~ 0 t) ~ X~
t T t t .tq .~1 G) ~o .,, Ul 0 a~
.,., , . .,, C) r ~, O--~ ~ Q; ~ X ~ ~ O
~ X O X ~o~S
O= t~ ~O ~ D o,~ ~ O

N

' U

Le A 27 929 - 12 --.:
-, ::

Z ~Z
O= c~ ~= Z~
3 ' :C
~ _ ~ -~ ~ ~ , ~

T
T
, ~n , ~ .,, Z ~ I
"
o ~ C,~ ~ , .
~, ~ " o z 0 7 ,~
I O I

LQ ~ 2?_~29 - 13 3 1~

It i~ preferxed to employ compound~ of the formula I in which R1 has the radicals mentioned in the compounds of the formula I as bsing preferred.

The following may preferably be mentioned as acyla~ing agents: carbsxylic acid halides, in particular chlorides, carboxylic anhydrides and carboxylic esters, in par-ticular Cl4-alkyl esters ~uch as methyl esters or ethyl es~ers. Compounds by which the acyl radical~ mentioned in R2 are introduced may preferably be mentioned.

The following may be mentioned individually~

CH3COCl C2HsCOCl 4-Cl-phenyl-COCl (CH3cO)2o 4-CH3-phenyl-CO-O-C2H5 4-Cl-phenyl-CH2-COOEt (CF3CO) 2 cyclopropylcarboxylic acid chloride cyclohexane carboxylic acid chloride Sulphonyl hallde~, in particular chlorides such as C14 alkylsulphonyl chlorides or optionally substituted phenylisulphonyl chloride.

Le A 27 929 - 14 -~3~3,~ J

CH3SO2Cl phenyl-SO2Cl 4-Cl-phenyl-SO2Cl 4-CH3-phenyl-SO2Cl Chloroformates in particular Cl-C-OC~3 o Cl-c-o- phenyl Cl-C-OCH2-phenyl Alkyl isocyanate~ or phenyl isocyanates Optionally sub~tituted Cl4-alkyl isocyanate~ or phenyl isocyanates, in particular CH3NCO, C2H5NCO, i-C3H7NCO, CH3-he~yl-~CO, phenyl-NCO, 4-Cl-phenyl-NCO, 4-CH3-phenyl-NCO, 3-Cl-phenyl-NCO, 3-CH3-phenyl-NCO, 2,4-Cl2-phenyl-NCO, 4-OCF3-phenyl-NCO, 3 t 4-Cl2-phenyl-NCO, phenyl-SO2 NCO.

Carbodiimides such as, in parkicular, dicyclohexyl Le A 27 9?9 - 15 -, .
- .~ ~ ~ ' . ' , 21 3 :~

carbodiimide, ditolylcarbodiimide, dii~opropyl-carbodiLmide.

The acylation reactions are carried out 1n a manner known per se. The compounds of the formula II and the acylating S agents are employed in an equimolar ratio. It is also possible to carry out ~he process using an exce~s of one or the other component. The reactions are carried out at temperatures from 0-200C, preferably a~ 50-150C. I'he reactions can be carried out in the presence of diluents.

Suitable diluents are all inert organic solvents. These include, in particular, aliphatic and aromatic, option-ally halogenated hydrocarbons ~uch as pentane, hexane, heptane, cyclohexane, petroleum ether, benzine, ligroin, benzene, toluene, methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichiorobenzene, furthermore ethers such a~ diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dio~ane, furthermore ketones such as acetone, methyl ethyl ketone, methyl isopropyl ketone and methyl isobutyl ketone, furthermore esters, such as methyl acetate and ethyl acetate, moreover nitriles such a~, for example, aceto-nitrile, propionitrile, benzonitrile, glutaronitrile, in addition amides such as dLmethylformamide, dLmethyl-acetamide and N-methylpyrrolidone, and al~o dimethyl sulphoxide, tetramethylene slllphone and hexamethylphoR-phoric triamide.

Le A 27 929 - 16 -2~
The reaction can be carried out in ~he presence of a base.

Suitable bases are inorganic and organic bases. Bases which may be mentioned are the hydroxides, carbonates, hydrogen carbonates and alcoholates of alkali metals and alkaline earth me~als, furthermore amines ~uch as, in particular, ter~iary amines, for example ~rimethylamine, triethylamine, N-methylmorpholine, pyridi~e, picoline, N-ethylpyrrolidine, diazabicyclo[4,3,0~undecene (DBU3, 1,4-diazabicyclo[2,2,2]octane (DABCO), diazabicyclo-t3,~,O]nonene (DBN), ethyl-diisopropylamine.

Acylating agents which may preferably be mentioned are optionally substituted Cla-alkyl halide~, in particular chlorides, bromides, iodide The following may be mentioned individually: CH3I, C2H5Br, i-C3H~I, C3H,I, C6H13I, phenyl-C~2I, 4-Cl-phenyl-CH2-Cl.

The following may preferably be mentioned as arylating agents: 4-Cl-nitroben~ene/ 3,4,5-trichloronitrobenzene.

The process is carried out by reacting a compound of the formul~ II with the alkylating agent or arylating agent in the presence of a base and of a diluent. Diluents which can be employed are all inert organic solvents which have already been mentioned further above.

The proce~s i8 carried out in the presence of ba~es.

Le A 27 929 - 17 -.
- , , ', ~ .

Preferred bases which m~y be menkioned are the alkali metal hydroxides such as ~odium hydroxide, alkali metal alcoholates such as sodium methylate or potassi~n butano-late, metal hydrides such as sodium hydride, or organic bases such as 1,8-diazabicyclo[5.40]undec-7-ene (DBU).

The process is carried out under atmospheric pressure and a~ temperatures between 20C and 140C.

The reaction is carried out hy combining equimolar amounts of the compound of the formula II and base, treating this mixture with an equimolar amount of ~he alkylating or arylating agent~, and heating the mixture to reaction temperature.

If, in accordance with process 2b for the preparation o~
the compounds of the formula I in which the radical R2 represents the phthaloyl radical and R3 represents hydrogen, 3-choro-4,5-dihydrophthalimidoisoxazoline is employed as compound of the formula III and potassium ethylate as alcoholate of the formula IV, the reaction can be reproduced by the following schematic representa-tion of formulae:

Le A 27 929 - 18 -- ' :
: ' ' ' ' ' :' ' .

.

2 Q 3 ~J

~ ~OYI: r --~N~C~

E t'~~JN~{'~~3 2 KOE~ ~
COOH

The 3-chloro compound is preferably employed a~ compound of the formula III.

Alcoholate~ of the formula IV which are preferably employed re alkali metal alcoholates and alkaline earth metal alcoholate~ in which R i~ as preferred in the case of R1 The following may be mentioned individually- Na-OC2H5, Na-OC6H~3, K-O-iC3H7, Na-OCHz-phe~yl, Na-~-ph~nyl, 4-Cl-phenyl-O-Na.

If the compound of the formula III is ro~cted with the alcoholate ~n approximately equimolar ratio, the cor-responding 3-oxy-4-phthalimido-isoxazoline i8 formed.

Le A 27 929 - 19 - - , . . . .

:

70 ~
The reaction is carried out at temperatures from 0-lOO~C
preferably 15-25C. Substances which act a~ diluents are the alcohols on which the alcoholates are based, or organic diluents which are inert under the reaction conditions, such as, for example, those mentioned further above in the case of process 2a.

When the reaction has ended, the solvent is distilled off, ~he residue i8 treated with wa~er, and the mixture is extracted with a solvent which is not miscible wi~h water. After the extractan~ ha~ been removed, ~he desired compound of the formula I is obtained.

If the compound of the formula II is reacted with an excess of alcoholate, the corresponding 3-oxy-4-phthalic monoamide 4,5-dihydroisoxazoline is formed. Surprisingly, the corresponding phkhalic amide ester is not formed in this reaction.

Compound of the formula III and alcoholate are employed in a ratio 1:2 to 1:10 prefexably 1:2 to 1:4.

The reaction i~ carried out as indicated above.

When the reaction has ended, the solvent is distilled off, the residue is treated with water, and the mixture is acidified. During thi~ proce~s, the desired compound of the formula I precipitates and can be filtered off.

If, according to proces~ 2c for the prepara~ion of ~he Le A 27 929 - 20 ~

~ 3;~

compounds of the formula I in which R2 and R3 represent hydrogen,3-phenoxy-4-phthalLmido-4,5-dihydroisoxazoleis employed as compound of the formula V, ~he reaction can be repre~ented by the following equation:
1~
~C~[3 _ -- H2 ~C C113NHNH2 ~N
N~ 1I N~
Compounds of the formula V which are preferably employed are those in which the radical R1 has the meaning indicatad in the case of the compound~ of the formula I
as being preferred. The following may be men~ioned individually:

Le A 27 929 - 21 -' :
.

~5 Il Rl i ~ 3H7 4-OCH3- phenyl 4-Cl- phenyl Sec ~C4Hg t Ct{2 ) 7-CH3 CH2-4-Cl- phenyl CH2 -Cy- Propyl -CH2-4-CO2CH3- phenyl - CH2 ~ 3 ~ 4 - C 12 ~ phenyl -CH2-~,4-C12- phenyl - C:H - CF3 - CH2 - 4 - OCH3 - }~her ,CH2F' -C~

-CH2-4-CF'3- phenyl -CH2~C13 The following are preferably employed :a8 alXylhydrazines of the formula VI: mothylhydrazine.

Le A 27_92~ - 22 -- ~ :
,, ~ :

~ 3 '?~ 'f~
The compounds of the formulae V and VI are employed in a ratio of 1:1 to 1 20 preferably 1:5 to 1:10.

~he reaction is carried out at temperatures from 0-100C
preferably 15-25C.

Diluents which could be employed are the diluents indicated in the case of proces~ 2a, A diluent which may be mentioned in particular is a mixture of methanol and tetrahydrofuran.

The compounds of the fo~mula V represent a preferred group from amongst the compounds of ~he formula I. They are prepared by process 4, which is identical with process 2b, in which the compound of the formula III is reacted with approximately equLmolar amountg of alcoholate. The compounds of the formula V act as active compounds as well as intermediates for the preparation of further compounds of the formula I. The compounds of the formula III have been disclosed for example in US Patent Specification 4,636,517.

While having low Toxicity to warm-blooded specie~, the active compounds are suitable for combating pathogenic endoparasites which occur in human~ and in animal keeping and livestock breeding, in productive livestock, breeding anLmals, zoo animals, laboratory anLmals, experimental animaIs snd pets. In this context, they are active again6t all or indi~idual stages of development of th~
pests and against re istant and normally-sensitive species. By combating the pathogenic endoparasites, i~ i~

Le A 27 929 - 23 -~ ' ' '' .,i.~., f i~ ~fj intended to reduce disease, dea~hs and decreasing perfor-mance (for example in the production of meat, milk, ~7001, hides, eggs, honey etc.), so that more economical and simpler animal keeping is possible by using the active compounds. The pathogenic endoparasites include Cestodes, Trematodest Nematodef and Acantocephalae, in particular:

From the order of the Pseudophyllidea, for example:
Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula 6pp., ~othridium spp., Diplogonoporus spp..

From the order of the Cyclophyllidea, for example:
Mesocestoides spp., Anoplocephala 8pp., Paranoplocephala spp., Moniezia spp., ~hysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia ~pp., Andyra spp., Bertiella spp., Taenia ~pp., Echinococcus spp., ~yda~igera spp., Davainea spp., Raillietina spp., Hymenolepis ~pp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium ~pp., Joyeuxiella spp., Diplopylidium spp..

From the subcla~s of the Monogenea, for example:
G~rodactylu~ 8pp ., Dactylogyrus spp~, Polystoma spp..

From the ~ubclas~ of the Digenea, for e~ample:
Diplostomum spp., Po~thodiplostomum spp., Schi~tosoma spp., Trichobilharzia ~pp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinoftoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum Le A 27 929 - 24 --2 ~ r,~
spp., Fasciola spp., Fascioli.des spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Calicophoron spp-, Cotylophoron spp., Gigantocotyle spp., Fischoederius spp. Gastrothylacus spp., Notocotylus 8pp., Catatropis spp., Plagiorchis spp., ProsthogonLmus spp., Dicrocoelium spp., Eurytrema 8pp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophye~us spp., Opisthorchi spp., Clonorchis spp., ~etoxchis ~pp., Heterophyes spp., Metagonimus spp..

From the order of the Enoplida, for example: Trichuris spp., Capillaria 8pp., Trichomosoides spp., Trichinella spp..

From the order of the Rhabditia, for exampleo Nicronema spp., Stronyyloides 8pp..

From the order of the Strongylida, for example: Stronylus spp., Triodon~ophorus qpp., Oesophagodontu~ spp., Trichonema spp., Gyalocephalu 8pp., Cylindropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus ~pp., Oesophagostomum spp., Chabertia spp., Stephanuru~ spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp., Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cy3tocaulus spp., Pneumostrongylus spp., ~picocaulus spp., ~laphostrongylus spp.
Parelaphostrongylus spp., Creno oma spp., Paracrenosoma spp., Angio3trongy1us spp., Aelurostrongylus spp., Le A 27 929 - 25 -- - ' ' .. ~ . .
, Filaroides 5pp ., Parafilaroides spp., Trichostrongylus spp., Ha~monchu~ spp., Ostertagia spp., Mar~hallagia spp., Cooperia ~pp., Nematodiruq spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp..

From the order of the Oxyurida, for example~ Oxyuris 8pp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp..

From the order of the Ascaridia, for example: Ascaris spp., Toxascari~ spp~, Toxocara spp., Paraecaris spp., Anisakis spp., Ascaridia spp..

From the order of the Spirurida, for example: Gnatho~toma spp., Physalop~era ~pp., Thelazia pp., Gongylonema spp., Habronema pp., Parabronema 8pp., Draschia 8pp., Dracunculus spp..

From the order o the Filariida, for example:
Stephanofilaria ~pp., Parafilaria 3pp., Setaria spp., Loa spp., Dirofilaria qpp., Litomosoides 8pp ., Brugia spp., Nuchereria spp., Onchocerca 8pp..

From the order o the Gigantorhynchida~ for example Filicollis spp., Moniliformi~ spp., Macracanthorhynchus spp., Prosthenorchis 8pp..

The productive live~tock and breeding anLmals include mam~als ~uch as, for example, cattle, hor~est ~heep, Le A 27 929 - 26 -pigs, goats, camels, water buffalos, donkey~, rabbits, fallow deer, reindeer, fur-bearing anLmals Quch a~, for example, mink, chinchilla, racoon, birds such as, for example, chickens, geese, turkeys, ducks, freshwater and salt-water fish such as, for example, trout, carps, eels, reptiles, insects such as, for example, honeybee and silkworm.

Labora~ory animals and experimental anLmals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

Pets include dogs and cat~.

Administration can be effected prophylactically as well as therapeutically.

The active compound3 are administered, directly or in the form of suitable preparations, enterally, parenterally, dermally, nasally, by environment treatment, or with the aid of active-compound~containing ~haped articles ~uch as, for example, ~trips, plates, bands, collar~, ear marks, limb bands, marking devices.

The active compounds are administered enterally, for example orally, in the form of powders, tablet~, capsules, pastes, drink~, granules, or solutions, suspen-8ion8 and ~mul~ions which can be admini tered orally, or boli, medicated feed or drinking water. De~mal adminis-tration i8 effected, for example, in the fo~m of dipping, spraying or pouring-on and spotting-on. Parenteral Le A 27 929 - 27 -~ . , S ", ~ ? ' ~

adminiætration is effected, for example, in the form of injection (intramuscularly, subcutaneously, intraven ously, intraperitoneally) or by implants.

Suitable preparations are:
Solutions such as solutions for in~ections, oral solu-tions, concentrates for oral administration after dilu-tion, solutions for use o~ the skin or on body cavities, pour-on and spot-on formula~ions, gels;

Emulsions and suspension for oral or dermal administra-tion and for injec~ion; semi-solid preparations; formula-tions in which the active compound is incorporated in a cream base or in an oil-in-water or water-in-oil emulsion base;

Solid preparations such as powder~, premixes or con-centrates, granules, pellets, tablets, boli, capsules;
aerosols and inhalants, shaped articles containing active compound.

Solutions for in~ection are administered intravenously, intramuscularly and ~ubcutaneously.

Solutions for in~ection are prepared by dissolving the active compound in a suitable solvent and, if appropri~
ate, adding additive~ such as ~olubilisers, acids, basest buffer salts, antioxidants and preservatives. The ~olu-tions are sterile-filtered and drawn off.

L~ A 27 929 - 28 -r ~ "J

The following may be mentioned as solvents: physiologi-cally accept2ble solvents such as wa~er, alcohols such as ethanol, butanol, benzyl acohol, glycerol, propylene glycol, polyethylene glycols, N methyl-pyrrolidone, and mixtures of theseO

If appropriate, the active compounds can also be dis-solved in physiologically acceptable vege~ablQ ox syn-thetic oils which are suitable for injection.

The following may be mentioned as ~olubilisers: olvents which enhance solution of the active compound in the main solvent, sr which prevent i~s precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated 30rbi~an esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic esters, n-butanol.

Oral solutions are admini~tered directly. Concentrate are administered orally after previously having been diluted to the administration concentratlon. Oral solu-tions and concentrates are prapared as described above in the case of the solutions for in~ection, it baing pos-sible to dispense with working under sterile conditions.

Soluti`ons for use on the 3kin are applied dropwise, bru~hed on t rubbed in, splashed on or sprayed on. The~e solutions are prepared as described above in the ca3e of solutions ~or in~ection.

Le A 27 929 - 29 -:~, It may be advantageous to add thickeners during theprepara~ion. Thickeners are: inorganic thickeners such as bentonite, colloidal silica, aluminium monostearate, organic thickeners such as cellulose derivatives, poly-vinyl alcohols and their copolymers, acrylates and metacrylAtes .

Gels are applied to, or brushed on, the skin, or intro-duced into body cavities. Gels are prepared by treating solutions which have been prepared a~ described in the case of the solutions for in~ection with such an amount of thickener that a clear substance of cream-like con-sistency is formed. Thickener~ employed are the thickeners indicated further above.

Pour-on and spot-on formulations are poured onto, or splashed onto, lim~ted areas of the skin, the active compound penetrating the skin and acting systemically.

Pour-on and spot-on formula~ion~ are prepared by dissol-ving, suspending or emulsifying the active compound in suitable solvents or ~olvent mixtures which are tolerated by the ~kin. If appropria~e, other ad~uvants such as colourants, resorption accelerators, antioxidants, agents which impart protection from light, and tackifiers are added.

Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as ben~yl alcohol, Le A 27 929 - 30 , phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ethers, diethylene glycol mono-butyl ethers, ketones such as acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dLmethylacetamide, N-methyl-pyrrolidone, 2,2~dimethyl-4-oxy-methylene-1,3-dioxolane.

Colourants are all colourants which are released for use on animals and which can be di~solved or suspended.

~xamples of resorption accPlerator~ are DMS0, spreading oils such as i~opropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid e~ters, ~ri-glycerides, fatty alcohols.

Antioxidant~ are sulphites or me~abisulphites such as potassium metabisulphite, ascorbic acid, butylhydroxy-toluene, butylhydroxyanisole, tocopherol.

Examples of agents which impart protection from light are novantisolic acid.

Examples of tackifiers are cellulose derivatives, ~tarch derivativ~s, polyacrylates, natural polymer~ 3uch a~
alginates, gelatine.

Emulsions can be administered oxally, dermally or in the form of in~e~tion~.

Le A 27 929 - 31 -, 2~-3~
Emulsions are either of the water-in-oil type or of the oil-in-water t~pe.

They are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and homogenising this phase with ~he solvent of the other pha~e, with the aid of suitable emulsifiers and, if appropriate, other ad~uvants such as colourants, resorp-tion accelerators, preservative3, antioxidants, ag0nt~
which impart protection from light, vi~co~ity-increa~ing ~ubstances.

The followi~g may be mentioned as the hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils such as sesame seed oil~ almond oil, castor oil, synthetic triglycerides such as caprylic~capric acid bigylceride, triglyceride mixture with vegetable fatty acids of chain length CB 12 or with other specifically selected natural fatty acids, partial ylyceride mixtures of saturated or un6aturated fatty acids which may al o contain hydroxyl groups, and mono- and diglycerides of the C8l0-fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain l~ngth Cl6-Cl8, i~opropyl myristate, isopropyl palmitate, caprylic/capric e6ters of satur&ted fa~ty alcohol~ of chain length Cl2-Cl8, isopropyl stearate, oleyl oleate, decyl oleate, ethyl Le A 27 929 32 -' ' ' ' ~ ' " ,' ' : ' ' ' ' .
;:
, ' ' oleate, ethyl lactate, waxy fatty acid esters such as artificial uropygial gland fat from ducks, dibutyl phthalate, diisopropyl adipate, es~er miY.tures related to ~he latter, etc.

Fatty alcohols such as isotridecyl alcohol, 2-octyl dodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as, for example, oleic acid and its mixtures.

The following may be mentioned a~ hydrophilic phase:
water, alcohol such as, for example, propylene glycol, glycerol, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: non-ionic surfactants, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan mono-stearate, glycerol monostearate, polyoxyethyl stearate,alkylphenol polyglycol ethers;

ampholytic sur~actants ~u~h as disodium ~-lauryl-~-iminodipropionate or lecithin;

anionic surfactants such as Na-lauryl sulphate, fatty alcohol ether sulphates, the monoethanol amine salt of mono~dialkylpolyglycol ether orthopho phoric ester~;

cationic ~urfactants such as cetyltrimethylammonium chloride.

Le A 27 929 - 33 ;

. ~ i. . - , ~3J ~3 ~
The following may be mentioned a~ other adjuvantsa viscosity-increasing subs~ances and substances which stabilise the emulsion, such as carboxymethylcellulose, methylcellulose and other cellulose and starch deriva-S tive~, polyacrylates, alginates, gelatine, gum arabic,polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica, or mix~ures of the substances mentioned.

Suspension can be administered orally, dermally or in the form of in~ection. They are prepared by suspending the active substance in an excipient liquid, if appro-priate with the addition of further adjuvants such as wetting agents, colourants, resorption accelerators, preservatives, antio~idants and agents which impart protection against light.

Excipient liquids which may be mentioned are all homogen-ous solvents and solvent mixtures.

Wetting agents (dispersants) which may be mentioned are the surfactants indicated further above.

Further adjuvants which may be mentioned are those indicated further above.

Semi-solid preparations can be administered orally or dermally. They are only distinguished from the above-de~cribed suspensions and emulsion~ by their higher Le A 27 929 - 34 -" ':. '' ' viscosity.

To prepare ~olid preparations, the active compound ismixed with ~uitable excipients, if appropriate with the addition of adjuvants, and ~he mixture is formulated as desired.

Excipients which may be mentioned are all phy~iologically accaptable solid inert sub~tances. Suitable as such are inorganic and organic ~ubstances. Examples of inorganic substances are sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates~ aluminium oxides, silicas, clay~, precipitated or colloidal silicon dioxide, and phosphates.

Examples of organic ~ubstances are sugars, cellulose, foods and animal feeds such as dried milk, animal meals, cereal meals and coarse cereAl meal~ and starche .

Adjuvants ~re pre~erva~ives, antioxidants and colourants which ha~e already been indicated further above.

Other suitable ad~uvants are the lubricants and gliding agents such as, for example, magnesium stearate, stearic acid, talc,~bentonites, di~integrants such as starch or cros~linked polyvinylpyrrolidone, binderQ such a~, for example, starch, gelatLne or linear poly~inylpyrrolidone, and also dry binders such as microcrystalline cellulo~e.

In the preparations, the active compounds can al80 be L~ A 27 929 - 35 -:: :

:

present in the form of a mixture with synergisks or with other active compound~ which act against pathogenic endoparasite~. Examples of such ac~ive compounds are L-2,3,5,6-tetrahydro-6-phenylimidazothiazole, benzimidaz-ole carbamate~, praziquantel, pyrantel, febantel.

Ready-to-use preparations contain the active compound in concentrations from 10 ppm ~ 20 percent by weight, preferably of from 0.1 to 10 percent by weight.

Preparations which are diluted prior to administration contain the active compound in concentrations of from 0.5 to gO percent by weight, preferably of from 5 to 50 percent by weight.

In general, it has proved advantageous ~o administer amounts of approximately 1 to approximately 100 mg of active compound per kg of body weight per day, to achieve effective xesults.

Example A
In vivo nematode test Trichostronsylu~ colubriformis/sheep Sheep which have been infected experimentally with Trichostrongylus colubri~ormis were txeated after the prepatency time of the para~ite had elap~ed. The active compounds w~re admini~tered orally in the form of pure Le A 27 929 - 36 -.

.
.

active compound in gelatine capsules.

The degree of effectiveness is determined by counting the worm eggs excreted with the stools before and after treatment.

Complete adjournment of egg excretion after the ~reatment means that the worms were aborted or are damaged ~o such a degree tha~ ~hey no longer produce eggs (dosis effectiva).

Tested active compounds and effective dosage rates (dosis effectiva) can be seen from the table which follows.

Active compound Dosis effectiva in Example No. mg/kg Example B
In vivo nematode test Haemonchus contortustsheep -Sheep which have been infected experLmentally with Haemonchus contortus were treated after the prepatency time of the paraRite had elapsed. The active compounds Le A 27 9~9 - 37 -were administered orally in the form of pure active compound in gelatine capsules.

The degree of effectiveness is determined by counting the worms excreted with the stools before and after treat-ment.

Complete adjournment of egg excretion after the treatment means that the worms were abor~ed or are damaged to such a degree that they no lvnger produce eggs (dosis effectiva).

Tested active compounds and effective dosage rates (dosis effectiva) can be seen from the table which follows.

Active compound Dosis effectiva in Example No. mg/kg Le A 27 929 - 38 ~

. , ;

.. - - ~ .
.

1, - , 3 li L~ ~ ) Preparation Examples Exam~le 1 - ll Excess ~C~ NaOCH3 1 >~<
Cl ~ ~ C ~ _3 ~3C ~ N ~ C02H
¦ I ll HOCH
~ O N~
(R)-N-(4,5-Dihydro-3-methoxy-4-isoazolyl)phthalamic acid 10 g (40 mmol) of (R)-3-Chloro-4,5-dihydro-4-phthalLmido-isoxazole and 9.1 g (160 mmol) of sodium methanolate are reacted for 1 hour at room temperature in 50 ml of anhydrous methanol. The solvent is distilled off, the residue is dissolved in 100 ml of water, and the excess acidified wi~h di.lute hydrochloric acid. The mixture iB
extracted three tLme~ using 30 ml of ethyl ac~tate and the combined organic extracts are dried using Yodium sulphate, and the mixture is then concentrated and the residue iæ dried in vacuo at 50C. Yield: 6.1 g (58%) of the phthalamic acid as the colourless solid of decom-position point 152C.

Le A 27_929 - 39 -;
:, .

. . .

2, ~ r .
Example 2 Cl~C~ C~

Excess Cl ~N~ C02H

NaH, THF

(R)-N~[4,5-Dihydro-3-(3-chlorophenyl)-methoxy-4-i~o-azolyl]phthalamic acid 5.0 g (20 mmol) of (R)-3-Chloro 4,5 dihydro-4-phthali-mido-isoxazole, 11 g (80 mmol) of 3-chlorobenzyl alcohol and 1.9 g t80 mmol) of ~odium hydride are reacted for 16 hours at room temperature in 30 ml of anhydrou~ tetra-hydrofuran. The solvent is distilled off and the re~idueis taken up in 250 ml of water. After extraction with 50 ml of dichloromethane, the aqueous pha~e is acidified using dilute ~ydrochloric acid, and the precipita~e i~
filtered off. For purification, the crudP product is dissolved in 200 ml of 20% strength sodium hydroxide solution and precipitated with 250 ml of 15% strength hydrochloric acid. The precipitate is fil~ered off~
washed with a little water and dried in ~acuo at 50C.
Yîeld: 7.1 g (95%) of the phthalamlc acid as colourless ~olid of decomposition point 149C.

Tho following are prepared analoyou~ly:

Le A 27 929 -~ 40 -. . : , .

~ ~3'.~ J f..J

Ra - 0~;~3'NH -~

COOH

Ex. No.Ra m-~C

3 O ~C~13 161C

.
4 ~ CH3 176 C
_ . ~ . _ __ ,~ ~CH~ 1 3 6 C
_ ,, ,__ ~ .... .. ._ - -6 ~O-Cl 180C
. ___ ~ . _ ___ __ 7 ~ 146 t:
8 ~ }CI 201C

. .__ 9 ~
( CH2 ) 7 ~ 5~3 eo c , .
~ CF3 .... _._ ~.. __ _ _ ~
12 ~O~F3 147 C

Lç! A 27 929 - 41 -:~' : - ' ;' , ( continuation ) ~ 3 Ex . No . Ra m . p . C
_ ~ . ___ , _ __ 13 ~ ~CCl3 138 C
. _ _ ~ .. __ 14 ~OCH3 145 C
-- _ _ _ . _ _ . . . _ . __ '~CCl 173 ~
.. . _ _ __ 16 ~> 17~C
_,___ __ ~r_ ~ ___ _ __ ____ _ __ ~ ___ 17 ~r ~F 171 C
. __ . _ ,,__. _ . .~

18 ,o~ ll Oil . _ . . _. _ _ 19 ~3 1?9 C

_ 3 ~l3 152~
... _ _ 21 ~ r 02CH3 ~ 125 C

- :
- - . : - .. , - ' , .

. ' .~ , ' , , ' "r~ r~
( continuation ) Ex. No. Ra m.p.C
. __ __ . ,, ,_ 22 ~ ~ 17~~

. .____ -- . r _ ~ _ __ 23 ~ 101C
. _ _ .__ ~

24 ~ 3 167C

_ .

~ 161C

.... _ _~_ _ , , . . _ ._ 26 ~`~J~CI 19~~
. ~ , . . ~ ~ .. __ 27 ~3 153C

~, . ._ _ 2~. ~ 133C

_ __ 29 ~ 1150~

Le A 27 929 - 43 -~,, -. , ' , . . -- - - : . .
- , ' ~

(continuation) E x . No . Ria m p . C

30. ~F 178C
~ .
31 ~O-H
Example 32 Cl ~ ~ ~guimol~r NaOCH~ H3Co (R)-4,5-Dihydro-3-methoxy~4-phthalimidoisoxazole 8.6 g (0.16 mol) of ~odium methanolate in 50 ml of methanol are added dropwise in the cour~e of 1 hour at room temperature to 40 g (0.16 mol) of (R)-3-Chloro-4,5-dihydro-4-phthalimido-isoxazole in 150 ml of dry methanol.

The mixture i3 ~ub~equently stirred for 15 hours and then concentrated, th~ residue i3 taken up in 400 ml of water and the mixture i8 extracted three times using 100 ml of Qthyl acetat0.

The combined organic e~tracts are dried using sodium sulphate and conc~ntrated. The re~idua i8 dried in vacuo at 50C, and 31.9 g (81~) of (R)-4,5-dihydro-3 metho~y-Le A 27 929 - 44 -.

.

..
.

4-phthalLmido-isoxazole are obtained as colourless solid of m.p. 122 DC .

ExampLe 33 o Il H3C~
H3Co--~C~3 ,N-Nli2 H3CO~N~2 ¦¦ CH30H, TMF' (R)-4-Amino-4,5-dihydro-3-methoxy-i~oxazole S A solution of 26.0 g (105 mmol) of (R)-4,5-dihydro-3-methoxy-4-phthalLmido-i~oxazole and 48.8 g (1.06 mol) of methylhydrazine in 500 ml of methanol/tetrahydrofuan (1:1) is concentrated at room ~emperature after 5 hours and the residue i8 extracted three tLmes with 100 ml o~
ether. The combined ether phases are concentrated, and the re~idue i8 purified by column chromatography over silica gel using dichloromethaneJmethanol (1:1) as the eluent.

Yield 7.4 g (60%~ of (R) 4-amino-4,5-dihydro-3-methoxy-isoxazole as colourless liquid of nD = 1 . 4792.

Le A 27 929 - 45 -., , " ' ~-' .': ' ~ ' "
: , ' ', ' ~ '.
~ ' ,

Claims (8)

1. 3-Oxy-substituted isoxazolines of the formula ) (I) in which R1 represents hydrogen or optionally substituted alkyl, R2 represents hydrogen, acyl, alkyl or aryl, R3 represents hydrogen, acyl, alkyl or aryl R2 and R3 together with the adjacent N atom represent a saturated heterocycle, where R1, R2 and R3 must not simultaneously represent hydrogen, and the corresponding tautomers and stereoisomers of these compounds.
2. Process for the preparation of 3-Oxy-substituted isoxazolines of the formula I

(I) in which Le A 27 929 - 46 -R1 represents hydrogen or optionally substituted alkyl, R2 represents hydrsgen, acyl, alkyl or aryl, R3 represents hydrogen, acyl, alkyl or aryl R2 and R3 together with the adjacent N atom represent a saturated heterocycle, where R1, R2 and R3 must not simultaneously represent hydrogen, characterised in that a) 3-Oxy-4-amino-substituted isoxazolines of the formula II

(II) in which R1 has the abovementioned meaning are reacted with mono- or bifunctional acylating, alkylating or arylating agents, b) in the case where in formula I R2 represents the phthaloyl radical and R3 represents hydrogen.

Le A 27 929 - 47 -Compounds of the formula III

(III) in which Hal represents halogen, are reacted with alcoholates of the formula IV
(R-O-)nM (IV) in which R represents optionally substituted alkyl, M represents a monovalent or polyvalent metal cation, n represents integers from 1-3, c) in the case where, in formula I, R2 and R3 repres-ent hydrogen, compounds of the formula V

Le A 27 929 - 48 - (V) in which R1 has the abovementioned meaning, are reacted with alkylhydrazines of the formula VI

in which R4 reprecents C1-4-alkyl.
3. Novel compounds of the formula (V) in which R1 has the meaning given under 1.
4. Process for the preparation of the compounds of the Le A 27 929 - 49 -formula III
(III) in which Hal represents halogen, reacted with alcoholates of the formula IV
(RO)nM
in which R, M and n have the meaning given in Claim 2.
5. Use of 3-oxy-substituted isoxazolines of the formula I according to Claim 1 for combating endoparasites.
6. Endoparasiticidal agents, characterised in that they contain at least one 3-oxy-substituted isoxazoline of the formula (I) according to Claim 1.
7. Process for the preparation of endoparasiticidal agents, characterised in that 3-oxy-substituted isoxazolines of the formula (I) according to Claim 1 are mixed with extenders and/or surface-active agents.

Le A 27 929 - 50 -
8. Use of 3-oxy-substituted isoxazolines of the formula (I) according to Claim 1 for the preparation of endoparasiticidal agents.

Le A 27 929 - 51 -
CA002054430A 1990-11-01 1991-10-29 3-oxy-substituted isoxazolines, process for their preparation and their use for combating endoparasites Abandoned CA2054430A1 (en)

Applications Claiming Priority (2)

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DEP4034713.3 1990-11-01
DE4034713A DE4034713A1 (en) 1990-11-01 1990-11-01 3-OXY-SUBSTITUTED ISOXAZOLINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR THE CONTROL OF ENDOPARASITES

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DE4219247A1 (en) * 1992-06-12 1993-12-16 Bayer Ag Use of 3-aryl-substituted 5-alkylisoxazole-4-carboxylic acid derivatives for the control of endoparasites, novel 3-aryl-substituted 5-alkylisoxazole-4-carboxylic acid derivatives and process for their preparation
AU2001231202A1 (en) * 2000-01-28 2001-08-07 Akkadix Corporation Methods for killing nematodes and nematode eggs using 4-phenoxy-6-aminopyrimidine derivatives

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US2845432A (en) * 1954-12-23 1958-07-29 Merck & Co Inc Benzamido and acetamido 4-amino-3-isoxazolidones and alkylated derivatives
US2815348A (en) * 1955-03-21 1957-12-03 Commercial Solvents Corp Process of producing acetyl cycloserine
US2967866A (en) * 1959-04-07 1961-01-10 Commercial Solvents Corp Nu-(p-chlorobenzyl) cycloserine
US3932439A (en) * 1973-08-01 1976-01-13 Merck & Co., Inc. N-substituted cycloserine compounds, salts thereof, and processes for preparing them
IL45174A (en) * 1973-08-10 1976-12-31 Merck & Co Inc Antibacterial compositions containing 3-fluoro-d-alanine type compound and n-substituted cycloserine compound
US4593024A (en) * 1985-08-15 1986-06-03 International Minerals & Chemical Corp. Dihydroisoxazole compounds and anthelmintic use

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