CA2031156A1 - Anthelmintics - Google Patents
AnthelminticsInfo
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- CA2031156A1 CA2031156A1 CA002031156A CA2031156A CA2031156A1 CA 2031156 A1 CA2031156 A1 CA 2031156A1 CA 002031156 A CA002031156 A CA 002031156A CA 2031156 A CA2031156 A CA 2031156A CA 2031156 A1 CA2031156 A1 CA 2031156A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- 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
- C07D413/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- General Chemical & Material Sciences (AREA)
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- Tropical Medicine & Parasitology (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
AP/5-17858/+
Anthelmintics Abstract Novel anthelmintics are described, which contain as active ingredient acompound of formula I
(I) or, in its hydrogenated form, formula Ia
Anthelmintics Abstract Novel anthelmintics are described, which contain as active ingredient acompound of formula I
(I) or, in its hydrogenated form, formula Ia
Description
,t.~f j AP/5-17858/+
Anthelmintics The present invention relates to novel 1,3-disubstituted 5-azolyloxy-phenylcarbamoyl-4,6-pyrimidinedione derivatives of the formula I below and the hydrogenated analogues thereof of the formula Ia below having anthelmintic activity; to the said compounds for use in a method of controlling helminths; to anthelmintic compositions that contain those compounds as active ingredients; to the preparation of the compounds and compositions; and to the use of the compounds or compositions for controlling helminths, especially nematodes, cestodes and trematodes in domestic animals and productive livestock of the class of mammals.
The compounds according to the invention have the formula I
Rl\ /O ~4 H-~ --CONH--~ ~i- (I) -or, in their hydrogenated form, formula Ia Rl\ ~O ~4 /N--\ /H ~- ~Rs H2_.\ ~--CONH--\ X- tIa) R2 ~iO =- OR3 :
wherein Rl and Rz are each independently of the other Cl-C6alkyl, allyl, Cl-C6cycloalkyl, benzyl or phenyl; and R3 is an unsubstituted or substi-tuted heteroaromatic five-membered ring azole, bonded via carbon, selected from the series benzimidazole, benzoxazole, benzothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole and triazole; and R4 and Rs are each independently of the other hydrogen, Cl-C6alkyl, Cl-C6haloalkyl, Ci-C6alkoxy or C1-C6haloalkoxy, and include their tautomeric forms and physiologically tolerable salts.
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~ '' ., - : ' .
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Anthelmintics The present invention relates to novel 1,3-disubstituted 5-azolyloxy-phenylcarbamoyl-4,6-pyrimidinedione derivatives of the formula I below and the hydrogenated analogues thereof of the formula Ia below having anthelmintic activity; to the said compounds for use in a method of controlling helminths; to anthelmintic compositions that contain those compounds as active ingredients; to the preparation of the compounds and compositions; and to the use of the compounds or compositions for controlling helminths, especially nematodes, cestodes and trematodes in domestic animals and productive livestock of the class of mammals.
The compounds according to the invention have the formula I
Rl\ /O ~4 H-~ --CONH--~ ~i- (I) -or, in their hydrogenated form, formula Ia Rl\ ~O ~4 /N--\ /H ~- ~Rs H2_.\ ~--CONH--\ X- tIa) R2 ~iO =- OR3 :
wherein Rl and Rz are each independently of the other Cl-C6alkyl, allyl, Cl-C6cycloalkyl, benzyl or phenyl; and R3 is an unsubstituted or substi-tuted heteroaromatic five-membered ring azole, bonded via carbon, selected from the series benzimidazole, benzoxazole, benzothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole and triazole; and R4 and Rs are each independently of the other hydrogen, Cl-C6alkyl, Cl-C6haloalkyl, Ci-C6alkoxy or C1-C6haloalkoxy, and include their tautomeric forms and physiologically tolerable salts.
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An interesting group comprises compounds of formula I wherein R3, R4 and Rs are as defined under formula I and R1 and R2 are each independently of the oth,er C~-C6alkyl, allyl, C3-C5cycloalkyl or phenyl.
The five-membered ring azole (R3) is accordingly always bonded via a carbon atom to the phenolic O-atom of the aminophenol moiety of the molecule and can in turn be unsubstituted or substituted. Compounds of formulae I and Ia wherein R3 has, for example, one of the meanings given below form, according to the definition of R3, one of the following preferred groups a) to f) according to the invention:
~roup R3 Type 4.~ R6 Benzimidazol-2-yl a) 3 N ' S Benzoxazol-2-yl 2/ y \,~ Benzothiazol-2-yl 4/R8 Imidazol-2-yl b) 3 N - Oxazol-2-yl 2 . 1! s Thiazol-2-yl 4 ~ 3 [ lH-1,2,4-Triazol]-5-yl c) S \ /~ 2 8 [1,2,4-Oxadiazol]-5-yl Z [1,2,4-Thiadiazol]-5-yl [1,2,4-Oxadiazol]-3-yl [l~2~4-Thiadiazol]-3 4 s/Ra d) 3 ~ ~ 1 [lH-1,2,4-Triazol]-3-yl ~N R11 e) 3 ~ - N 4 [1,3,4-Oxadiazol]-2-yl 2 . . s [1,3,4-Thiadiazol]-2-yl / y Rg [4H-1,2,4-Triazol]-5-yl or R~1 f) 1~ ~ 2 ~N 3 R9 [lH-1,2,4-Triazol]-5-yl . . .
, .
An interesting group comprises compounds of formula I wherein R3, R4 and Rs are as defined under formula I and R1 and R2 are each independently of the oth,er C~-C6alkyl, allyl, C3-C5cycloalkyl or phenyl.
The five-membered ring azole (R3) is accordingly always bonded via a carbon atom to the phenolic O-atom of the aminophenol moiety of the molecule and can in turn be unsubstituted or substituted. Compounds of formulae I and Ia wherein R3 has, for example, one of the meanings given below form, according to the definition of R3, one of the following preferred groups a) to f) according to the invention:
~roup R3 Type 4.~ R6 Benzimidazol-2-yl a) 3 N ' S Benzoxazol-2-yl 2/ y \,~ Benzothiazol-2-yl 4/R8 Imidazol-2-yl b) 3 N - Oxazol-2-yl 2 . 1! s Thiazol-2-yl 4 ~ 3 [ lH-1,2,4-Triazol]-5-yl c) S \ /~ 2 8 [1,2,4-Oxadiazol]-5-yl Z [1,2,4-Thiadiazol]-5-yl [1,2,4-Oxadiazol]-3-yl [l~2~4-Thiadiazol]-3 4 s/Ra d) 3 ~ ~ 1 [lH-1,2,4-Triazol]-3-yl ~N R11 e) 3 ~ - N 4 [1,3,4-Oxadiazol]-2-yl 2 . . s [1,3,4-Thiadiazol]-2-yl / y Rg [4H-1,2,4-Triazol]-5-yl or R~1 f) 1~ ~ 2 ~N 3 R9 [lH-1,2,4-Triazol]-5-yl . . .
, .
- 3 - h-.;~'~
wherein Y is oxygen, sulfur or NR1o;
Z is oxygen, sulfur or NH;
R6 and R7 are each independently of the other hydrogen, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy, Cl-C4haloalkoxy, Cl-C4alkylthio, Cl-C4-alkylsulfonyl, Cl-C4alkylsulfinyl, Cl-C4haloalkylsulfonyl, Cl-C4halo-alkylsulfinyl, (Cl-C4alkyl)2N, (C1-C4alkyl)HN, halogen, nitro or cyano;
Rg and Rg are each indepcndently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, Cl-C6alkoxy, Cl-C6alkylthio, halogen or nitro; or are each independently of the other unsubstituted or halo- or Cl-C3-alkyl-substituted C3-C7cycloalkyl;
Rlo is hydrogen or Cl-C6alkyl; and Rll is Cl-C6alkyl.
Within groups b) to f), interesting compounds of formulae I and Ia are also those wherein Y, Z, Rlo and Rll are as defined above but Rg and Rg are each independently of the other unsubstituted or halo- or Cl-C3alkyl-substituted C3-C7cycloalkyl, preferably cyclopropyl or cyclohexyl.
The substituent R3 accordingly has, inter alia, the following meanings:
~ R~ ~ R6 .~ R6 .~R6 a) 11 11 1 ~ lNI il 1 lNI 11 1 , 11 il 1 .
R ~ ~ R7 ~ R7 R7 : ~ 8 ~a /R8 /Rg N I ~ N ~; .
b) ~ I~ 1, 1!
/ ~ ~9 / \~N/ \Rg / \O Rg S Rg 1!1 Rl o /Rg /Ra ~R8 N_ . . ~-- 1 I
C) ~ \o~ ' ~ !`S~ ' R/g \~ R/
.
' r~
/Ra ~==.
~N Rl;
e) S ; ~ \Z , 2/.\ /,\s , / \S/ \R ' Rll ~N Rs wherain the substituents R6 to Rll are as defined above.
Preferred groups of compounds of formulae I and Ia are all those which are formed formally by combination of the molecule fragments I' and Ia' ~N~ 4~ ~N--~ H .~4.~Rs H- ~ ~ / -CONH \ XO_ or H2- ~ / CONH \ XO_ (I') (Ia') wherein Rl, R2, R4 and Rs are as defined under formula I, with one of the azoles R3 mentioned under a) to f). The present invention relates to each of those groups.
Within all the said sub-groups, preferred compounds of formulae I and Ia are those wherein Rl and R2 are each independently of the other methyl, ethyl, isopropyl, allyl or cyclopropyl, and R4 and Rs are each independently of the other hydrogen, methyl, CF3, OCH3, OCHF2 or OCF3.
' ,,.~. ' ' :
Within the group in which the five-membered ring azole is a grouping indicated under a), additional preferred compounds of formulae I and Ia are those wherein R6 and R7 are each independently of the other hydrogen, methyl, CF3, methoxy, halomethoxy, fluorine, chlorine or bromine, and the other substituents are as defined above.
Within the groups in which the five-membered ring azole is one of the groupings indicated under b) to f), additional preferred compounds of formulae I and Ia are those wherein R8 and Rg are each independently of the other hydrogen, methyl, ethyl, C3-C7cycloalkyl, CF3, C2Fs, C3F7, CCl3, CHCl2, CHzCl, SCH3 or halogen; Rlo is hydrogen or methyl and Rll is C~-C4alkyl, especially methyl.
Compounds of formulae I and Ia wherein the OR3 group is bonded to the phenyl radical in the para-position are especially noteworthy.
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Only one of the numerous possible betaine structures is given in formula I; other isoelectronic structural formulae are, for example:
R~ CONH~ R~ CON~
H- ~ ~ ~ -CONH~ X~---~ \ -CONh--~ ~X
or, to summarise:
R ~ \ _.XoR3 - 6 - ~J t~ ,~ i'.i ', The compounds of formula Ia may exist, for example, in the following tautomeric forms:
Rl\ ~O ~4 Rl\N /OH ~4 \ / \-/CONH ~ --CONH--~
H /N--~ \ XOR H /N--~ =- OR3 The present invention extends to all forms of the compounds of formulae I
and Ia.
Depending upon the number of carbon atoms indicated, the term alkyl by itself or as a component of another substituent is to be understood within the scope of the present invention as including, for example, the following straight-chain and branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, etc.. Haloalkyl by itself or as a component of haloalkoxy is a mono- to per-halogenated alkyl substituent, for example CHzCl, CHCl2, CCl3, CH2F, CHF2, CF3, CH2Br, CHBr2, CBr3, CH2I, CI3, CHClF, CHBrCl, CFBrCl, C2Fs, CH2CH2Cl, CHClCH3, C2Cls, CHFCHClz, etc., preferably CF3. Here and hereinbelow, halogen is to be understood as being fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, but especially chlorine.
Cycloalkyl by itself or as a component of a substituent is, depending upon the number of carbon atoms indicated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.. Cyanoalkyl is an alkyl group in which a hydrogen atom has been replaced by CN, preferably an alkyl group in which the CN group is located at the terminal carbon atom.
The term "physiologically tolerable salts" of compounds of formulae I and Ia includes the alkali metal, ammonium or amine salts, with sodium, potassium, ammonium or alkylamine salts, especially triethylamine salts, being preferred. The term also includes, however, the addition salts of inorganic and organic acids formed by the addition of an equivalent amount of a salt-forming acid to the base molecule.
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Examples of salt-forming acids are inorganic acids: hydrohalic acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, and also sulfuric acid, phosphoric acid, phosphorous acid, nitric acid, and organic acids, for example acetic acid, trifluoro-acetic acid, trichloroacetic acid, propionic acid, glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, formic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, salicylic acid, p-aminosalicylic acid, phthalic acid, 2-phenoxybenzoic acid or 2-acetoxybenzoic acid.
The compounds of formulae I and la are for the most part stable solids at room temperature that have a melting point of from approximately 100 to approximately 300C. They have very valuable anthelmintic properties and can be used curatively and preventively for the control of a number of worm-related disorders in warm-blooded animals, especially in domestic animals and productive livestock, more especially mammals.
Especially preferred individual compounds of formula I are:
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(6-fluoro-[5-or 7-chloro]-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine.
Especially preferred compounds of formula Ia are:
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(6-fluoro-[5- or 7-chloro]-benzothiazol-2-yloxy~-phenylcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione.
S ~ r-~ 8 ~ f~
The compounds of formulae I and Ia are prepared according to the inven-tion by desulfurizing a compound of formula II
R1\N /OH ~4 S=-\ ~--CONH--~ ~ (II) /N--~ =- OR3 in which R1 ? R2, R3, R4 and Rs are as defined for formulae I and Ia.
The desulfurization can be carried out, for example, by hydrogenation, preferably by catalytic hydrogenation. In a preferred embodiment, the compound of formula II is hydrogenated in an inert solvent or solvent mixture at tempera~ures ranging from 20 to 180C~ preferably from 60 to 120C, especially at reflux temperature, with trialkyltin hydride, trialkyltin halide, trialkylgermanium hydride, trialkylgermanium halide, alkylmercury hydride or alkylmercury halide, the reaction being carried out additionally in the presence of NaBH4 when a halide is used. In this context, alkyl is preferably C1-C6alkyl, especially C2-C4alkyl, and halide is especially chloride or bromide. The chlorides are especially suitable. A further suitable hydrogenating agent that may be mentioned is tris(trimethylsilyl)silane ([(CH3)3Si]3SiH).
The hydrides and halides are used in at least an equimolar amount, based on the starting compound of formula II. NaBH4 can also be added in an equimolar amount.
..
The reaction can, in addition, be carried out in the presence of a radical initiator, which can be added in catalytic amounts. Suitable radical initiators are, for example, azoisobutyronitrile (AiBN), peroxides, such as benzoyl peroxide, and also UV light or heat. Examples of suitable inert solvents, alone or in admixture, are: aliphatic and aromatic hydrocarbons, for example pentane, hexane, petroleum ether, ligroin, benzene? toluene, xylenes, etc.; ethers and ethereal substances, such as tetrahydrofuran, anisole, dioxane, etc.; halogenated hydro-carbons, such as carbon tetrachloride, tetrachloroethylene, chloro-benzene, etc..
_ 9 _ ~t .r~ r~ 1 ~
The compounds I and Ia are generally obtained together, but by suitableselection of the solvent it is possible so to arrange the system that, for example, the sparingly soluble betaines of formula I are precipitated and can be removed from the reaction mixture, for example, by filtration, whilst the more soluble compounds of formula Ia can be obtained from the solution, for example, by concentration or precipitation. It is also possible, however, to isolate a mixture of compounds I and Ia and then to separate the two compounds, for example on the basis of their different solution behaviour, for example by fractional crystallisation or by column chromatography. The skilled choice of solvents, however, may also result in pure products, that is to say either wholly in compounds I or wholly in compounds Ia. The compounds of formula I can be converted into the compounds of formula Ia according to conventional methods by hydro-genation, for example with Raney nickel, NaBH4, tributyltin hydride, etc..
As has already been mentioned, the compounds of formulae I and Ia can also be in the form of adducts with bases or acids.
Whilst acid addition salts have already been described in detail at thebeginning, mention has yet to be made of the inorganic and organic bases suitable as adduct formers. These are, for example, preferably tertiary amines, such as trialkylamines (for example trimethylamine, triethylamine or tripropylamine), pyridine and pyridine bases (for example 4-dimethyl-aminopyridine or 4-pyrrolidylaminopyridine), picolines and lutidines and also oxides, hydroxides, carbonates and hydrogen carbonates of alkali metals and alkaline earth metals (for example CaO, BaO, NaOH, KOH, KHCO3, NaHCO3, Ca(OH)2, K2CO3 or Na2CO3), and also acetates, for example CH3COONa or CH3COOK. In addition, alkali metal alcoholates, for example sodium ethanolate, sodium propanolate, potassium tert.-butanolate or sodium methanolate, are also suitable bases. The base is advantageous-ly added in an amount of from 10 to 100 % of the equimolar amount in relation to the reactants.
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In many cases it may be advantageous to carry out the reaction under a protective gas atmosphere. Suitable protective gases are, for example, nitrogen, helium and argon.
The reaction of compounds II with trialkyltin hydride, especially in the presence of a radical initiator, is especially preferred.
The thiobarbiturates of formula II are known, for example from EuropeanPublished Application EP-192,180 or the corresponding British Patent GB 2 171 099 B, or can be prepared analogously to the compounds described therein.
The compounds of formulae I and Ia according to the invention can existin different tautomeric forms, namely in the keto or enol form or as a mixture of the keto and enol forms. The present invention relates to the individual tautomers and mixtures thereof, and also to the salts of any of those forms, and to the preparation thereof.
The present invention relates to the described prepara~ion process including all variants.
It is generally known that of the endoparasites occurring in warm-blooded animals it is particularly the helminths that cause great damage to the animals infested with them. Where there is chronic and especially epidemic occurrence of worm-related disorders in herds of animals, such damage caused by helminthiases can assume serious economic proportions.
In the animals affected, the damage manifests itself inter alia as losses of productivity, reduced resistance to other diseases and in-creased mortality. Especially dangerous worm-related disorders are caused by helminths parasitising the gastro-intestinal tract and other organs and may occur, for example, in ruminants such as cattle, sheep and goats as well as in horses, pigs, fowl, red deer, dogs and cats.
In this description the term "helminths" is to be understood as meaningespecially parasitic worms that belong to the Platyhelminthes (cestodes, trematodes) and Nemathelminthes (nematodes and related species), there-fore tapeworms, sucker worms and roundworms of the gastro-intestinal tract and other organs (for example the liver, lungs, kidneys, lymph vessels, blood etc.).
There is therefore an urgent need to develop therapeutic agents suitable for controlling helminths in all stages of their development and also for guarding against attack by such parasites.
Although a number of substances having anthelmintic activity are known that have been proposed for controlling the various species of helminth, these have not proved completely satisfactory either because at a tolerable dose it is not possible to make full use of their spectrum of activity or because at therapeutically effective doses they exhibit undesired side effects or properties. In this respect, the resistance to certain classes of substances, which occurs more and more today, is also increasingly significant. "Albendazol", which is described, for example, in the literature (British Pat. No. 1464326; Am. J. Vet. Res. 38, 1425-1426 (1g77); Am. J. Vet. Res. 37, 1515-1516 (1976); Am. J. Vet.
Res. 38, 807-808 (19~7); Am. J. Vet. Res. 38, 1247-1248 (1977)), has only a limited spectrum of anthelmintic activity in ruminants. Its action against benzimidazole-resistant nematodes and adult liver flukes is completely inadequate, and in particular the pathogenically important immature migrating forms of the latter are not affected at doses tolerated by the host animal.
It has surprisingly been found that the novel compounds of formulae I and Ia have a broad spectrum of activity against helminths that parasitise the animal organism, especially mammals, such as nematodes, cestodes and trematodes, their action being directed especially against nematodes (roundworms).
As a particular feature of the compounds of formulae I and Ia attentionis drawn to their surprisingly high tolerability by warm-blooded animals, as a result of which they are superior to the known thiobarbituric acid derivatives. The practical handling thereof in the treatment of worm-infested animals is extraordinarily simplified by the fact that they aretolerated by the treated animals without symptoms even at relatively high doses.
The novel compounds of formulae I and Ia according to the invention aresuitable, for example, for controlling parasitic nematodes of the orders (according to K.I. Skrajabin) Rhabditida, Ascaridida, Spirurida, Trichocephalida, or for controlling cestodes of the orders (according to Wardle & McLeod) Cyclophyllidae, Pseudophyllidae, or for controlling trematodes of the order Digenea, in domestic animals and productive livestock, such as cattle, sheep, goats, horses, pigs, red deer, cats, dogs and fowl. They may be administered to the animals either as a single dose or repeatedly, the single doses preferably being from 1 to 20 mg per kg of body weight depending upon the species of animal. In many cases, protracted administration may result in an improved action or may permit the use of smaller total doses.
The compositions according to the invention are prepared by bringing the compounds of formula I or Ia into contact with liquid and/or solid formulation adjuvants, by mixing and/or grinding in stages, in such a manner that an optimum display of the anthelmintlc activity of the formulation, conformable to the application, is achieved.
The formulation stages can be supplemented by kneading, granulating (granulates) and optionally compressing (pellets).
Suitable formulation adjuvants are, for example, solid carriers, solvents and, where appropriate, surface-active substances (surfactants~.
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The following formulation adjuvants are used to prepare the compositions according to the invention:
solid carriers, for example kaolin, talcum, bentonite, sodium chloride, calcium phosphate, carbohydrates, cellulose powder, cottonseed meal, polyethylene glycol ethers, where appropriate binders such as, for example, gelatin, soluble cellulose derivatives, if desired with the addition of surface-active substances, such as ionic or non-ionic dispersants; and also natural mineral fillers, such as calcite, mont-morillonite or attapulgite. In order to improve the physical properties it is also possible to add highly dispersed silicic acid or highly dispersed absorbent polymers. Suitable granulated adsorptive carriers are porous types, for example pumice, broken brick, sepiolite or bentonite;
and suitable nonsorbent carriers are, for example, calcite or sand. In addition, a great number of pregranulated materials of inorganic or organic nature can be used, e.g. especially dolomite or pulverised plant material.
Suitable solvents are: aromatic hydrocarbons, preferably the fractions containing 8 to 12 carbon atoms, e.g. xylene mixtures or substituted naphthalenes, phthalates such as dibutyl phthalate or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexane or parafins, alcohols and glycols and their ethers and esters, such as ethanol, ethylene glycol, ethylene glycol monomethyl or monoethyl ether, ketones such as cyclo-hexanone, strongly polar solvents such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, as well as vegetable oils or epoxidised vegetable oils, such as epoxidised coconut oil or soybean oil, and water.
Depending on the nature of the compound of formula I or Ia to be formulated, suitable surface-active compounds are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and wetting properties. The term "surfactants" will also be understood as comprising mixtures of s~rfactants.
Both so-called water-soluble soaps and water-soluble synthetic surface-active compounds are suitable anionic surfactants.
1.,.. ' ' .
.
.~ :
14 ~ ~ ~
Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (ClO-C2z), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained e.g. from coconut oil or tallow oil. Mention may also be made of fatty acid methyltaurin salts.
Frequently, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.
The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and contain a C~-C22alkyl radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of lignosulfonic acid, of dodecyl sulfate or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfated and sulfonated fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalene-sulfonic acid, or of a condensate of naphthalenesulfonic acid and formaldehyde.
Also suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 moles of ethylene oxide, or phospholipids.
Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the aliphatic hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.
. ~ ' . ' " '.
- 15 - ~ ~ ~
Further suitable non-ionic surfactants are the water-soluble adducts ofpolyethylene oxide with polypropylene glycol, ethylenediaminopoly-propylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit.
Examples of non-ionic surfactants are nonylphenolpolyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxy-polyethoxyethanol.
Fatty acid esters of polyoxyethylene sorbitan, e.g. polyoxyethylene sorbitan trioleate, are also suitable non-ionic surfactants.
Cationic surfactants are preferably quaternary ammonium salts which contain, as N-substituent, at least one C8-Czzalkyl radical and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl or hydroxy-lower alkyl radicals. The salts are preferably in the form of halides, methyl sulfates or ethyl sulfates, e.g. stearyltrimethylammonium chloride or benzyldi(2-chloroethyl)ethylammonium bromide.
The surfactants customarily employed in the art of formulation are described, inter alia, in the following publications:
"Mc Cutcheon's Detergents and Emulsifiers Annual", MC Publishing Corp., Ridgewood New Jersey, 1980;
Sisley and Wood, "Encyclopedia of Surface Active Agents", Chemical Publishing Co., Inc. New York, 1980.
Suitable binders for tablets and boli are chemically modified natural polymer substances that are soluble in water or alcohol, such as starch, cellulose or protein derivatives (e.g. methylcellulose, carboxymethyl-cellulose, ethylhydroxyethylcellulose, proteins such as zein, gelatin and the like) and synthetic polymers, such as, for example, polyvinyl ~ 16 ~ ~ rJ ,~
alcohol, polyvinylpyrrolidone etc.. The tablets also contain fillers (e.g. starch, microcrystalline cellulose, sugar, lactose, etc.), glidants and disintegrators.
If the anthelmintic compositions are in the form of feed concentrates, then the carriers used are, for example, performance feed, feed grain or protein concentrates. In addition to the active ingredients, such feed concentrates or compositions may contain additives, vitamins, anti-biotics, chemotherapeutic agents or other pesticides, especially bacteriostatics, fungistatics or coccidiostatics, or hormone prepara-tions, substances having an anabolic activity or substances that promote growth, influence the meat quality of animals for slaughtering or are useful to the organism in some other way. If the compositions or the compounds of formula I or Ia contained therein are added directly to the feed or to animal drinks, then the prepared feed or the prepared drink preferably contains the active ingredients in a concentration of approximately from 0.0005 to 0.02 percent by weight (5-200 ppm).
The compositions according to the invention can be administered to the animals to be treated perorally, parenterally or subcutaneously, the compositions being in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boli and capsules.
The anthelmintic compositions according to the invention generally contain from 0.1 to 99 % by weight, preferably from 0.1 to 95 % by weight, of the compound of formula I, formula Ia or a mixture of the two, from 99.9 to 1 % by weight, preferably from 99.8 to 5 % by weight, of a solid or liquid adjuvant, including from 0 to 25 % by weight, preferably from 0.1 to 25 % by weight, of a surfactant.
Whereas commercial products will preferably be formulated as concen-trates, the end user will normally employ dilute formulations.
The compositions may also contain further auxiliaries such as stabilisers, antifoams, viscosity regulators, binders and tackifiers as well as other active ingredients for obtaining special effects.
.. .
The present invention relates also to such anthelmintic compositions employed by the end user.
In each of the methods according to the invention for controlling pestsand in each of the pesticidal compositions according to the invention, the compounds of formulae I and Ia can be used in any of their tautomeric forms, as mixtures thereof or in the form of their salts.
The invention also includes a method for the prophylactic protection ofanimals against parasitic helminths, which method comprises administering the compounds of formulae I and Ia or the active ingredient formulations to the animals as an additive to feed or to drinks or in solid or liquid form orally, by injection or parenterally.
The following Examples serve to illustrate the invention without implying any limitation thereof.
1. Preparation Examples 1.1. Preparation of 1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine A solution of 5.3 g (10 mmol) of 1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylcarbamoyl~-2-thiobarbituric acid, 126 mg (0.8 mmol) of azoisobutyronitrile and ô.ô g (30 mmol) of tributyltin hydride is stirred under reflux in benzene for 3 hours and under a nitrogen atmosphere. After the reaction mixture has cooled to room temperature, the precipitated product is filtered off, washed repeatedly with diiso-propyl ether and dried, yielding 1.2 g (24 ~0) of the title compound. M.p.
230-232C.
1H-NMR (300 MHz, DMSO d~, TMS): 11.00, s, NH; 9.16, s, H-C(3); 7.40, d, J=9.5, 2H; 7.32, d, J=9.5, lH; 7.23, 6rs, lH; 6.92-6.81, m, lH; 6.87, d, J=9.5, 2H; 3.16, s, 2 x CH3.
wherein Y is oxygen, sulfur or NR1o;
Z is oxygen, sulfur or NH;
R6 and R7 are each independently of the other hydrogen, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy, Cl-C4haloalkoxy, Cl-C4alkylthio, Cl-C4-alkylsulfonyl, Cl-C4alkylsulfinyl, Cl-C4haloalkylsulfonyl, Cl-C4halo-alkylsulfinyl, (Cl-C4alkyl)2N, (C1-C4alkyl)HN, halogen, nitro or cyano;
Rg and Rg are each indepcndently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, Cl-C6alkoxy, Cl-C6alkylthio, halogen or nitro; or are each independently of the other unsubstituted or halo- or Cl-C3-alkyl-substituted C3-C7cycloalkyl;
Rlo is hydrogen or Cl-C6alkyl; and Rll is Cl-C6alkyl.
Within groups b) to f), interesting compounds of formulae I and Ia are also those wherein Y, Z, Rlo and Rll are as defined above but Rg and Rg are each independently of the other unsubstituted or halo- or Cl-C3alkyl-substituted C3-C7cycloalkyl, preferably cyclopropyl or cyclohexyl.
The substituent R3 accordingly has, inter alia, the following meanings:
~ R~ ~ R6 .~ R6 .~R6 a) 11 11 1 ~ lNI il 1 lNI 11 1 , 11 il 1 .
R ~ ~ R7 ~ R7 R7 : ~ 8 ~a /R8 /Rg N I ~ N ~; .
b) ~ I~ 1, 1!
/ ~ ~9 / \~N/ \Rg / \O Rg S Rg 1!1 Rl o /Rg /Ra ~R8 N_ . . ~-- 1 I
C) ~ \o~ ' ~ !`S~ ' R/g \~ R/
.
' r~
/Ra ~==.
~N Rl;
e) S ; ~ \Z , 2/.\ /,\s , / \S/ \R ' Rll ~N Rs wherain the substituents R6 to Rll are as defined above.
Preferred groups of compounds of formulae I and Ia are all those which are formed formally by combination of the molecule fragments I' and Ia' ~N~ 4~ ~N--~ H .~4.~Rs H- ~ ~ / -CONH \ XO_ or H2- ~ / CONH \ XO_ (I') (Ia') wherein Rl, R2, R4 and Rs are as defined under formula I, with one of the azoles R3 mentioned under a) to f). The present invention relates to each of those groups.
Within all the said sub-groups, preferred compounds of formulae I and Ia are those wherein Rl and R2 are each independently of the other methyl, ethyl, isopropyl, allyl or cyclopropyl, and R4 and Rs are each independently of the other hydrogen, methyl, CF3, OCH3, OCHF2 or OCF3.
' ,,.~. ' ' :
Within the group in which the five-membered ring azole is a grouping indicated under a), additional preferred compounds of formulae I and Ia are those wherein R6 and R7 are each independently of the other hydrogen, methyl, CF3, methoxy, halomethoxy, fluorine, chlorine or bromine, and the other substituents are as defined above.
Within the groups in which the five-membered ring azole is one of the groupings indicated under b) to f), additional preferred compounds of formulae I and Ia are those wherein R8 and Rg are each independently of the other hydrogen, methyl, ethyl, C3-C7cycloalkyl, CF3, C2Fs, C3F7, CCl3, CHCl2, CHzCl, SCH3 or halogen; Rlo is hydrogen or methyl and Rll is C~-C4alkyl, especially methyl.
Compounds of formulae I and Ia wherein the OR3 group is bonded to the phenyl radical in the para-position are especially noteworthy.
.
Only one of the numerous possible betaine structures is given in formula I; other isoelectronic structural formulae are, for example:
R~ CONH~ R~ CON~
H- ~ ~ ~ -CONH~ X~---~ \ -CONh--~ ~X
or, to summarise:
R ~ \ _.XoR3 - 6 - ~J t~ ,~ i'.i ', The compounds of formula Ia may exist, for example, in the following tautomeric forms:
Rl\ ~O ~4 Rl\N /OH ~4 \ / \-/CONH ~ --CONH--~
H /N--~ \ XOR H /N--~ =- OR3 The present invention extends to all forms of the compounds of formulae I
and Ia.
Depending upon the number of carbon atoms indicated, the term alkyl by itself or as a component of another substituent is to be understood within the scope of the present invention as including, for example, the following straight-chain and branched groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, etc.. Haloalkyl by itself or as a component of haloalkoxy is a mono- to per-halogenated alkyl substituent, for example CHzCl, CHCl2, CCl3, CH2F, CHF2, CF3, CH2Br, CHBr2, CBr3, CH2I, CI3, CHClF, CHBrCl, CFBrCl, C2Fs, CH2CH2Cl, CHClCH3, C2Cls, CHFCHClz, etc., preferably CF3. Here and hereinbelow, halogen is to be understood as being fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, but especially chlorine.
Cycloalkyl by itself or as a component of a substituent is, depending upon the number of carbon atoms indicated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.. Cyanoalkyl is an alkyl group in which a hydrogen atom has been replaced by CN, preferably an alkyl group in which the CN group is located at the terminal carbon atom.
The term "physiologically tolerable salts" of compounds of formulae I and Ia includes the alkali metal, ammonium or amine salts, with sodium, potassium, ammonium or alkylamine salts, especially triethylamine salts, being preferred. The term also includes, however, the addition salts of inorganic and organic acids formed by the addition of an equivalent amount of a salt-forming acid to the base molecule.
r - ! ~
Examples of salt-forming acids are inorganic acids: hydrohalic acids, such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydriodic acid, and also sulfuric acid, phosphoric acid, phosphorous acid, nitric acid, and organic acids, for example acetic acid, trifluoro-acetic acid, trichloroacetic acid, propionic acid, glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, formic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, salicylic acid, p-aminosalicylic acid, phthalic acid, 2-phenoxybenzoic acid or 2-acetoxybenzoic acid.
The compounds of formulae I and la are for the most part stable solids at room temperature that have a melting point of from approximately 100 to approximately 300C. They have very valuable anthelmintic properties and can be used curatively and preventively for the control of a number of worm-related disorders in warm-blooded animals, especially in domestic animals and productive livestock, more especially mammals.
Especially preferred individual compounds of formula I are:
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(6-fluoro-[5-or 7-chloro]-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine.
Especially preferred compounds of formula Ia are:
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(6-fluoro-[5- or 7-chloro]-benzothiazol-2-yloxy~-phenylcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione.
S ~ r-~ 8 ~ f~
The compounds of formulae I and Ia are prepared according to the inven-tion by desulfurizing a compound of formula II
R1\N /OH ~4 S=-\ ~--CONH--~ ~ (II) /N--~ =- OR3 in which R1 ? R2, R3, R4 and Rs are as defined for formulae I and Ia.
The desulfurization can be carried out, for example, by hydrogenation, preferably by catalytic hydrogenation. In a preferred embodiment, the compound of formula II is hydrogenated in an inert solvent or solvent mixture at tempera~ures ranging from 20 to 180C~ preferably from 60 to 120C, especially at reflux temperature, with trialkyltin hydride, trialkyltin halide, trialkylgermanium hydride, trialkylgermanium halide, alkylmercury hydride or alkylmercury halide, the reaction being carried out additionally in the presence of NaBH4 when a halide is used. In this context, alkyl is preferably C1-C6alkyl, especially C2-C4alkyl, and halide is especially chloride or bromide. The chlorides are especially suitable. A further suitable hydrogenating agent that may be mentioned is tris(trimethylsilyl)silane ([(CH3)3Si]3SiH).
The hydrides and halides are used in at least an equimolar amount, based on the starting compound of formula II. NaBH4 can also be added in an equimolar amount.
..
The reaction can, in addition, be carried out in the presence of a radical initiator, which can be added in catalytic amounts. Suitable radical initiators are, for example, azoisobutyronitrile (AiBN), peroxides, such as benzoyl peroxide, and also UV light or heat. Examples of suitable inert solvents, alone or in admixture, are: aliphatic and aromatic hydrocarbons, for example pentane, hexane, petroleum ether, ligroin, benzene? toluene, xylenes, etc.; ethers and ethereal substances, such as tetrahydrofuran, anisole, dioxane, etc.; halogenated hydro-carbons, such as carbon tetrachloride, tetrachloroethylene, chloro-benzene, etc..
_ 9 _ ~t .r~ r~ 1 ~
The compounds I and Ia are generally obtained together, but by suitableselection of the solvent it is possible so to arrange the system that, for example, the sparingly soluble betaines of formula I are precipitated and can be removed from the reaction mixture, for example, by filtration, whilst the more soluble compounds of formula Ia can be obtained from the solution, for example, by concentration or precipitation. It is also possible, however, to isolate a mixture of compounds I and Ia and then to separate the two compounds, for example on the basis of their different solution behaviour, for example by fractional crystallisation or by column chromatography. The skilled choice of solvents, however, may also result in pure products, that is to say either wholly in compounds I or wholly in compounds Ia. The compounds of formula I can be converted into the compounds of formula Ia according to conventional methods by hydro-genation, for example with Raney nickel, NaBH4, tributyltin hydride, etc..
As has already been mentioned, the compounds of formulae I and Ia can also be in the form of adducts with bases or acids.
Whilst acid addition salts have already been described in detail at thebeginning, mention has yet to be made of the inorganic and organic bases suitable as adduct formers. These are, for example, preferably tertiary amines, such as trialkylamines (for example trimethylamine, triethylamine or tripropylamine), pyridine and pyridine bases (for example 4-dimethyl-aminopyridine or 4-pyrrolidylaminopyridine), picolines and lutidines and also oxides, hydroxides, carbonates and hydrogen carbonates of alkali metals and alkaline earth metals (for example CaO, BaO, NaOH, KOH, KHCO3, NaHCO3, Ca(OH)2, K2CO3 or Na2CO3), and also acetates, for example CH3COONa or CH3COOK. In addition, alkali metal alcoholates, for example sodium ethanolate, sodium propanolate, potassium tert.-butanolate or sodium methanolate, are also suitable bases. The base is advantageous-ly added in an amount of from 10 to 100 % of the equimolar amount in relation to the reactants.
~ ~ 3 ~
In many cases it may be advantageous to carry out the reaction under a protective gas atmosphere. Suitable protective gases are, for example, nitrogen, helium and argon.
The reaction of compounds II with trialkyltin hydride, especially in the presence of a radical initiator, is especially preferred.
The thiobarbiturates of formula II are known, for example from EuropeanPublished Application EP-192,180 or the corresponding British Patent GB 2 171 099 B, or can be prepared analogously to the compounds described therein.
The compounds of formulae I and Ia according to the invention can existin different tautomeric forms, namely in the keto or enol form or as a mixture of the keto and enol forms. The present invention relates to the individual tautomers and mixtures thereof, and also to the salts of any of those forms, and to the preparation thereof.
The present invention relates to the described prepara~ion process including all variants.
It is generally known that of the endoparasites occurring in warm-blooded animals it is particularly the helminths that cause great damage to the animals infested with them. Where there is chronic and especially epidemic occurrence of worm-related disorders in herds of animals, such damage caused by helminthiases can assume serious economic proportions.
In the animals affected, the damage manifests itself inter alia as losses of productivity, reduced resistance to other diseases and in-creased mortality. Especially dangerous worm-related disorders are caused by helminths parasitising the gastro-intestinal tract and other organs and may occur, for example, in ruminants such as cattle, sheep and goats as well as in horses, pigs, fowl, red deer, dogs and cats.
In this description the term "helminths" is to be understood as meaningespecially parasitic worms that belong to the Platyhelminthes (cestodes, trematodes) and Nemathelminthes (nematodes and related species), there-fore tapeworms, sucker worms and roundworms of the gastro-intestinal tract and other organs (for example the liver, lungs, kidneys, lymph vessels, blood etc.).
There is therefore an urgent need to develop therapeutic agents suitable for controlling helminths in all stages of their development and also for guarding against attack by such parasites.
Although a number of substances having anthelmintic activity are known that have been proposed for controlling the various species of helminth, these have not proved completely satisfactory either because at a tolerable dose it is not possible to make full use of their spectrum of activity or because at therapeutically effective doses they exhibit undesired side effects or properties. In this respect, the resistance to certain classes of substances, which occurs more and more today, is also increasingly significant. "Albendazol", which is described, for example, in the literature (British Pat. No. 1464326; Am. J. Vet. Res. 38, 1425-1426 (1g77); Am. J. Vet. Res. 37, 1515-1516 (1976); Am. J. Vet.
Res. 38, 807-808 (19~7); Am. J. Vet. Res. 38, 1247-1248 (1977)), has only a limited spectrum of anthelmintic activity in ruminants. Its action against benzimidazole-resistant nematodes and adult liver flukes is completely inadequate, and in particular the pathogenically important immature migrating forms of the latter are not affected at doses tolerated by the host animal.
It has surprisingly been found that the novel compounds of formulae I and Ia have a broad spectrum of activity against helminths that parasitise the animal organism, especially mammals, such as nematodes, cestodes and trematodes, their action being directed especially against nematodes (roundworms).
As a particular feature of the compounds of formulae I and Ia attentionis drawn to their surprisingly high tolerability by warm-blooded animals, as a result of which they are superior to the known thiobarbituric acid derivatives. The practical handling thereof in the treatment of worm-infested animals is extraordinarily simplified by the fact that they aretolerated by the treated animals without symptoms even at relatively high doses.
The novel compounds of formulae I and Ia according to the invention aresuitable, for example, for controlling parasitic nematodes of the orders (according to K.I. Skrajabin) Rhabditida, Ascaridida, Spirurida, Trichocephalida, or for controlling cestodes of the orders (according to Wardle & McLeod) Cyclophyllidae, Pseudophyllidae, or for controlling trematodes of the order Digenea, in domestic animals and productive livestock, such as cattle, sheep, goats, horses, pigs, red deer, cats, dogs and fowl. They may be administered to the animals either as a single dose or repeatedly, the single doses preferably being from 1 to 20 mg per kg of body weight depending upon the species of animal. In many cases, protracted administration may result in an improved action or may permit the use of smaller total doses.
The compositions according to the invention are prepared by bringing the compounds of formula I or Ia into contact with liquid and/or solid formulation adjuvants, by mixing and/or grinding in stages, in such a manner that an optimum display of the anthelmintlc activity of the formulation, conformable to the application, is achieved.
The formulation stages can be supplemented by kneading, granulating (granulates) and optionally compressing (pellets).
Suitable formulation adjuvants are, for example, solid carriers, solvents and, where appropriate, surface-active substances (surfactants~.
' ' ' ' ' ' ' :. . ': . ' ' ' '.
:, .
- 13 - ~t ~ .~ i` ,J ' j~
The following formulation adjuvants are used to prepare the compositions according to the invention:
solid carriers, for example kaolin, talcum, bentonite, sodium chloride, calcium phosphate, carbohydrates, cellulose powder, cottonseed meal, polyethylene glycol ethers, where appropriate binders such as, for example, gelatin, soluble cellulose derivatives, if desired with the addition of surface-active substances, such as ionic or non-ionic dispersants; and also natural mineral fillers, such as calcite, mont-morillonite or attapulgite. In order to improve the physical properties it is also possible to add highly dispersed silicic acid or highly dispersed absorbent polymers. Suitable granulated adsorptive carriers are porous types, for example pumice, broken brick, sepiolite or bentonite;
and suitable nonsorbent carriers are, for example, calcite or sand. In addition, a great number of pregranulated materials of inorganic or organic nature can be used, e.g. especially dolomite or pulverised plant material.
Suitable solvents are: aromatic hydrocarbons, preferably the fractions containing 8 to 12 carbon atoms, e.g. xylene mixtures or substituted naphthalenes, phthalates such as dibutyl phthalate or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexane or parafins, alcohols and glycols and their ethers and esters, such as ethanol, ethylene glycol, ethylene glycol monomethyl or monoethyl ether, ketones such as cyclo-hexanone, strongly polar solvents such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, as well as vegetable oils or epoxidised vegetable oils, such as epoxidised coconut oil or soybean oil, and water.
Depending on the nature of the compound of formula I or Ia to be formulated, suitable surface-active compounds are non-ionic, cationic and/or anionic surfactants having good emulsifying, dispersing and wetting properties. The term "surfactants" will also be understood as comprising mixtures of s~rfactants.
Both so-called water-soluble soaps and water-soluble synthetic surface-active compounds are suitable anionic surfactants.
1.,.. ' ' .
.
.~ :
14 ~ ~ ~
Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (ClO-C2z), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained e.g. from coconut oil or tallow oil. Mention may also be made of fatty acid methyltaurin salts.
Frequently, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.
The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and contain a C~-C22alkyl radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of lignosulfonic acid, of dodecyl sulfate or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfated and sulfonated fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalene-sulfonic acid, or of a condensate of naphthalenesulfonic acid and formaldehyde.
Also suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 moles of ethylene oxide, or phospholipids.
Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the aliphatic hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.
. ~ ' . ' " '.
- 15 - ~ ~ ~
Further suitable non-ionic surfactants are the water-soluble adducts ofpolyethylene oxide with polypropylene glycol, ethylenediaminopoly-propylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit.
Examples of non-ionic surfactants are nonylphenolpolyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxy-polyethoxyethanol.
Fatty acid esters of polyoxyethylene sorbitan, e.g. polyoxyethylene sorbitan trioleate, are also suitable non-ionic surfactants.
Cationic surfactants are preferably quaternary ammonium salts which contain, as N-substituent, at least one C8-Czzalkyl radical and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl or hydroxy-lower alkyl radicals. The salts are preferably in the form of halides, methyl sulfates or ethyl sulfates, e.g. stearyltrimethylammonium chloride or benzyldi(2-chloroethyl)ethylammonium bromide.
The surfactants customarily employed in the art of formulation are described, inter alia, in the following publications:
"Mc Cutcheon's Detergents and Emulsifiers Annual", MC Publishing Corp., Ridgewood New Jersey, 1980;
Sisley and Wood, "Encyclopedia of Surface Active Agents", Chemical Publishing Co., Inc. New York, 1980.
Suitable binders for tablets and boli are chemically modified natural polymer substances that are soluble in water or alcohol, such as starch, cellulose or protein derivatives (e.g. methylcellulose, carboxymethyl-cellulose, ethylhydroxyethylcellulose, proteins such as zein, gelatin and the like) and synthetic polymers, such as, for example, polyvinyl ~ 16 ~ ~ rJ ,~
alcohol, polyvinylpyrrolidone etc.. The tablets also contain fillers (e.g. starch, microcrystalline cellulose, sugar, lactose, etc.), glidants and disintegrators.
If the anthelmintic compositions are in the form of feed concentrates, then the carriers used are, for example, performance feed, feed grain or protein concentrates. In addition to the active ingredients, such feed concentrates or compositions may contain additives, vitamins, anti-biotics, chemotherapeutic agents or other pesticides, especially bacteriostatics, fungistatics or coccidiostatics, or hormone prepara-tions, substances having an anabolic activity or substances that promote growth, influence the meat quality of animals for slaughtering or are useful to the organism in some other way. If the compositions or the compounds of formula I or Ia contained therein are added directly to the feed or to animal drinks, then the prepared feed or the prepared drink preferably contains the active ingredients in a concentration of approximately from 0.0005 to 0.02 percent by weight (5-200 ppm).
The compositions according to the invention can be administered to the animals to be treated perorally, parenterally or subcutaneously, the compositions being in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boli and capsules.
The anthelmintic compositions according to the invention generally contain from 0.1 to 99 % by weight, preferably from 0.1 to 95 % by weight, of the compound of formula I, formula Ia or a mixture of the two, from 99.9 to 1 % by weight, preferably from 99.8 to 5 % by weight, of a solid or liquid adjuvant, including from 0 to 25 % by weight, preferably from 0.1 to 25 % by weight, of a surfactant.
Whereas commercial products will preferably be formulated as concen-trates, the end user will normally employ dilute formulations.
The compositions may also contain further auxiliaries such as stabilisers, antifoams, viscosity regulators, binders and tackifiers as well as other active ingredients for obtaining special effects.
.. .
The present invention relates also to such anthelmintic compositions employed by the end user.
In each of the methods according to the invention for controlling pestsand in each of the pesticidal compositions according to the invention, the compounds of formulae I and Ia can be used in any of their tautomeric forms, as mixtures thereof or in the form of their salts.
The invention also includes a method for the prophylactic protection ofanimals against parasitic helminths, which method comprises administering the compounds of formulae I and Ia or the active ingredient formulations to the animals as an additive to feed or to drinks or in solid or liquid form orally, by injection or parenterally.
The following Examples serve to illustrate the invention without implying any limitation thereof.
1. Preparation Examples 1.1. Preparation of 1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine A solution of 5.3 g (10 mmol) of 1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylcarbamoyl~-2-thiobarbituric acid, 126 mg (0.8 mmol) of azoisobutyronitrile and ô.ô g (30 mmol) of tributyltin hydride is stirred under reflux in benzene for 3 hours and under a nitrogen atmosphere. After the reaction mixture has cooled to room temperature, the precipitated product is filtered off, washed repeatedly with diiso-propyl ether and dried, yielding 1.2 g (24 ~0) of the title compound. M.p.
230-232C.
1H-NMR (300 MHz, DMSO d~, TMS): 11.00, s, NH; 9.16, s, H-C(3); 7.40, d, J=9.5, 2H; 7.32, d, J=9.5, lH; 7.23, 6rs, lH; 6.92-6.81, m, lH; 6.87, d, J=9.5, 2H; 3.16, s, 2 x CH3.
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- 18 - ~ t.~
1.2. Preparation of 1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylcarbamoyl]-4~6-(lH~3H~5H)-pyrimidinedione The filtrate obtained according to Example 1.1. is concentrated and the precipitated product is filtered off and recrystallised repeatedly from diisopropyl ether, yielding 2.03 g (46 %) of the title compound. M.p.
109-113C.
lH-NMR (300 MHz, CDCl3, TMS): 18.25, s, OH; 11.91, s, NH; 7.73, d, J=8.0, 2H; 7.59, d, J=6.5, lH; 7.55, brs, lH; 7.32, d, J=8.0, 2H; 7.28-7.23, m, lH; 4.51, s, H2-C(3); 3.01, s, CH3; 2.97, s, CH3.
1.3. Preparation of 1,3-dimethvl-5-[4-(5-tert.-butYl-1.3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione A solution of 5 g (11 mmol) of 1,3-dimethyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-2-thiobarbituric acid, 9 ml (34 mmol) of tributyltin hydride and 90 mg (0.5 mmol) of azoisobutyronitrile is stirred under reflux in 200 ml of toluene for 5 hours (nitrogen atmosphere). After cooling to room temperature the mixture is concen-trated and the crude product is washed with hexane/ether, filtered, dried and recrystallised from ethyl acetate, yielding 2.1 g of the title compound. M.p. 128-130C.
1H-NMR (300 MHz, CDCl3, TMS): 18.22, s, OH; 11.88, s, NH; 7.53, d, J=9.5, 2H; 7.18, d, J=9.S, 2H; 4.50, s, H2-C(3); 3.02, s, CH3; 2.96, s, CH3;
1.42, s, 9H.
1.4. Preparation of 1,3-dimethyl-5-[4-(5- or 7-chloro-6-fluoro-benzo-thiazol-2-yloxy)-phenYlcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione A suspension of 461 mg (1 mmol) of 1,3-dimethyl-5-[4-(5- or 7-chloro-6-fluoro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine and 68 mg (2 mmol) of NaBH4 in 10 ml of ethanol is stirred at room temperature under nitrogen for 1 hour. The reaction mixture is cooled to 0C, acidified with 2N HCl, then neutralised with saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is washed with saturated NaHCO3 solution and ~, .
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1 9 _ f. , ~ 1 3 then with aqueous saturated NaCl solution, dried on MgSO4 and con-centrated. After recrystallisation from ethyl acetate, 253 mg of the title compound are obtained. M.p. 179-183C.
H-NMR (300 MHz, CDC13, TMS): 18.25, s, OH; 11.93, s, NH; 7.80-7.16, m, 6H; 4.52, s, H2-C(3); 3.03, s, CH3; 2.98, s, CH3.
The compounds of formulae I and Ia mentioned in the following Tables can be prepared analogously to the described procedures.
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-- 32 -- C? r 3 ` ~ i 2. Formulation Examples (throughout, percentages are by weight) 2.1. Emulsifiable concentrates a) b) c) a compound of the Tables25 % 40 % 50 %
calcium dodecylbenzenesulfonate5 % 8 % 6 %
castor oil polyethylene glycol ether (36 moles of ethylene oxide) 5 %
tributylphenol polyethylene glycol ether (30 moles of ethylene oxide) - 12 % 4 %
cyclohexanone - 15 % 20 %
xylene mixt~re 65 % 25 % 20 %
Emulsions of any desired concentration can be produced from such concen-trates by dilution with water.
2.2. Emulsifiable concentrates a) b) c) a compound of the Tables10 % 8 % 60 %
octylphenol polyethylene glycol ether (4-5 moles of ethylene oxide) 3 % 3 % 2 %
calcium dodecylbenzenesulfonate3 % 4 % 4 %
castor oil polyglycol ether (35 moles of ethylene oxide) 4 % 5 % 4 %
cyclohexanone 30 % 40 % 15 %
xylene mixture 50 % 40 % 15 %
Emulsions of any desired concentration can be produced from such concen-trates by dilution with water.
2.3. Suspension concentrate a compound of the Tables 40 %
ethylene glycol 10 %
nonylphenol polyethylene glycol ether (15 moles of ethylene oxide) 6 %
sodium lignosulfonate 10 %
carboxymethylcellulose 1 %
33 - ~ '' ` `' ' 37 % aqueous formaldehyde solution 0.2 %
silicone oil in the form of a 75 %
aqueous emulsion 0.8 %
water 32 %
The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired concentration can be obtained by dilution with water.
2.4. Powder mixtures dispersible in water a) b) c) a compound of the Tables 25 % 50 % 75 %
sodium lignosulfonate 5 % 5 %
oleic acid 3 % ~ 5 %
sodium diisobutylnaphthalene-sulfonate - 6 % 10 %
octylphenol polyethylene glycol ether (7-8 moles of ethylene oxide) - 2 %
highly dispersed silicic acid 5 % 10 % 10 %
kaolin 62 % 27 %
The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders which can be diluted with water to give suspensions of the desired concentration.
2.5. Dusts a) b) a compound of the Tables 2 % 5 %
highly dispersed silicic acid1 % 5 %
talcum 97 %
kaolin - 90 %
Ready-for-use dusts are obtained by intimately mixing the carriers with the active ingredient and grinding the mixture.
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2.6. Granulate a) b) a compound of the Tables 5 % lO %
kaolin 94 %
highly dispersed silicic acid l ~0 attapu:Lgite - 90 %
The active ingredient is dissolved in methylene chloride, the solution is sprayed onto the carrier, and the solvent is subsequently evaporated off in vacuo. Such granulates can be admixed with the animal feed.
2.7. Granulate a compound of the Tables 10 %
sodium lignosulfonate 2 %
carboxymethylcellulose l %
kaolin 87 %
The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
2.8. Granulate a compound of the Tables 3 %
polyethylene glycol (mol. wt. 200) 3 %
kaolin 94 %
The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granulates are obtained in this manner.
2.9. Tablets or boli I a compound of the Tables 33.00 %
methylcellulose 0.80 %
highly dispersed silicic acid 0.80 %
cornstarch 8.40 %
, II crystalline lactose 22.50 % ~ ;7 ~ f cornstarch 17.00 %
microcrystalline cellulose 16.50 %
magnesium stearate 1.00 %
I The methylcellulose is stirred into water. Once the material has swelled, the silicic acid is stirred in and the mixture is made into a homogeneous suspension. The active ingredient and cornstarch are mixed together and the aqueous suspension is incorporated into that mixture which is then kneaded to a paste. The mass so obtained is granulated through a 12M sieve and dried.
II All 4 adjuvants are thoroughly mixed.
III The pre-mixes obtained according to I and II are mixed together and compressed to form tablets or boli.
2.10. In,jectable formulations A. OilY vehicle (slow release) a compound of the Tables0.1-1.0 g groundnut oil ad 100 ml a compound of the TablesO.l-l.O g sesame oil ad 100 ml Preparation: The active ingredient is dissolved in a portion of the oil with stirring and optionally with gentle heating, and after cooling the solution is made up to the desired volume and sterile-filtered through a suitable 0.22 ~m membrane filter.
B. Water-miscible solution (medium rate of release) a compound of the Tables0.1-1.0 g 4-hydroxymethyl-1,3-dioxolane (glycerol formal) 40 g 1,2-propanediol ad 100 ml .
, .
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a compound of the Tables 0.1-1.0 g glycerol dimethylketal 40 g 1,2-propanediol ad 100 ml Preparation: The active ingredient is dissolved in a portion of the solvent with stirring, and the solution is made up to the desired volume and sterile-filtered through a suitable 0.22 ,um membrane filter.
C Aqueous solubilisate (rapid release) .
a compound of the Tables 0.1-1.0 g polyethoxylated castor oil (40 ethylene oxide units) 10 g 1,2-propanediol 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml a compound of the Tables 0.1-1.0 g polyethoxylated sorbitan monooleate (20 ethylene oxide units) 8 g 4-hydroxymethyl-1,3-dioxolane (glycerol formal) 20 g ben~yl alcohol 1 g aqua ad inject. ad 100 ml Preparation: The active ingredient is dissolved in the solvents and thesurfactant, and the solution is made up to the desired volume with water.
Sterile-filtration is then carried out through a suitable membrane filter of 0.22 ~m pore diameter.
The aqueous systems can also be used in a preferred manner for oral and/or intraruminal administration.
3. Biological Examples The anthelmintic activity is demonstrated by means of the following tests:
f ~ r~ f ..~
3.1. Trial with sheep infested with nematodes such as Haemonch~us contortus and Trichostrongylus colubriformis The active ingredient is administered in the form of a suspension using a stomach probe or by intraruminal injection to sheep that have previously been artificially infested with nematodes such as Haemonchus contortus and Trichostrongylus colubriformis. 1 to 3 animals are used for each dose per trial. Each sheep is treated only once with a single dose.
A first evaluation is made by comparing the number of worm eggs excreted in the faeces of the sheep before and after treatment.
Seven to ten days after treatment the sheep are sacrificed and dis~ected.
The evaluation is carried out by counting the worms remaining in the intestine after the treatment. Sheep simultaneously and similarly infested but untreated are used as a control or comparison.
In this test a marked reduction in nematode infestation is achieved with compounds of formulae I and Ia. For example, a reduction in nematode infestation of approximately 90 % is achieved using 20 mg of active ingredient per kg of body weight with the following compounds: 1.1, 5.1 and 5.2. ~ith some compounds this result is obtained even with a further reduced dosage, for example with 10 mg of active ingredient per kg of body weight or even smaller amounts of active ingredient.
3.2. Trial with sheep infested with cestodes such as Moniezia benedeni The active ingredient is administered in the form of a suspension using a stomach probe or by intraruminal injection to sheep that have previously been artificially infested with cestodes such as Moniezia benedeni. 3 animals are used for each dose per trial. Each sheep is treated only once with a single dose.
Seven to ten days after treatment the sheep are sacrificed and dissected.
The evaluation is carried out by counting the worms remaining in the intestine after the treatment. Sheep simultaneously and similarly infested but untreated are used as a control or comparison. In this test, ,,,, -- : ' ' .
.
~ .: C.r .~ . Cr an approximately 90 ~0 reduction in cestode infestation is achieved with compounds of the Tables, such as, for example, compounds Nos. 1.1, 5.1 and 5.2, at doses of less than 20 mg/kg of body weight.
3.3. Trial with sheep infested with Fasciola hepatica The active ingredient is administered in the form of a suspension using a stomach probe or by intraruminal injection to sheep that have previously been artificially infested with Fasciola hepatica. 3 animals are used for each dose per trial. Each sheep is treated only once with a single dose.
A first evaluation is made by comparing the number of worm eggs excreted in the faeces of the sheep before and after treatment.
Three to four weeks after treatment the sheep are sacrificed and dis-sected. The evaluation is carried out by counting the liver flukes remaining in the gall-bladder ducts after the treatment. Sheep simultane-ously and similarly infested but untreated are used as a control or comparison. The difference in the number of liver flukes counted in the two groups gives the degree of effectiveness of the test compound.
In this test, pronounced activity against Fasciola hepatica is achieved with compounds of the Tables at doses of less than 20 mg/kg of body weight.
. ~ .
- 18 - ~ t.~
1.2. Preparation of 1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylcarbamoyl]-4~6-(lH~3H~5H)-pyrimidinedione The filtrate obtained according to Example 1.1. is concentrated and the precipitated product is filtered off and recrystallised repeatedly from diisopropyl ether, yielding 2.03 g (46 %) of the title compound. M.p.
109-113C.
lH-NMR (300 MHz, CDCl3, TMS): 18.25, s, OH; 11.91, s, NH; 7.73, d, J=8.0, 2H; 7.59, d, J=6.5, lH; 7.55, brs, lH; 7.32, d, J=8.0, 2H; 7.28-7.23, m, lH; 4.51, s, H2-C(3); 3.01, s, CH3; 2.97, s, CH3.
1.3. Preparation of 1,3-dimethvl-5-[4-(5-tert.-butYl-1.3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione A solution of 5 g (11 mmol) of 1,3-dimethyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-2-thiobarbituric acid, 9 ml (34 mmol) of tributyltin hydride and 90 mg (0.5 mmol) of azoisobutyronitrile is stirred under reflux in 200 ml of toluene for 5 hours (nitrogen atmosphere). After cooling to room temperature the mixture is concen-trated and the crude product is washed with hexane/ether, filtered, dried and recrystallised from ethyl acetate, yielding 2.1 g of the title compound. M.p. 128-130C.
1H-NMR (300 MHz, CDCl3, TMS): 18.22, s, OH; 11.88, s, NH; 7.53, d, J=9.5, 2H; 7.18, d, J=9.S, 2H; 4.50, s, H2-C(3); 3.02, s, CH3; 2.96, s, CH3;
1.42, s, 9H.
1.4. Preparation of 1,3-dimethyl-5-[4-(5- or 7-chloro-6-fluoro-benzo-thiazol-2-yloxy)-phenYlcarbamoyl]-4,6-(lH,3H,5H)-pyrimidinedione A suspension of 461 mg (1 mmol) of 1,3-dimethyl-5-[4-(5- or 7-chloro-6-fluoro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(lH,5H)-pyrimidinium betaine and 68 mg (2 mmol) of NaBH4 in 10 ml of ethanol is stirred at room temperature under nitrogen for 1 hour. The reaction mixture is cooled to 0C, acidified with 2N HCl, then neutralised with saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is washed with saturated NaHCO3 solution and ~, .
sr r~
1 9 _ f. , ~ 1 3 then with aqueous saturated NaCl solution, dried on MgSO4 and con-centrated. After recrystallisation from ethyl acetate, 253 mg of the title compound are obtained. M.p. 179-183C.
H-NMR (300 MHz, CDC13, TMS): 18.25, s, OH; 11.93, s, NH; 7.80-7.16, m, 6H; 4.52, s, H2-C(3); 3.03, s, CH3; 2.98, s, CH3.
The compounds of formulae I and Ia mentioned in the following Tables can be prepared analogously to the described procedures.
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-- 32 -- C? r 3 ` ~ i 2. Formulation Examples (throughout, percentages are by weight) 2.1. Emulsifiable concentrates a) b) c) a compound of the Tables25 % 40 % 50 %
calcium dodecylbenzenesulfonate5 % 8 % 6 %
castor oil polyethylene glycol ether (36 moles of ethylene oxide) 5 %
tributylphenol polyethylene glycol ether (30 moles of ethylene oxide) - 12 % 4 %
cyclohexanone - 15 % 20 %
xylene mixt~re 65 % 25 % 20 %
Emulsions of any desired concentration can be produced from such concen-trates by dilution with water.
2.2. Emulsifiable concentrates a) b) c) a compound of the Tables10 % 8 % 60 %
octylphenol polyethylene glycol ether (4-5 moles of ethylene oxide) 3 % 3 % 2 %
calcium dodecylbenzenesulfonate3 % 4 % 4 %
castor oil polyglycol ether (35 moles of ethylene oxide) 4 % 5 % 4 %
cyclohexanone 30 % 40 % 15 %
xylene mixture 50 % 40 % 15 %
Emulsions of any desired concentration can be produced from such concen-trates by dilution with water.
2.3. Suspension concentrate a compound of the Tables 40 %
ethylene glycol 10 %
nonylphenol polyethylene glycol ether (15 moles of ethylene oxide) 6 %
sodium lignosulfonate 10 %
carboxymethylcellulose 1 %
33 - ~ '' ` `' ' 37 % aqueous formaldehyde solution 0.2 %
silicone oil in the form of a 75 %
aqueous emulsion 0.8 %
water 32 %
The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired concentration can be obtained by dilution with water.
2.4. Powder mixtures dispersible in water a) b) c) a compound of the Tables 25 % 50 % 75 %
sodium lignosulfonate 5 % 5 %
oleic acid 3 % ~ 5 %
sodium diisobutylnaphthalene-sulfonate - 6 % 10 %
octylphenol polyethylene glycol ether (7-8 moles of ethylene oxide) - 2 %
highly dispersed silicic acid 5 % 10 % 10 %
kaolin 62 % 27 %
The active ingredient is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders which can be diluted with water to give suspensions of the desired concentration.
2.5. Dusts a) b) a compound of the Tables 2 % 5 %
highly dispersed silicic acid1 % 5 %
talcum 97 %
kaolin - 90 %
Ready-for-use dusts are obtained by intimately mixing the carriers with the active ingredient and grinding the mixture.
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2.6. Granulate a) b) a compound of the Tables 5 % lO %
kaolin 94 %
highly dispersed silicic acid l ~0 attapu:Lgite - 90 %
The active ingredient is dissolved in methylene chloride, the solution is sprayed onto the carrier, and the solvent is subsequently evaporated off in vacuo. Such granulates can be admixed with the animal feed.
2.7. Granulate a compound of the Tables 10 %
sodium lignosulfonate 2 %
carboxymethylcellulose l %
kaolin 87 %
The active ingredient is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
2.8. Granulate a compound of the Tables 3 %
polyethylene glycol (mol. wt. 200) 3 %
kaolin 94 %
The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granulates are obtained in this manner.
2.9. Tablets or boli I a compound of the Tables 33.00 %
methylcellulose 0.80 %
highly dispersed silicic acid 0.80 %
cornstarch 8.40 %
, II crystalline lactose 22.50 % ~ ;7 ~ f cornstarch 17.00 %
microcrystalline cellulose 16.50 %
magnesium stearate 1.00 %
I The methylcellulose is stirred into water. Once the material has swelled, the silicic acid is stirred in and the mixture is made into a homogeneous suspension. The active ingredient and cornstarch are mixed together and the aqueous suspension is incorporated into that mixture which is then kneaded to a paste. The mass so obtained is granulated through a 12M sieve and dried.
II All 4 adjuvants are thoroughly mixed.
III The pre-mixes obtained according to I and II are mixed together and compressed to form tablets or boli.
2.10. In,jectable formulations A. OilY vehicle (slow release) a compound of the Tables0.1-1.0 g groundnut oil ad 100 ml a compound of the TablesO.l-l.O g sesame oil ad 100 ml Preparation: The active ingredient is dissolved in a portion of the oil with stirring and optionally with gentle heating, and after cooling the solution is made up to the desired volume and sterile-filtered through a suitable 0.22 ~m membrane filter.
B. Water-miscible solution (medium rate of release) a compound of the Tables0.1-1.0 g 4-hydroxymethyl-1,3-dioxolane (glycerol formal) 40 g 1,2-propanediol ad 100 ml .
, .
,, - 36 - ~ 5 ~ t.
a compound of the Tables 0.1-1.0 g glycerol dimethylketal 40 g 1,2-propanediol ad 100 ml Preparation: The active ingredient is dissolved in a portion of the solvent with stirring, and the solution is made up to the desired volume and sterile-filtered through a suitable 0.22 ,um membrane filter.
C Aqueous solubilisate (rapid release) .
a compound of the Tables 0.1-1.0 g polyethoxylated castor oil (40 ethylene oxide units) 10 g 1,2-propanediol 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml a compound of the Tables 0.1-1.0 g polyethoxylated sorbitan monooleate (20 ethylene oxide units) 8 g 4-hydroxymethyl-1,3-dioxolane (glycerol formal) 20 g ben~yl alcohol 1 g aqua ad inject. ad 100 ml Preparation: The active ingredient is dissolved in the solvents and thesurfactant, and the solution is made up to the desired volume with water.
Sterile-filtration is then carried out through a suitable membrane filter of 0.22 ~m pore diameter.
The aqueous systems can also be used in a preferred manner for oral and/or intraruminal administration.
3. Biological Examples The anthelmintic activity is demonstrated by means of the following tests:
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3.1. Trial with sheep infested with nematodes such as Haemonch~us contortus and Trichostrongylus colubriformis The active ingredient is administered in the form of a suspension using a stomach probe or by intraruminal injection to sheep that have previously been artificially infested with nematodes such as Haemonchus contortus and Trichostrongylus colubriformis. 1 to 3 animals are used for each dose per trial. Each sheep is treated only once with a single dose.
A first evaluation is made by comparing the number of worm eggs excreted in the faeces of the sheep before and after treatment.
Seven to ten days after treatment the sheep are sacrificed and dis~ected.
The evaluation is carried out by counting the worms remaining in the intestine after the treatment. Sheep simultaneously and similarly infested but untreated are used as a control or comparison.
In this test a marked reduction in nematode infestation is achieved with compounds of formulae I and Ia. For example, a reduction in nematode infestation of approximately 90 % is achieved using 20 mg of active ingredient per kg of body weight with the following compounds: 1.1, 5.1 and 5.2. ~ith some compounds this result is obtained even with a further reduced dosage, for example with 10 mg of active ingredient per kg of body weight or even smaller amounts of active ingredient.
3.2. Trial with sheep infested with cestodes such as Moniezia benedeni The active ingredient is administered in the form of a suspension using a stomach probe or by intraruminal injection to sheep that have previously been artificially infested with cestodes such as Moniezia benedeni. 3 animals are used for each dose per trial. Each sheep is treated only once with a single dose.
Seven to ten days after treatment the sheep are sacrificed and dissected.
The evaluation is carried out by counting the worms remaining in the intestine after the treatment. Sheep simultaneously and similarly infested but untreated are used as a control or comparison. In this test, ,,,, -- : ' ' .
.
~ .: C.r .~ . Cr an approximately 90 ~0 reduction in cestode infestation is achieved with compounds of the Tables, such as, for example, compounds Nos. 1.1, 5.1 and 5.2, at doses of less than 20 mg/kg of body weight.
3.3. Trial with sheep infested with Fasciola hepatica The active ingredient is administered in the form of a suspension using a stomach probe or by intraruminal injection to sheep that have previously been artificially infested with Fasciola hepatica. 3 animals are used for each dose per trial. Each sheep is treated only once with a single dose.
A first evaluation is made by comparing the number of worm eggs excreted in the faeces of the sheep before and after treatment.
Three to four weeks after treatment the sheep are sacrificed and dis-sected. The evaluation is carried out by counting the liver flukes remaining in the gall-bladder ducts after the treatment. Sheep simultane-ously and similarly infested but untreated are used as a control or comparison. The difference in the number of liver flukes counted in the two groups gives the degree of effectiveness of the test compound.
In this test, pronounced activity against Fasciola hepatica is achieved with compounds of the Tables at doses of less than 20 mg/kg of body weight.
. ~ .
Claims (18)
1. A compound of general formula I
(I) or, in its hydrogenated form, formula Ia (Ia) wherein R1 and Rz are each independently of the other C1-C6alkyl, allyl, C3-C6-cycloalkyl, benzyl or phenyl; and R3 is an unsubstituted or substituted heteroaromatic five-membered ring azole, bonded via carbon, selected from the series benzimidazole, benzoxazole, benzothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole and triazole; and R4 and R5 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6-haloalkoxy, including its tautomeric forms and physiologically tolerable salts.
(I) or, in its hydrogenated form, formula Ia (Ia) wherein R1 and Rz are each independently of the other C1-C6alkyl, allyl, C3-C6-cycloalkyl, benzyl or phenyl; and R3 is an unsubstituted or substituted heteroaromatic five-membered ring azole, bonded via carbon, selected from the series benzimidazole, benzoxazole, benzothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole and triazole; and R4 and R5 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6-haloalkoxy, including its tautomeric forms and physiologically tolerable salts.
2. A compound according to claim 1, wherein R1 and R2 are each inde-pendently of the other C1-C6alkyl, allyl, C3-C6cycloalkyl or phenyl, and R3, R4 and R5 are as defined in claim 1.
3. A compound of formula I or Ia according to claim 2, wherein R1 and R2 are each independently of the other C1-C6alkyl, allyl, C3-C6cyclo-alkyl or phenyl; R4 and R5 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy or C1-C6haloalkoxy, and R3 is one of the following heterocycles selected from the group:
Benzimidazol-2-yl a) Benzoxazol-2-yl Benzothiazol-2-yl Imidazol-2-yl b) Oxazol-2-yl Thiazol-2-yl [1H-1,2,4-Triazol]-5-yl c) [1,2,4-Oxadiazol]-5-yl [1,2,4-Thiadiazol]-5-yl [1,2,4-Oxadiazol]-3-yl [1,2,4-Thiadiazol]-3-yl d) [1H-1,2,4-Triazol]-3-yl e) [1,3,4-Oxadiazol]-2-yl [1,3,4-Thiadiazol]-2-yl [4H-1,2,4-Triazol]-5-yl and f) [1H-1,2,4-Triazol]-5-yl wherein Y is oxygen, sulfur or NR10;
Z is oxygen, sulfur or NH;
R6 and R7 are each independently of the other hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4-alkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfonyl, C1-C4 haloalkylsulfinyl, (C1-C4alkyl)2N, (C1-C4alkyl)HN, halogen, nitro or cyano;
R8 and R9 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkylthio, halogen or nltro; or are each independently of the other unsubstituted or halo-or C1-C3alkyl-substututed C3-C7cycloalkyl;
R10 is hydrogen or C1-C6alkyl; and R11 is C1-C6alkyl.
Benzimidazol-2-yl a) Benzoxazol-2-yl Benzothiazol-2-yl Imidazol-2-yl b) Oxazol-2-yl Thiazol-2-yl [1H-1,2,4-Triazol]-5-yl c) [1,2,4-Oxadiazol]-5-yl [1,2,4-Thiadiazol]-5-yl [1,2,4-Oxadiazol]-3-yl [1,2,4-Thiadiazol]-3-yl d) [1H-1,2,4-Triazol]-3-yl e) [1,3,4-Oxadiazol]-2-yl [1,3,4-Thiadiazol]-2-yl [4H-1,2,4-Triazol]-5-yl and f) [1H-1,2,4-Triazol]-5-yl wherein Y is oxygen, sulfur or NR10;
Z is oxygen, sulfur or NH;
R6 and R7 are each independently of the other hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4-alkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfonyl, C1-C4 haloalkylsulfinyl, (C1-C4alkyl)2N, (C1-C4alkyl)HN, halogen, nitro or cyano;
R8 and R9 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkylthio, halogen or nltro; or are each independently of the other unsubstituted or halo-or C1-C3alkyl-substututed C3-C7cycloalkyl;
R10 is hydrogen or C1-C6alkyl; and R11 is C1-C6alkyl.
4. A compound of formula I according to claim 3, wherein R1, R2, R3, R4, R5, Y, Z and R8, R9, R10 and R11 are as defined in claim 3.
5. A compound of formula I or Ia according to claim 3, wherein within groups b) to f) R8 and R9 are each independently of the other unsubsti-tuted or halo- or C1-C3alkyl-substituted C3-C7cycloalkyl. and the other substituents are as defined in claim 2.
6. A compound of formula I or Ia according to claim 3, wherein R3 is one of the following groups:
a) , , , , b) , , , , c) , , , , , d) , e) , , , f) , wherein Y is oxygen, sulfur or NR10;
Z is oxygen, sulfur or NH;
R6 and R7 are each independently of the other hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4-alkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfonyl, C1-C4-haloalkylsulfinyl, halogen, nitro or cyano;
R8 and R9 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkylthio, halogen or nitro or are each independently of the other unsubstituted or halo- or C1-C3alkyl-substituted C3-C7cycloalkyl;
R10 is hydrogen or C1-C6alkyl; and R11 is C1-C6alkyl.
a) , , , , b) , , , , c) , , , , , d) , e) , , , f) , wherein Y is oxygen, sulfur or NR10;
Z is oxygen, sulfur or NH;
R6 and R7 are each independently of the other hydrogen, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4-alkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfonyl, C1-C4-haloalkylsulfinyl, halogen, nitro or cyano;
R8 and R9 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6alkylthio, halogen or nitro or are each independently of the other unsubstituted or halo- or C1-C3alkyl-substituted C3-C7cycloalkyl;
R10 is hydrogen or C1-C6alkyl; and R11 is C1-C6alkyl.
7. A compound of formula I or Ia according to any one of claims 1 to 6, wherein R1 and R2 are each independently of the other methyl, ethyl, isopropyl, allyl or cyclopropyl, R4 and R5 are each independently of the other hydrogen, methyl, CF3, OCH3, OCHF2 or OCF3, and the other substi-tuents are as defined above.
8. A compound of formula I according to claim 2, selected from the series:
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(6-fluoro-[S- or 7-chloro]-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine.
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(6-fluoro-[S- or 7-chloro]-benzothiazol-2-yloxy)-phenyl-carbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine; 1,3-di-methyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4(6)-oxo-6(4)-oxido-(1H,5H)-pyrimidinium betaine.
9. A compound of formula Ia according to claim 2, selected from the series:
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyll-4,6-(1H,3H,5H)-pyrimidinedione 1,3-dimethyl-5-[4-(6-fluoro-[5- or 7-chloro]-benzothiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3M,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3H,5H)-pyrimidinedione.
1,3-dimethyl-5-[4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenyl-carbamoyll-4,6-(1H,3H,5H)-pyrimidinedione 1,3-dimethyl-5-[4-(6-fluoro-[5- or 7-chloro]-benzothiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3M,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(5-tert.-butyl-1,3,4-thiadiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3H,5H)-pyrimidinedione; 1,3-dimethyl-5-[4-(6-chloro-benzothiazol-2-yloxy)-phenylcarbamoyl]-4,6-(1H,3H,5H)-pyrimidinedione.
10. A process for the preparation of a compound of the formula I
(I) or, in its hydrogenated form, the formula Ia (Ia) wherein R1 and R2 are each independently of the other C1-C6alkyl, allyl, C3-C6-cycloalkyl, benzyl or phenyl; and R3 is an unsubstituted or substituted heteroaromatic five-membered ring azole, bonded via carbon, selected from the series benzimidazole, benzoxazole, benzothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole and triazole; and R4 and R5 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6-alkoxy or C1-C6haloalkoxy, including its tautomeric forms and physiologically tolerable salts, wherein a compound of formula II
(II) wherein R1, R2, R3, R4 and R5 are as defined under formulae I and Ia, is desulfurized.
(I) or, in its hydrogenated form, the formula Ia (Ia) wherein R1 and R2 are each independently of the other C1-C6alkyl, allyl, C3-C6-cycloalkyl, benzyl or phenyl; and R3 is an unsubstituted or substituted heteroaromatic five-membered ring azole, bonded via carbon, selected from the series benzimidazole, benzoxazole, benzothiazole, imidazole, oxazole, thiazole, oxadiazole, thiadiazole and triazole; and R4 and R5 are each independently of the other hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6-alkoxy or C1-C6haloalkoxy, including its tautomeric forms and physiologically tolerable salts, wherein a compound of formula II
(II) wherein R1, R2, R3, R4 and R5 are as defined under formulae I and Ia, is desulfurized.
11. A process according to claim 10, wherein the desulfurization is carried out by catalytic hydrogenation in an inert solvent or solvent mixture at temperatures ranging from 20 to 180°C, preferably from 60 to 120°C, especially at reflux temperature.
12. A process according to claim 11, wherein the hydrogenation is carried out with a trialkyltin hydride, trialkyltin halide, trialkylgermanium hydride, trialkylgermanium halide, alkylmercury hydride or alkylmercury halide and in cases where a halide is used additionally in the presence of NaBH4.
13. A process according to claim 12, wherein the reaction is carried out in the presence of a radical initiator.
14. An anthelmintic composition which contains as active ingredient at least one compound of formula I or Ia, a tautomer or a salt thereof according to claims 1 to 9, together with customary carriers and further adjuvants.
15. A method of controlling parasitic helminths, which comprises administering to an animal an anthelmintically effective amount of a compound of formula I or Ia according to claims 1 to 9.
16. The use of a compound of formula I or Ia according to claims 1 to 9 for the control of parasitic helminths.
17. A compound of formula I or Ia according to any one of claims 1 to 9 for use in a method for the control of worm-related disorders in domestic animals and productive livestock.
18. A compound of formula I or Ia according to any one of claims 1 to 9 for the manufacture of a veterinary pharmaceutical.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH429989 | 1989-12-01 | ||
| CH4299/89-9 | 1989-12-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2031156A1 true CA2031156A1 (en) | 1991-06-02 |
Family
ID=4273502
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002031156A Abandoned CA2031156A1 (en) | 1989-12-01 | 1990-11-29 | Anthelmintics |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0430883A3 (en) |
| JP (1) | JPH03181481A (en) |
| AU (1) | AU633661B2 (en) |
| CA (1) | CA2031156A1 (en) |
| IE (1) | IE904326A1 (en) |
| IL (1) | IL96509A0 (en) |
| ZA (1) | ZA909630B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI401023B (en) | 2008-02-06 | 2013-07-11 | Du Pont | Mesoionic pesticides |
| UA107804C2 (en) | 2009-08-05 | 2015-02-25 | Du Pont | Mixtures of pesticides mezoionnyh |
| UA110924C2 (en) | 2009-08-05 | 2016-03-10 | Е. І. Дю Пон Де Немур Енд Компані | Mesoionic pesticides |
| JP2013501063A (en) * | 2009-08-05 | 2013-01-10 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | Mesoionic insecticide |
| AU2010279574A1 (en) * | 2009-08-05 | 2012-02-09 | E. I. Du Pont De Nemours And Company | Mesoionic pesticides |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2171099B (en) * | 1985-02-15 | 1988-10-19 | Ciba Geigy Ag | 5-(azolyloxphenylcarbamoyl)barbituric acid derivatives as anthelmintics |
| EP0430885A3 (en) * | 1989-12-01 | 1991-11-06 | Ciba-Geigy Ag | Anthelmintical compounds |
-
1990
- 1990-11-22 EP EP19900810905 patent/EP0430883A3/en not_active Withdrawn
- 1990-11-29 CA CA002031156A patent/CA2031156A1/en not_active Abandoned
- 1990-11-29 IL IL96509A patent/IL96509A0/en unknown
- 1990-11-30 IE IE432690A patent/IE904326A1/en unknown
- 1990-11-30 ZA ZA909630A patent/ZA909630B/en unknown
- 1990-11-30 AU AU67648/90A patent/AU633661B2/en not_active Expired - Fee Related
- 1990-11-30 JP JP2330873A patent/JPH03181481A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IE904326A1 (en) | 1991-06-05 |
| JPH03181481A (en) | 1991-08-07 |
| IL96509A0 (en) | 1991-08-16 |
| EP0430883A3 (en) | 1991-11-06 |
| AU633661B2 (en) | 1993-02-04 |
| AU6764890A (en) | 1991-06-06 |
| EP0430883A2 (en) | 1991-06-05 |
| ZA909630B (en) | 1991-08-28 |
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| Date | Code | Title | Description |
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| FZDE | Discontinued |