WO2003082836A1 - New dioxomorpholines for combating endoparasites - Google Patents
New dioxomorpholines for combating endoparasites Download PDFInfo
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- WO2003082836A1 WO2003082836A1 PCT/EP2003/002854 EP0302854W WO03082836A1 WO 2003082836 A1 WO2003082836 A1 WO 2003082836A1 EP 0302854 W EP0302854 W EP 0302854W WO 03082836 A1 WO03082836 A1 WO 03082836A1
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- alkyl
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- alkoxy
- halogenoalkyl
- phenyl
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- 0 CC1(*)C=C(C=NS(C2=C*(*)C=CC=C2)(=O)=O)C=CC=C1 Chemical compound CC1(*)C=C(C=NS(C2=C*(*)C=CC=C2)(=O)=O)C=CC=C1 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
Abstract
The present invention relates to new dioxomorpholines, to their use for combating endoparasites and to processes for their preparation.
Description
New dioxomorpholmes for combating endoparasites
The present invention relates to new dioxomorpholmes, to their use for combating endoparasites and to processes for their preparation.
Certain dioxomorpholmes and processes for their preparation are already known (cf. for example Liebigs Ann. Chem. 1952 (1982), Makromol. Chem., Rapid Commun., 6 (1985), 607; Tetrahedron, 37 (1981), 2797; WO 9403441A1;), although nothing has been disclosed to date concerning the use of these compounds against endoparasites.
WO 96/15 121 discloses dioxomorpholmes which are suitable for combating endoparasites. The compounds described do not, however, contain a sulphonamide side chain.
1. Compounds of the formula (I)
R! represents hydrogen, halogen, nitro, cyano, alkyl, aryl, trialkylsilyl, alkoxy or -S(O)rR, which are optionally substituted,
R2 represents hydrogen, halogen, nitro, cyano, alkyl, aryl, trialkylsilyl, alkoxy or -S(O)rR, which are optionally substituted,
R3 represents optionally substituted alkyl,
R4 represents optionally substituted alkyl or
R3 and R4 together represent a spirocyclic radical which is optionally substituted,
R5 represents hydrogen, alkyl, arylalkyl or substituted phenyl, which is optionally substituted,
r represents 0, 1 or 2,
R represents optionally substituted alkyl,
m represents 0, 1, 2, 3, 4 or 5,
n represents 0, 1, 2, 3, 4 or 5,
and optical isomers and racemates thereof.
The compounds of the formula (I) can, depending on the type and number of substituents, optionally be present in the form of geometrical and/or optical isomers or regioisomers or mixtures of isomers of various composition. Both the pure isomers and the isomeric mixtures are claimed according to the invention.
It has also been found that dioxomorpholines of the formula (I) can be prepared by reacting δ-hydroxycarboxylic acids of the formula (LT)
in which
R1, R2, R3, R4, R5, m and n have the abovementioned meaning,
with a dehydrating agent in an intramolecular lactonization reaction.
The dioxomorpholines according to the invention are generally defined by the formula (I).
R1 preferably represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, tri- (Cι-C6-alkyl)silyl, Cι-C6-alkyl, Cι-C6-halogenoalkyl, Cι.-C6-alkoxy, Ci-C6- halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W1 substituents.
R2 preferably represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, tri- (Cι-C6-alkyl)silyl, Cι-C6-alkyl, -Cό-halogenoalkyl, d-Cό-alkoxy, Cι-C6- halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W1 substituents.
R3 preferably represents Ci-Cβ-alkyl which is optionally substituted by C Ce- halogenoalkyl or -Cβ-alkoxy.
R4 preferably represents C Cθ-al yl which is optionally substituted by Ci-C6- halogenoalkyl or CrCβ-alkoxy.
R3 and R4 can also preferably together represent C3-C8-alkylene, -(CH2)-O-(CH2)- or -(CH2) -O-(CH2)2-, which can in each case optionally be mono- or polysubstituted by fluorine, chlorine, bromine, CrCe-alkyl or Cι-C6-alkoxy, thereby forming a spirocyclic radical.
R5 preferably represents hydrogen, Cι-C6-alkyl or benzyl or phenyl, wherein benzyl and phenyl optionally contain one or more identical or different W1 substituents.
R preferably represents C].-C6-alkyl or Cι-C6-halogenoalkyl.
m preferably represents 0, 1, 2, 3 or 4.
n preferably represents 0, 1, 2, 3 or 4.
r preferably represents 0,1 or 2.
W1 preferably represents hydrogen, bromine, chlorine, fluorine, Cι-C6-alkyl, Q- C6-halogenoalkyl, -Ce-alkoxy, CrCβ-halogenoalkoxy, -S(O)rR, cyano or nitro.
R1 particularly preferably represents hydrogen, bromine, chlorine, fluorine, cyano, tri-(C1-C4-alkyl)silyl, C1-C4-alkyl, C1-C4-halogenalkyl, C1-C4-alkoxy, C!-C4-halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W* substituents.
R2 particularly preferably represents hydrogen, bromine, chlorine, fluorine, cyano, tri-(C1-C -alkyl)silyl3 Cι-C4-alkyl, C1-C4-halogenoalkyl, Cι-C4- alkoxy, C1-C -halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W* substituents.
R3 particularly preferably represents Cι-C4-alkyl which is optionally substituted by CrGi-halogenoalkyl or Cι-C4-alkoxy.
R4 particularly preferably represents C1-C4-alkyl which is optionally substituted by CrC4-halogenoalkyl or C1-C4-alkoxy.
R3 and R4 can also particularly preferably together represent C3-C6-alkylene, -(CH2)- O-(CH2)- or -(CH2)2-O-(CH2) -, which can in each case optionally be mono- or poly substituted by fluorine, chlorine, bromine, Cι-C4-alkyl or Cι-C4- alkoxy, thereby forming a spirocyclic radical.
R5 particularly preferably represents hydrogen, Cι-C4-alkyl or benzyl or phenyl, wherein benzyl and phenyl optionally contain one or more identical or different W1 substituents.
R particularly preferably represents CrC4-alkyl or C1-C4-halogenoalkyl.
m particularly preferably represents 0, 1, 2 or 3.
n particularly preferably represents 0, 1, 2 or 3.
r particularly preferably represents 0,1 and 2.
W1 particularly preferably represents hydrogen, bromine, chlorine, fluorine, C\- C4-alkyl, Cι-C4-halogenoalkyl, Cr -alkoxy. C1-C -halogenoalkoxy,
-S(O)rR, cyano or nitro.
R1 very particularly preferably represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, trirnethylsilyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, trifluoroethyl. methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, trifluoromethoxy,
trifluoroethoxy, -SCH3, -SC2H5, -SOCH3, -SOC2H5, -SO2CH3, -SO2C2H5 or phenyl, wherein the phenyl group optionally contains one or more identical or different W substituents.
R2 very particularly preferably represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, trimethylsilyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, trifluoromethoxy, trifluoroethoxy, -SCH3, -SC2H5, -SOCH3, -SOC2H5, -SO2CH3, -SO2C2H5 or phenyl, wherein the phenyl group optionally contains one or more identical or different W* substituents.
R3 very particularly preferably represents methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, trifluoroethyl, -CH2CH2OCH3 or-CH2CH2OCH2CH3.
R4 very particularly preferably represents methyl, ethyl, n-propyl, i-propyl, n- buryl, i-butyl, s-butyl, t-butyl, trifluoromethyl, trifluoroethyl, -CH2CH2OCH3 or-CH2CH2OCH2CH3.
R3 and R4 can also very particularly preferably together represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, methoxycyclohexyl, ethoxycyclohexyl, -(CH2)2-O-(CH2)2- or -(CH2)2-O-CH(CH3)CH2-, thereby forming a spirocyclic radical.
R5 very particularly preferably represents hydrogen, methyl, ethyl, n-propyl, i- propyl, n-butyl, i-butyl, s-butyl or t-butyl, or benzyl or phenyl, wherein benzyl and phenyl optionally contain one or more identical or different W substituents.
m very particularly preferably represents 0, 1 or 2.
n very particularly preferably represents 0, 1 or 2.
W1 very particularly preferably represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, trimethylsilyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, trifluoromethoxy, trifluoroethoxy, -SCH3, -SC2H5, -SOCH3, -SOC2H5, -SO2CH3, -SO2C2H5, cyano or nitro.
To prepare the compounds of the formula (I), the compounds of the formula (II) are subjected to intramolecular lactonization under the action of a dehydrating agent (or a coupling reagent) and optionally in the presence of a solvent and optionally a base according to the following scheme:
(ID (0
Preferred dehydrating agents are acids, such as for example 4-toluenesulphonic acid, methanesulphonic acid or trifluoromethanesulphonic acid. They can be used in catalytic or excess quantities.
Hydrocarbons, such as for example toluene, or halogen-containing solvents, such as for example 1,2-dichloroethane, are preferably used as solvents. The reaction temperatures are preferably 20 to 200°C, and particularly preferably 60 to 120°C (cf. G. Kardassis et al, Tetrahedron 1998, 54, 3479).
So-called peptide coupling reagents, such as for example isobutyl chloroformate, can also be used. Reagents such as CDI, DCC, EDCI, BOP, BOP-C1 and DEAD Ph3P are also suitable.
Tertiary amines, such as for example N-methylmorpholine, are preferably used as auxiliary bases. Preferred diluents are halogen-containing solvents, such as for example dichloromethane. THF, DMF and CH3CN can also be used. The reaction temperatures are preferably minus 30 to plus 60°C, and particularly preferably minus 20 to plus 40°C.
Compounds of the formula (II) are prepared by the hydrolysis of esters of the formula (III) according to the following scheme:
(H (II)
Alkali metal hydroxides, such as for example sodium hydroxide, are preferred for the hydrolysis.. Preferred diUuents are alcohols, such as for example methanol, or dioxan or water or mixtures thereof. The reaction temperatures are preferably minus 10 to plus 60°C, and particularly preferably 0 to plus 30°C.
Compounds of the formula (III) can be prepared by reacting β-lactams of the formula (IN) with α-amino esters of the formula (N) according to the following scheme:
(IV) (V) (ill)
-Amino esters of the formula (N) are known or can be prepared by known methods (see in this regard, for example, Houben-Weyl, Methoden der organischen Chemie/Methods of Organic Chemistry). They can be used as the free base or as the hydrochloride. The reaction is usually carried out in the presence of a base and in the presence of a diluent. Suitable bases are alkali metal carbonates or alkali metal hydrogen carbonates and alkali metal hydroxides and tertiary amines, the latter being preferred; an example which may be mentioned is n-methylmorpholine. Suitable solvents are hydrocarbons, THF, CH3CΝ, dioxan or halogenated hydrocarbons, the latter being preferred; dichloromethane may be mentioned as an example. The preferred reaction temperatures are 0 to plus 120°C, particularly preferably 20 to plus 60°C (cf. I. Ojima et al, J. Org. Chem. 1994, 59, 1249; C. Palomo et al, J. Chem. Soc.Chem. Comm. 1994, 1957.)
β-Lactams of the formula (IN) can be prepared by known methods (cf. N. Srirajan et al, Tetrahedron Asymmetry 1996, 7, 2733.), namely by [2 + 2] -cyclo addition of Ν- tosyl imines of the formula (NI) and acetoxyketene. Acetoxyketene is prepared in situ by the base-induced dehydrodehalogenation of acetoxyacetyl chloride according to the following scheme:
Tertiary amines, such as for example triethylamine, are preferably used as bases. Halogen-containing solvents, such as for example dichloromethane, are preferably used. The reaction temperatures are preferably minus 40 to plus 60°C, and particularly preferably minus 20 to plus 30°C.
Acetoxyacetyl chloride is known and is commercially available.
The tosyl imines of the formula (NI) are in part known or they can be prepared by known methods by the condensation of aryl sulphonamides of the formula (Nil) with benzaldehydes or benzaldehyde acetals of the formula (NIII) according to the following scheme (cf. N. Srirajan et al, Tetrahedron Asymmetry 1996, 7, 2733.):
The compounds of the formulae (Nil) and (NIII) are in part commercially available or they can be prepared by known methods (see for example Houben-Weyl, Methoden der organischen Chemie/Methods of Organic Chemistry).
The active compounds have a favourable level of toxicity to warm-blooded animals and are suitable for combating pathogenic endoparasites which occur in humans and in the keeping and breeding of animals, in livestock, zoo animals, laboratory animals, animals for experiments and pet animals. They are active against all or individual stages of development of the pests and against resistant and normally sensitive species.
The aim of combating pathogenic endoparasites is to reduce disease, deaths and reductions in yield (e.g. in the production of meat, milk, wool, hides, eggs, honey and the like) and the use of the active compounds thus makes the keeping of animals more economic and simple. The pathogenic endoparasites include cestodes, trematodes, nematodes and Acanthocephala, and in particular:
From . the order of the Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp., Schistocephalus spp., Ligula spp., Bothridium spp. and Diphlogonoporus spp..
From the order of the Cyclophyllidea, for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., 'Thysanosomsa spp., Thysaniezia spp., Avitellina spp., Stilesia spp., Cittotaenia spp., Andyra spp., Bertiella spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp.,
Joyeuxiella spp. and Diplopylidium spp..
From the subclass of the Monogenea, for example: Gyrodactylus spp., Dactylogyrus spp. and Polystoma spp..
From the subclass of the Digenea, for example: Diplostomum spp.,
Posthodiplostomum spp., Schistosoma spp.,- TrichobiUiarzia spp., Ornithobilharzia spp., Austrobilharzia spp., Gigantobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostoma spp., Echinoparyphium spp., Echinochasmus spp., Hypoderaeum spp., Fasciola spp., Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp., Paramphistomum spp., Cahcophoron spp., Cotylophoron spp.,
Gigantocotyle spp., Fischoederius spp., Gastrothylacus spp., Notocotylus spp.,
Catatropis spp., Plagiorchis spp., Prosthogonimus spp., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus. spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp., Metorchis spp., Heterophyes spp. and Metagonismus spp..
From the order of the Enoplida, for example: Trichuris spp., Capillaria spp., Tri- chomosoides spp., Trichinella spp..
From the order of the Rhabditia, for example: Micronema spp. and Strongyloides spp..
From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylmdropharynx spp., Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum spp., Globocephalus spp., Syngamus spp., Cyathostoma spp.,
Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylus spp., Neo- strongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Marshallagia spp., Cooperia spp., Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp. and Ollulanus spp..
From the order of the Oxyurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp. and Heterakis spp..
From the order of the Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp. and Ascaridia spp..
From the order of the Spirurida, for example.: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp. and Dracunculus spp..
From the order of the Filariida, for example: Stephanofilaria spp., Parafilaria spp.,
Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp. and Onchocerca spp..
From the order of the Gigantorhynchida, for example: Filicollis spp., Momliformis spp., Macracanthorhynchus spp. and Prosthenorchis spp..
Livestock and breeding animals include mammals, such as for example cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer and reindeer, fur-bearing animals such as, for example, mink, chinchillas and racoons, birds, such as for example chickens, geese, turkeys and ducks, fresh water and salt water fish, such as for example trout, carp and eels, reptiles and insects, such as for example the honey bee and the silkworm.
Laboratory and test animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
Pet animals include dogs and cats.
The compounds can be used both prophylactically and therapeutically.
The active compounds are used directly or in the form of suitable formulations, enterally, parenterally, dermally, nasally, by treatment of the environment or with the aid of shaped articles containing the active compound, such as for example strips, plates, tapes, collars, ear tags, limb bands or marking devices.
The enteral administration of the active compounds is effected for example orally in the form of powders, tablets, capsules, potions, granules, solutions suitable for oral
administration, suspensions and emulsions, boli, medicated feed or drinking water. Dermal application is effected for example by dipping, spraying or pouring-on. or spotting-on. Parenteral administration is effected for example by (intramuscular, subcutaneous, intravenous or intraperitoneal) injection or by means of implants.
Suitable formulations are:
solutions such as injection solutions, oral solutions, concentrates for oral aάrrnnistration after dilution, solutions for use on the skin or in body cavities, pour-on formulations or gels;
emulsions and suspensions for oral or dermal administration and for injection; semi- solid formulations;
formulations in which the active compound is incorporated in an ointment base or in an oil-in-water or water-in-oil emulsion base;
solid formulations such as powders, premixes or concentrates, granules, pellets, tablets, boh, capsules; aerosols and inhalation products and shaped articles containing active compounds.
Injection solutions are administered intravenously, intramuscularly and subcutaneously. Injection solutions are prepared by dissolving the active compound in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants and preservatives. The solutions are subjected to sterile filtration and placed in containers.
Solvents which may be mentioned are: physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycols, N-methylpyrrolidone and mixtures thereof.
If appropriate, the active compounds can also be dissolved in physiologically compatible vegetable or synthetic oils suitable for injection.
Solubilizers which may be mentioned are: solvents which promote the dissolution of the active compoiund in the main solvent or which prevent its precipitation. Examples are polyvinyl pyrrolidone, polyoxyethylated castor oil and polyoxyethylated sorbitan esters.
Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoates and n-butanol.
Oral solutions are administered directly. Concentrates are administered orally after prior dilution to the use concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, although sterile conditions can be dispensed with.
Solutions for use on the skin are applied in drops, spread on, rubbed in, misted on or sprayed on. These solutions are prepared as described above for the injection solutions.
It may be advantageous to add thickeners during the preparation. Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminium monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and copolymers, acrylates and methacrylates thereof.
Gels are applied or spread onto the skin or introduced into body cavities. Gels are prepared by adding to solutions which have been prepared as described for the injection solutions, such a quantity of thickener that a clear mass with an ointment-like consistency is formed. Thickeners which are used are the thickeners described further above.
Pour-on formulations are poured or sprayed onto limited areas of the skin, the active compound penetrating the skin and acting systemically .
Pour-on formulations are prepared by dissolving, suspending or emulsifying the active compound in suitable skin-compatible solvents or solvent mixtures. If desired, further auxiliaries such as colorants, absorption-promoting substances, antioxidants, light protection agents and adhesives are added.
Solvents which may be mentioned are: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, aromatic alcohols such as benzyl alcohol, phenyl ethanol, phenoxy ethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers, such as dipropylene glycol monomethyl ether, diethylene glycol mono-butyl ether, ketones such as acetone, methyl ethyl ketone, aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, di- methylacetamide, N-methylpyrrolidone or 2,2-dimethyl-4-oxy-methylene-l,3-dioxo- lane.
Colorants are all colorants permitted for use on animals, and they may be dissolved or suspended.
Absorption-promoting substances are for example DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides and fatty alcohols.
Antioxidants are sulphites or metabisulphites, such as potassium metabisulphite, ascorbic acid, butyl hydroxy toluene, butyl hydroxy anisole and tocopherol.
Light protection agents are, for example, Novantisol acid.
Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates and natural polymers such as alginates and gelatin.
Emulsions can be administered orally, dermally or as injections.
Emulsions are either of the water-in-oil type or of the oil-in-water type.
They are prepared by dissolving the active compound either in the hydrophobic or in the hydrophilic phase and homogenizing this phase with the solvent of the other phase, with the aid of suitable emulsifiers and, if appropriate, other auxiliaries, such as colorants, absorption-promoting substances, preservatives, antioxidants, light protection agents and viscosity-increasing substances.
The following may be mentioned as the hydrophobic phase (oils): paraffin oils, silicone oils, natural vegetable oils, such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic/capric acid biglyceride, a triglyceride mixture with vegetable fatty acids of chain length C8-12, or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated fatty acids possibly also containing hydroxyl groups, and mono- and diglycerides of C8/Cι.o fatty acids.
Fatty acid esters such as ethyl stearate, di-n-buryryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length and saturated fatty alcohols of chain length C16-C18, isopropyl myristate, isopropyl palmitate, caprylic/capric acid esters of saturated fatty alcohols of chain length C12-C18, isopropyl stearate, oleyl oleate, decyl oleate, ethyl oleate, ethyl lactate, wax-like fatty acid esters such as synthetic duck uropygial gland fat, dibutyl phthalate, diisopropyl adipate and ester mixtures related to the latter, etc.
Fatty alcohols, such as isotridecyl alcohol, 2-octyl dodecanol, cetylstearyl alcohol and oleyl alcohol.
Fatty acids, such as for example oleic acid and mixtures thereof.
The following may be mentioned as the hydrophilic phase: water, alcohols, such as for example propylene glycol, glycerol, sorbitol und mixtures thereof.
The following may be mentioned as emulsifiers: non-ionic surfactants, such as for example, polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate and alkylphenol polyglycol ether;
ampholytic surfactants such as disodium N-lauryl-β-iminodipropionate or lecithin;
anionic surfactants such as sodium lauryl sulphate, fatty alcohol ether sulphates and the monoethanolamine salt of mono/dialkylpolyglycol ether orthophosphoric ester.
Further auxiliaries which may be mentioned are: viscosity-increasing and emulsion- stabilizing substances such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal silica or mixtures of the substances listed.
Suspensions can be administered orally, dermally or by injection. They are prepared by suspending the active compound in a carrier liquid, with the optional addition of further auxiliaries such as wetting agents, colorants, abso tion-promoting substances, preservatives, antioxidants and light protection agents.
Carrier liquids which may be mentioned are all homogeneous solvents and solvent mixtures.
' Wetting agents (dispersants) which may be mentioned are the surfactants mentioned further above.
Further auxiliaries which may be mentioned are those mentioned further above.
Semi-solid preparations can be administered orally or dermally. They differ from the above-described suspensions and emulsions only in their higher viscosity.
For the preparation of solid formulations the active compound is mixed with suitable carrier substances, optionally with the addition of auxiliaries, and brought into the desired form.
Carrier substances which may be mentioned are all physiologically compatible sohd inert substances. These can be inorganic and organic substances. Inorganic substances are for example common salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminium oxides, silicic acids, argillaceous earths, precipitated or colloidal silicon dioxide and phosphates.
Organic substances are for example sugar, cellulose, foodstuffs and feedstuffs, such as milk powder, animal meals, fine or coarse cereal meals and starches.
Auxiliary substances are preservatives, antioxidants and colorants which have already been listed further above.
Further suitable auxiliaries are lubricants and slip agents such as for example magnesium stearate, stearic acid, talc, bentonites, disintegration-promoting substances, such as starch or crosslinked polyvinyl pyrrolidone, binders such as for example starch, gelatin or linear polyvinyl pyrrolidone and dry binders, such as macrocrystalline cellulose.
The active compounds can be also be present in the formulations as a mixture with synergists or with other active compounds which act against pathogenic endoparasites. Such active compounds are for example L-2,3,5,6-tehahydro-6-phenylimidazothiazole, benzimidazole carbamate, praziquantel, pyrantel and febantel.
Ready-to-use formulations contain the active compound in concentrations of 10 ppm - 20 per cent by weight, and preferably 0.1 - 10 per cent by weight.
Formulations which are diluted before use contain the active compound in concentrations of 0.5 to 90 % by weight, and preferably 5 - 50 % by weight.
In general it has proven advantageous to administer amounts of about 1 to about 100 mg of active compound per kg of body weight per day in order to obtain effective results.
Compounds of the formula (I) which have no endoparasitic action or only slight endoparasitic action are suitable for use as valuable intermediates for the preparation of highly effective active compounds.
Preparation examples
Example NI-1
Ν-p-toluenesulphonyl-benzyldimine
Benzaldehyde dimethylacetal (8.24 g, 0.12 mol) and p-toluenesulphonamide (17.10 g, 0.10 mol) are heated at 120-130°C and methanol is distilled off continuously.
After a reaction time of 4 hours, the mixture is cooled to room temperature and the residue is recrystallized from toluene/methyl t-butyl ether.
Yield = 21.20 g, 82 % of theory. M.p. = 85-87°C
The following compounds of the formula (NI) are prepared in an analogous manner:
Example IN-1
Cis-l-(p-toluenesulphonyl)-3-acetoxy-4-phenylacetidin-2-one
Ν-p-toluenesulphonyl-benzaldimine (2.59 g, 10.00 mmol) and triethylamine (1.31 g, 13.00 mmol) are initially introduced into dichloromethane (20 ml) and cooled to -20°C. A solution of acetoxyacetyl chloride (1.64 g, 12.00 mmol) in dichloromethane (8 ml) is added slowly dropwise and then the mixture is subsequently stirred overnight at room temperature. The reaction solution is washed
successively with O.IN hydrochloric acid (20 ml), a saturated aqueous sodium hydrogen carbonate solution (20 ml) and water (20 ml). The organic phase is dried over sodium sulphate, filtered and evaporated in vacuo in a rotary evaporator. The crude product is purified by chromatography on silica gel (eluent: dichloromethane/n-hexane, 1:1, v/v) followed by recrystallization (dichlormethane/n- hexane).
1.90 g (53 % of theory) of cis-l-(p-toluenesulphonyl)-3-acetoxy-4-phenylacetidin-2- one is obtained.
M. p: 135°C
The following compounds of the formula (IV) are prepared analogously:
Example III-l
Methyl Ν-(toluenesulphonyl)-O-acetyl-3-phenylisoserinyl-2,2-dimethylglycinate
Cis-l-(p-toluenesulphonyl)-3-acetoxy-4-phenylacetidin-2-one (1.80 g, 5.00 mmol), methyl aminoisobutyrate hydrochloride (0.92 g, 6.00 mmol) and N-methyl- morpholine (0.61 g, 6.00 mol) are stirred in dichloromethane (25 ml) overnight at room temperature. The reaction solution is washed with water (20 ml). The organic phase is dried over sodium sulphate, filtered and evaporated in vacuo in a rotary evaporator. The crude product is purified by recrystallization from ethyl acetate.
1.69 g (71 % of theory) of methyl N-(toluenesulphonyl)-O-acetyl-3-phenylisoserinyl-
2,2-dimethyl-glycinate is obtained.
M.p: 175-176°C
The following compounds of the formula (III) are prepared in an analogous manner:
Explanations of the abbreviations:
4-OMe-cyclohexyl 4-OEt-cyclohexyl
2-Me-tetrahydropyranyl
Example II- 1
N-(toluenesulphonyl)-3-phenylisoserinyl-2,2-dimethyl-glycine
Methyl N-(toluenesulphonyl)-O-acetyl-3-phenylisoserinyl-2,2-dimethylglycinate (1.60 g, 3.36 mmol) is added at room temperature to a solution of sodium hydroxide (0.50 g, 12.6 mmol) in water (30 ml) and subsequently stirred at this temperature for 4 hours. The pH value is adjusted to pH 2-3 with 2N hydrochloric acid and the reaction solution is exfracted with ethyl acetate (3 x 50 ml). The organic phase is dried over sodium sulphate, filtered and evaporated in vacuo in a rotary evaporator.
1.30 g (92 % of theory) of N-(toluenesulphonyl)-3-phen iisoserinyl-2,2-dimethyl- glycine is obtained.
The crude product is reacted further without purification.
The following compounds of the formula (II) are prepared analogously.
Example 1
6-(p-ToluenesulphonylaminomethyI)-(α-phenyl)-morpholine-3,3-dimethyl-2,5- dione
N-(toluenesulphonyl)-3-phenylisoserinyl-2,2-dimethyl-glycine (1.20 g, 2.86 mmol), methanesulphonic acid (0.20 g, 2.0 mmol) and 1,2-dichloromethane (200 ml) are heated under reflux in a Soxhlet apparatus (containing a 3A molecular sieve) for about 16 hours (or until the starting material has completely reacted). The dehydrating agent is filtered off and the solvent is evaporated off in vacuo in a rotary evaporator. The crude product is purified by recrystallization from ethyl acetate.
0.63 g (55 % of theory) of 6-(p-toluenesulphonylaminomethyl)-(α-phenyl)- morpholine-3,3-dimethyl-2,5-dione is obtained.
The following compounds of the formula (I) are prepared analogously:
Biological example:
Nematode infection in sheep
The compounds were examined for their anthelmintic activity against Haemonchus contortus in sheep. The egg reduction test was used as the test method, in which the number of eggs was determined per gramme of faeces from infected sheep which had or had not been treated (as the control).
Egg reduction test: Sheep (Merino or Blackheaded with a body weight of 25-35 kg) were experimentally infected with 5000 H. contortus third-stage larvae and freated with the test compound at the end of the prepatent period of the parasite. The test compounds were applied orally in gelatin capsules. The anthelmintic activity of the test substances was determined as a function of the reduction in the faecal excretion of eggs in sheep. For the purpose of counting the number of eggs, the faeces of the test animals were used in the fresh state and treated according to the McMaster method modified by Wetzel, and the number of eggs per gramme of faeces was determined. The number of eggs was determined at regular intervals before and after . the treatment. The anthelmintic activity is expressed as a function of the reduction in the number of eggs, i.e. the reduction in the number of eggs is expressed in per cent compared with the excretion of eggs prior to treatment:
Claims
Claims
1. Compounds of the formula (I)
R! represents hydrogen, halogen, nitro, cyano, alkyl, aryl, trialkylsilyl, alkoxy or -S(O)rR, which are optionally substituted,
R2 represents hydrogen, halogen, nitro, cyano, alkyl, aryl, trialkylsilyl, alkoxy or -S(O)rR, which are optionally substituted,
R3 represents optionally substituted alkyl,
R4 represents optionally substituted alkyl or
R3 and R4 together represent a spirocyclic radical which is optionally substituted,
R5 represents hydrogen, alkyl, arylalkyl or substituted phenyl, which is optionally substituted,
r represents 0, 1 or 2,
R represents optionally susbtituted alkyl,
m represents 0, 1, 2, 3, 4 or 5,
. n represents 0, 1, 2, 3, 4 or 5,
and optical isomers and racemates thereof.
2. Compounds according to claim 1, wherein s
R1 represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, tri-(C1- C6-alkyl)silyl, Ci-Cβ-alkyl, ,CrC6-halogenoalkyl, Cι.-C6-alkoxy, Cι- C6-halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W1 substituents,
R2 represents hydrogen, bromine, chlorine, fluorine, cyano, nitro, tri-(Cι- C6-alkyl)silyl, CrCe-alkyl, -Cό-halogenoalkyl, Cι-C6-alkoxy, - C6-halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W1 substituents,
R3 represents Ci-C6-alkyl which is optionally substituted by Cι-C6- halogenoalkyl or Cι-C6-alkoxy,
R4 represents Cι-C6-alkyl which is optionally substituted by Ci-Cβ- halogenoalkyl or CrC6-alkoxy,
R3 and R4 together represent C3-C8-alkylene, -(CH2)-O-(CH2)- or -(CH2)2-O- (CH2)2-, which can in each case optionally be mono- or polysubstituted by fluorine, chlorine, bromine, CrCδ-alkyl or Cι-C6- alkoxy, thereby forming a spirocyclic radical,
R5 represents hydrogen, Ci-Cό-alkyl or benzyl or phenyl, wherein benzyl and phenyl optionally contain one or more identical or different W1 substituents,
R represents Ci-C6-alkyl or Cι-C6-halogenoalkyl,
m represents 0, 1, 2, 3 or 4,
n represents 0, 1, 2, 3 or 4,
r represents 0,1 or 2,
W1 represents hydrogen, bromine, chlorine, fluorine, Ci-Cδ-alkyL - - halogenoalkyl, Cι-C6-alkoxy, -Cό-halogenoalkoxy, -S(O)rR, cyano or nitro.
3. Compounds of the formula (I) according to claim 1, wherein
R1 represents hydrogen, bromine, chlorine, fluorine, cyano, tri-(C1-C4- alkyl)silyl, C1-C4-alkyl, C1-C4-halogenoalkyl, C1-C4-alkoxy, Cι-C4- halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W* substituents,
R2 represents hydrogen, bromine, chlorine, fluorine, cyano, tri-(C1-C4- alkyl)silyl, Cι-C -alkyl, C1-C4-halogenoalkyl, Cι-C4-alkoxy, Cι-C4- halogenoalkoxy, -S(O)rR or phenyl, wherein the phenyl group optionally contains one or more identical or different W substituents,
R3 represents C1-C4-alkyl which is optionally substituted by C1-C4- halogenoalkyl or Cι-C4-alkoxy,
R4 represents C1-C4-alkyl which is optionally substituted by Cι-C4- halogenoalkyl or Ci-C4-alkoxy,
R3 and R4 together represent C3-C6-alkylene, -(CH2)-O-(CH2)- or -(CH2)2-O- (CH2)2-, which can optionally in each case be mono- or polysubstituted by fluorine, chlorine, bromine, Cι-C4-alkyl or Cι-C4- alkoxy, thereby forming a spirocyclic radical,
R5 represents hydrogen, C1-C4-alkyl or benzyl or phenyl, wherein benzyl and phenyl optionally contain one or more identical or different W1 substituents,
R represents C1-C4-alkyl or C1-C4-halogenoalkyl,
m represents 0, 1, 2 or 3,
n represents 0, 1, 2 or 3 steht,
r represents 0, 1 and 2 and
W1 represents hydrogen, bromine, chlorine, fluorine, C1-C4-alkyl, Cι-C - halogenoalkyl, Cι-C4-alkoxy, d-C4-halogenoalkoxy, -S(O)rR, cyano or nitro.
Process for the preparation of compounds of the formula (I) according to claim 1, characterized in that a dehydrating agent or a coupling reagent is allowed to act on compounds of the formula (II)
in which
R1, R2, R3, R4 and R5 have the meanings given in claim 1.
5. Use of compounds of the formula (I) according to claim 1 for the preparation of medicaments for combating endoparasites.
6. Compositions containing compounds of the formula (I) according to claim 1 as well as suitable carriers and/or auxiliaries.
7. A method of producing compositions according to claim 6, characterized in that compounds of the formula (I) according to claim 1 are mixed with suitable excipients and/or auxiliaries.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2003212367A AU2003212367A1 (en) | 2002-03-28 | 2003-03-19 | New dioxomorpholines for combating endoparasites |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN02108270A CN1448393A (en) | 2002-03-28 | 2002-03-28 | Novel dioxomorpholine for antiendoparasite |
| CN02108270.7 | 2002-03-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2003082836A1 true WO2003082836A1 (en) | 2003-10-09 |
Family
ID=28458290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2003/002854 WO2003082836A1 (en) | 2002-03-28 | 2003-03-19 | New dioxomorpholines for combating endoparasites |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1448393A (en) |
| AU (1) | AU2003212367A1 (en) |
| WO (1) | WO2003082836A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130209392A1 (en) * | 2012-02-09 | 2013-08-15 | Novus International Inc. | Heteroatom containing cyclic dimers |
| US9452143B2 (en) | 2012-07-12 | 2016-09-27 | Novus International, Inc. | Matrix and layer compositions for protection of bioactives |
| US10266512B2 (en) | 2017-08-10 | 2019-04-23 | Novus International, Inc. | Processes for preparing heteroatom containing cyclic dimers |
| US10584306B2 (en) | 2017-08-11 | 2020-03-10 | Board Of Regents Of The University Of Oklahoma | Surfactant microemulsions |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4771048A (en) * | 1986-07-12 | 1988-09-13 | Bayer Aktiengesellschaft | Use of thiadiazinones for combating endoparasites |
| WO1994003441A1 (en) * | 1992-07-31 | 1994-02-17 | E.I. Du Pont De Nemours And Company | Process for the preparation of 3-, 6-substituted 2,5-morpholinediones |
| WO1996015121A1 (en) * | 1994-11-10 | 1996-05-23 | Bayer Aktiengesellschaft | Use of dioxomorpholines to combat endoparasites, novel dioxomorpholines and process for their production |
-
2002
- 2002-03-28 CN CN02108270A patent/CN1448393A/en active Pending
-
2003
- 2003-03-19 WO PCT/EP2003/002854 patent/WO2003082836A1/en not_active Application Discontinuation
- 2003-03-19 AU AU2003212367A patent/AU2003212367A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4771048A (en) * | 1986-07-12 | 1988-09-13 | Bayer Aktiengesellschaft | Use of thiadiazinones for combating endoparasites |
| WO1994003441A1 (en) * | 1992-07-31 | 1994-02-17 | E.I. Du Pont De Nemours And Company | Process for the preparation of 3-, 6-substituted 2,5-morpholinediones |
| WO1996015121A1 (en) * | 1994-11-10 | 1996-05-23 | Bayer Aktiengesellschaft | Use of dioxomorpholines to combat endoparasites, novel dioxomorpholines and process for their production |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130209392A1 (en) * | 2012-02-09 | 2013-08-15 | Novus International Inc. | Heteroatom containing cyclic dimers |
| US9011832B2 (en) * | 2012-02-09 | 2015-04-21 | Novus International, Inc. | Heteroatom containing cyclic dimers |
| US9284294B2 (en) | 2012-02-09 | 2016-03-15 | Novus International, Inc. | Functionalized polymer compositions |
| US9447068B2 (en) | 2012-02-09 | 2016-09-20 | Novus International, Inc. | Functionalized polymer compositions |
| AU2013216832B2 (en) * | 2012-02-09 | 2016-09-22 | Novus International Inc. | Heteroatom containing cyclic dimers |
| US10457660B2 (en) | 2012-02-09 | 2019-10-29 | Novus International, Inc. | Heteroatom containing cyclic dimers |
| US9452143B2 (en) | 2012-07-12 | 2016-09-27 | Novus International, Inc. | Matrix and layer compositions for protection of bioactives |
| US9655863B2 (en) | 2012-07-12 | 2017-05-23 | Novus International, Inc. | Matrix and layer compositions for protection of bioactives |
| US10266512B2 (en) | 2017-08-10 | 2019-04-23 | Novus International, Inc. | Processes for preparing heteroatom containing cyclic dimers |
| US10584306B2 (en) | 2017-08-11 | 2020-03-10 | Board Of Regents Of The University Of Oklahoma | Surfactant microemulsions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1448393A (en) | 2003-10-15 |
| AU2003212367A1 (en) | 2003-10-13 |
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