CA2122614A1 - Antiparasitic agents - Google Patents
Antiparasitic agentsInfo
- Publication number
- CA2122614A1 CA2122614A1 CA002122614A CA2122614A CA2122614A1 CA 2122614 A1 CA2122614 A1 CA 2122614A1 CA 002122614 A CA002122614 A CA 002122614A CA 2122614 A CA2122614 A CA 2122614A CA 2122614 A1 CA2122614 A1 CA 2122614A1
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- Prior art keywords
- group
- oximino
- compound according
- optionally substituted
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- 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
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- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Tropical Medicine & Parasitology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Dentistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Antiparasitic agents of formula (I), (II) or (III) where R1 and R2 are independently H or optionally substituted C1-C8 alkyl, alkenyl, alkynyl, C2-C8 alkanoyl, alkenoyl or alkynoyl, arylalkanoyl, arylcarbonyl, or C1-C8 alkylsulphonyl or arylsulphonyl, at least one of R1 and R2 being other than H, R3 is oxo, optionally O-substituted oximino or optionally substituted methylene, R4 is oxo, optionally substituted imino, optionally O-substituted oximino or -OR5 where R5 is as defined for R1.
Description
WO 93/l112g PC~/EP9~/0269/
212~14 ANTIPARASITIC AGENTS
This invention relates to antiparasitic agents, related to the milbemycins and to processes for their preparation and compositions thereof.
The avermectins and milbemycins form an important group of broad spectrum antiparasitic agents possessing anthelmintic, ectoparasiticidal, insecticidal, antibacterial and antifungal activity with application in the areas of animal and human health, agriculture and horticulture. The avermectins are a group of macrolide compounds (previously referred to as C-076) isolated from the fermentation broth of an avermectin producing-~6train of Stre~tomyces avermitilis such as those deposlted strains ATCC 31267, ATCC 31271, ATCC 31272 as described in US patents 4310519 and 4429042. ~uropean patents 214731 and 276103 disclose a related series of compounds differing from the C-076 compounds in the nature of the substituent at C-25. The milbemycins form another group of related macro1ides which are distinguished from the avermectins in lacking a sugar residue attached at C-13.
Examples of such compounds are the B-41 series as described in UK patent 1390336, the LL-F28249 series- - -described in European patent EP 170006, the E225 compounds described in European patent 254583 and the N787-182 compounds d~scribed in European patent ` ~-application 334484. In addition to these fermentation products a large number of publications describe compounds derived semi-synthetically from these fermentation products many of which possess useful antiparasitic activities. Some of this chemistry is~
reviewed by Davies, H.G. and Green, R.H. in Natura~
Product Reports (1986), 3, 87-121.
~'093J11129 PCT/EP9~/0269, ~122614 Our European Patent Application 410615 describes a compound, herein designated UK-86956 of formula:
CH~
~ 0~0 (~CH3 OH
It may be made by fermentation of a micro~organism deposited at the American Type Culture Collection under accession number ATCC 53928.
It has been found that certain semi-synthetic :
derivatives of the above-mentioned compound UK-86956,-also have antiparasitic activity. Thus one aspect of :
this invention provides compound~ of formula (I): .
CH,~,CH, ;~CH, (I) -OR~
where Rl and R2 are independently selected from H, C~-C8 alkyl, alkenyl, alkynyl, Cz-C8 alkanoyl, alkenoyl and alkynoyl, arylalkanoyl, arylcarbonyl and C~-C8 alkylsulphonyl an~ arylsulphon~ gro~ps, wherein all these groups other than H may optionally be substituted with at least one hydroxy, C~-C8 alkoxy, carboxy or halo group with the pro~iso that at least one of Rl and R2 are other than hydrogen. The alkane, alkene and alkyne WO 93/11129 ~ 1 ~ 2 6 1 4 PCT/EP92/0269, groups may be straight or branched-chain. Halo means F, Cl, Br or I.
Compounds within this aspect of the invention include those in which Rl is methyl and R2 is H or methyl.
Another aspect of this invention provides compounds of formula (II~:
CH3 R ~ ~C~3 CH3~ C~3 C~3 '- 0~5~
~ (rr) ' ' where R3 is oxo, optionally O-substituted oximino or methylene optionally substituted with cyano or a Cl-C8 alkyl, cycloalkyl, aryl, aralkyl or C~-C8 alkoxycarbonyl group which groups may optionally be substituted by a halo, carboxy and/or other groups; R4 is O-Rs where Rs is as defined for Rl in formula (I) and the oxygen is attached at C-5 by a single bond or R4 is oxo, optionally substituted imino or optionally O-substituted oximino, the broken line representing an double bond.
The oximino groups may be O-substituted by a wide variety of substituents including linear or branched CI-C~
alkyl, alkenyl, alkynyl, trialkylsilyl and a~alkyl~groups which may themselves be substituted by halo, carboxy and/or other groups.
Compounds within this aspect of the invention include those in which R3 is methylene and R4 is OH or :.:
oximino and those in which R3 is oxo and R4 is~hy~roxy, methoxy or oximino.
A further aspect of the invention provides compounds of formula (III):
WO93/11129 212 2 61 1 PCT/EP92/0269, CH3 R1o~ ,~CH3 / CH3 C'3 O~CH3 I l ~ (III) where R1 is as defined for formula (I) and R4 is oxo or oximino optionally s~ubstituted as for compounds of formula (II).
Compounds within this aspect of the invention include that in which R1 is -OH and R4 is oximino.
The compounds of the invention have several ¦ :
asymmetric centres, the number of such centres depending on the nature of substituents R1-R4, and accordingly may exist as several pairs of stereoisomers. Compound UK
86956, when prepared by fermentation of micro-organism ATCC 53928 is believed to have the following relative stereochemistry.
CH3 HO,,~.,~CH3 ~ J~CH~
CH ""~ : ~ CH3 CH3 ~CH, OH
The compounds of the invention may be prepared by .
replacement of one-or more of the hydroxy ~roups at the 5 :
and 22 positions of compound UK 86956 by the appropriate ~'093/1t129 ~ 1~ 2 6 1 4 PCT/EP92/0269-substituents. These substitutions may be carried out by means of reactions which are known in the art. However, in preparing these compounds it is necessary to react selectively at one of the 5 and 22 hydroxy groups. In some instances this may be achieved by choice of appropriate reagent, for example manganese dioxide which selectively converts the 5-hydroxy group to a 5-oxo group. Alternatively selective reaction may be achieved using suitable protecting groups such as acyl or silyl derivatives. A particularly preferred protecting group is the tert-butyldimethylsilyl group (TBDMS) which is readily removed when required using either an acid in a protic solvent such as methanol or with a fluoride ion source such as tetrabutylammonium fluoride dissolved in a suitable inert solvent such as tetrahydrofuran.
Alkylation of compound UK-86,956 (or a derivative thereof retaining a hydroxy group at position 5 or 22) may be achieved using conventional methodology such as treatment with an alkyl halide, preferably an alkyl iodide, in the presence of a silver salt or silver oxide.
Alternatively other reactive alkylating agents known to those skilled in the art such as alkyl triflates or ~-diazoalkanes may be employed and may show differing_ ', tendencies to react at the free hydroxy groups at the 5 ~, and 22 positions. Similarly acylation or sulphonylation `
of UK-86,956 or its derivatives can be achieved-using-standard procedures for example by using an acyl or sulphonyl halide or anhydride in the presence of a base such as triethylamine, pyridine or diisopropylami-ne-.
Oxidation of the hydroxy group at C-22 may be carried, out using a suitable oxidising agent such as ¦
dimethylsulphoxide/oxalyl chloride. Using, t~ese~ ~-conditions the C-S hydroxy group will also be oxidised if !
WO 93/11129 PCT/EP9~/0269, ~122614 not protected for example using the TBDMS group. The oxo group at C-5 or C-22 may be reduced to a hydroxy group although the stereochemical outcome of this reaction will depend on the choice of reducing agent. For example sodium borohydride will reduce either a C-5 or C-22 oxo group to a hydroxy group possessing substantially the same stereo~hemistry as that found in the UK-86,~56 starting compound. However, other reducing agents such as lithium tri-sec-bu~ylborohydride (L-selectride, Aldrich Chemical Company) will reduce the C-22 oxo group to give a hydroxy group with the opposite stereochemistry to that found in the starting compound.
The oxo group at either C-5 or C-22 is a useful functional group for performing furthçr semi-synthetic modification to the compounds. For example reaction between a phosphor~ne of the general formula XYZP=CHR6, where X, Y and Z are substituents such as phenyl, phenoxy, alkoxy or oxo and a 22-oxo derivative of UK-86,956 in an inert solvent yields a 22-methylene or when R6 is other than H, a mono-substituted methylene deri~ative. R6 is ~ or a substituent such as an alkyl, cyano, phenyl, alkanoyl or alkoxycarbonyl group.
Alternatively the oxo group at C-5 and~or C-22 may be converted to an oximino group or O-substituted oximino group by reaction with an optionally O-substituted hydroxylamine or salt thereof in a suitable solvent such as methanol, dioxane or water or combination thereof. O-substituted oximino derivatives may alternatively be prepared by reaction of the oximino derivative with a suitable alkylating or acylating agent.
Oximino and substituted methylene derivatives may exist as E or Z isomers and both stereoisomers are within the scope of this invention. In addition those derivatives o~ UK-86,956 which are singly bonded at C-22 may be prepared with two possible geometries and both are within the scope of this invention (including the epi-hydroxy compound).
WO93/11129 ~ l~ 2 6 1 ~ PCT/EP9~/0269-The compounds of the invention are highly active antiparasitic agents having particular utility as anthelmintics, ectoparasiticides, insecticides and acaricides.
Thus the compounds are effective in treating a variety of conditions caused by endoparasites including, in particular, helminthiasis which is most frequently caused by a group of parasitic worms described as nematodes and which can cause severe economic losses in - swine, sheep, horses and cattle as well as affecting domestic animals and poultry. The compounds are also effective against oth`er nematodes which affect various species of animals including, for exa~ple, Dirofilaria and various parasites of dogs and cats which can infect humans including gastro-intestinal parasites such as AncYlostoma, Necator, Ascaris, StronqYloides, Trichinella, CaPillaria, Trichuris, Enterobius and ~;~
parasites which are found in the blood or other tissues .
and organs such as filiarial worms and the extra ¦
intestinal stages of Strona~loides and Trichinella.
The compounds are also of value in treating ;
ectoparasite infections including in particular arthropod ectoparasites of animals and birds such as ticks, mites,-lice, fleas, blowfly, biting insects and migrating dipterous larvae whlch can affect swine, sheep, cattle and horses as well as affecting domestic animals- an* -~
poultry.
The compounds are also insecticides active against household pests such as the cockroach, clothes moth, carpet beetle and the housefIy as well as being us~eful against insect pests of stored grain and of agricultural plants such as spider mites, aphids, caterpillar&~and against migratory orthopterans such as locusts.
WV93/11129 ~ 6 ~ l PCT/EP92/0269 The compounds of the invention possess a number of beneficial properties compared to similar compounds such as the natural product UK-86,956 in terms of their efficacy, pharmacokinetics and toleration. The benefits ~-~that arise from this unexpected combination of properties include efficacy against the important parasitic wcrms or arthropods afflicting livestock, domesticated animals or humans at lower doses than are currently employed for related çompounds and, in addition, the ability to treat animals previously regarded as ~ensitive to this class of macrolide with a greater margin of safety.
Tha compounds of formula (I), (II) or (III~ are administered as a formulation appropriate to the specific use envisaged and to the particular species of host animal being treated and the parasite or insect involved. j For use as an anthelmintic the compounds are preferably administered ~y injection, either subcutaneously or intramuscularly, alternatively they may be administered orally in the form of a capsule, bolus, tablet, chewable tablet or liquid drench, or they may be administered as a pour-on formulation or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice.- Thus capsules, boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier, additionally containing a aisi-ntegrating agent and/or binder such as starch, lactose, talc or magnesium stearate. A drench formulation may be prepared by dispersing the active ingredient in an aqueous solution together with dispersing or wetting agents and injectable formulations may be prepared_in the form of a sterile solution or emulsion. These_formulations will vary with regard to the weight of active compound depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host.
WO93/11129 PCT/EP9~0269-~ ~2~611 g Generally for oral administration a dose of from about O.OO1 to 10 mg per Kg of animal body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but of course there can be instances where higher or lower dosage ranges are indicated and such are within the scope of this invention.
As an alternative the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For use as an insecticide and for treating agricultural pests the compounds are applied as sprays, ~;
dusts, pour-on formulations, emulsions and the like in accordance with standard agricultural practice. I :
For human use the compounds may be administered as a ¦~-pharmaceutically acceptable formulation of conventional type. ~-, .
7 122~1 l The preparation of compounds according to the invention and certain intermediate compounds is illustrated by the following Examples. "Silica" refers to Kieselgel 60, 230-400 mesh, Merck, Art. 9385. The reaction steps described in the Examples are illustrated by accompanying Figure 1.
5-Keto-UK-86 95 UK-86,956 (500mg) was dissolved in diethyl ether (anhydrous, 50ml) and manganese dioxide (activated, Aldrich Chemical Co. Ltd., 2.0g) was added. The suspension was stirred at room temperature for 18h and a further aliquot of manganese diox~de ~1.0g~ was added.
After a further 8h the mixture was filtered, the solid washed with et~yl acetate and the com~ined filtrate evaporated under vacuum to give an off-white powder which was used directly in the following Example 2.
5-Oximino-UK-86,956 5-Keto-UK-86,9S6 (300mg) was dissolved in methanol (7.5ml) at room temperat~ and~then was added, in sequence, dioxan (7.5ml), hydroxylamine hydrochloride (300mg) and water (7.5ml). After stlrring for 18h the mixture was added to diethyl-ether and water, the upper layer was separated and washed twice with water. The lower layer was extracted with diethyl ether and the combined organic layers were dried over anhydrous sodium sulphate and evaporated under vacuum to give a colourless glass (460mg). Final puri~ication was achieved by column .
chromatography on silica (Klesèlgel 60, 230-400 mesh, Merck) (50g) eluting with methylene chloride-methanol 50:1 to give the pure titl~ compound. Mass and NMR
spectra were fully consistent with the structur~ shown in Figure 1.
W093/11129 ~ 1 ~ 2 ~1~ PCT/EP92/0269 5-MethoxY-UK-86 956 To a solution of UK-86,956 (500mg) in anhydrous diethyl ether (125ml) was added iodomethane (lOml) and freshly prepared silver (I) oxide (2.5g). The mixture was stirred for 60h at a room temperature, filtered and evaporated under vacuum to give the crude product (600mg). This was purified by high pressure liquid chromatography on a Dynamax column (41.4 x 300mm, 8~m ;~
ODS-silica, Rainin) eluting with methanol-water 87:13 at ~-~
70ml per minute to give the title compound (198mg) and 5,22-dimet~oxy-UX-86,956 (200mg) from later fractions.
Macs and NMR spectra were fully consistent with the ~
proposed structures. `
i '' 5-Tertbutyldimethylsilyoxy~UK-86 956 To a solution of UK-86,956 (4.9g) in anhydrous methylene chloride (lOOml) was added tertbutyl-dimethylsilyl chloride (3.62g) and imidazole (3.2g~ and the mixture was neated under reflux for 2h. Water (50ml) was then added and the organic layer separated. The -aqueous layer was extracted once with methylene chloride (20ml) and the combined organic solution was washed with dilute hydrochloric acid, water and then dried over anhydrous sodium sulphate before evaporating to-dry~ess~
under vacuum to give the crude product (7.58g) as~a yellow foam. This material was purified by column chromatography twice on silica (Kieselgel 60, 230-400-mesh, Merck) (50g) eluting with methylene chloride to -give the title compound, 3.77g as a white foam. The N~R
spectrum of this material was fully consistent wi~h- ~he proposed structure. !-WO 93/11129PCT/EP92~0269ï
~122614 5-TertbutYldimethYlsilYloxY-22-keto-UK-86,956 To a solution of oxalyl chloride (0.5ml) in anhydrous methylene chloride (5ml) under nitrogen at ~78C was added a solution of dimethylsulphoxide (0.4ml) in anhydrous methylene chloride (lOml) at such a rate that the temperature did not rise above -60C. After 10 minutes gas evolution had ceased and a solution of 5-tertbutyldimethylsilyloxy-UK-86,956 (150mg) o~tained from Example 4 in anhydrous methylene chloride (Sml) was added quickly. After stirring for lh at -78C a solution of diisopropylethylamine (2.Oml) in anhydrous methylene chloride (5ml) was added. The yellow solution was then allowed to warm to room temperature. After 30 minutes diethyl ether (50ml) was added and the solution was washed quickly with ice cold dilute hydrochloric acid (SOml). The aqueous layer was extracted with diethyl ether (20ml) and the combined organic solutions were washed with water (4 x 20ml), dried over anhydrous sodium sulphate and evaporated under vacuum to give the crude product (292mg) as a yellow oil. This material was purified by column chromatography on silica (Kieselgel 60, 230-400 mesh, Merck)- (30g) eluting with methylene chloride to give the pure title compound (125mg). The NMR spectrum was fully consistent with the proposed structure. ~~ ~~- -22-Keto-UK-86,956 5-Tertbutyldimethylsilyloxy-22-keto-UK-86,956 (116mg) from Example S-was dissolved in methanol and p-toluenesulphonic acid--(S8mg3 was added. The mixture was stirred at room temperature for lh then a mixture of saturated aqueous p~tassium hydrogen carbonate solution and diethyl ether WO 93/1 l 129 ~ 1 2 2 S 1 4 PCT/EP92/0269, was added. The organic layer was separated and the ;~
aqueous layer was extracted with diethyl ether. The combined organic solution was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate solution and evaporated under vacuum to give the crude product as a white solid (120mg). Final purification was achieved by column ~
chromatography on silica (12g) eluting initially with `-methylene chloride followed by methylene chloride:
methanol }00:1 to give the pure title compound (lOOmg).
Mass and NMR spectra were fully consistent with the proposed structure. ~ ;
5-MethoxY--22-keto-UK 86 956 To a solution of 22-keto-UK-86,956 from Example 6 1 ~-(lOOmg) in anhydrous ether (25ml) was added iodomethane -(2.Oml) and silver (I) oxide (0.5g). The mixture was stirred at room temperature for 18h then filtered and evaporated to dryness under vacuum. The crude product -~
was purified by column chromatography on silica (12g) `
eluting initially with methylene chloride followed by methylene~chloride: methanol 100:1 to give the desired -product (77.9mg). Final purlfication was achieved by reverse~phase high pressure liquid chromatography on a Zorbax- column (21.2 x 250mm, 8~m ODS-silica, Dupont)~
eluting with acetonitrile:water 85:15 to give the pure -~
title compound (30mg). Mass and NMR spectra were fully ~-consistent with the proposed structure.
`` ` ' - . `
22-MethYlene-UK-86 956 - -n-Butyllithium (1.6M in hexanes, 0.375ml) was added dropwise to a stirred suspension of triphenylmethyl-phosphonium bromide in anhydrous tetrahydrofuran (lOml) W093/11129 ' 1 2 2 5 1 I PCT/EP9~/0269, under nitrogen at 0C. After 15 minutes a solution of 5-tertbutyldimethylsilyloxy-22-keto-UK-86,956 (Example 5) in anhydrous tetrahydrofuran (5ml) was added. The mixture was allowed to warm to room temperature and ~stirred for lh before adding saturated ammonium chloride solution (50ml) and methylene chloride (20ml). The organic layer was separated and the aqueous layer extracted with methylene chloride. The combined organic solution was dried over anhydrous sodium sulphate and evaporated to dryness under vacuum to give crude 5-tertbutyldimethylsilyloxy-22-methylene-UK-86,956 (216mg) which was purified by column chromatography on silica (20g) eluting with hexane: diethyl ether 2:1. This material (60mg) was dissolved in methanol (1.5ml) containing p-toluenesulphonic acid (30mg) and stirred at 40C for 30 minutes. Potassium hydrogen carbonate solution was then added followed by diethyl ether and the organic layer was separated, washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulphate. The crude product was purified by column chromatography on silica (lOg) eluting with methylene chloride:methanol 50:1 to give the pure title compound (47.5mg). The mass and NMR spectra were fully consistent with the proposed structure.
The product of Fxample 8 may be converted to the corresponding 5-oxo and 5-oxi~i~o-compounds by the methods described in Examples 1 and 2.
,.: ,; -" ,, : -WO 93/1 1 1 29 212 2 S 1~ PCI /EP92/0269 1 Figure I
a~, "~ " C~ o c o,o Cll, a~, 2 Clt, ~ C1~, Cl(, .
Il o~ O,~r o~ clll (~c", ., o ~I~ -' I ' ....
Ci1, ItO~ ~C11, CH, HO~ , ,,CII, ~
~ ~ ;o~CI~, 1'~ ~o,~C11, '' ci~, cl~ 3 CH~ 1I Cl~, Cl~
O 0~, ~:
~a~, O~-CH, ~-~
O~t OCI~
- 14,S ' ' ' ",~,,.
al~ ~CHJ CH, H,C;~,~ ,Cii, --:
~/~o~CI~, =o~CK, I , CH, ~ CH, Cit, 7, 6 l~ o O Cit, CH, 1 ~$CI~, ~C~
OSiMcz'Bu OH
¦ G . ~i ¦ 1, 2 CH, ~,Cii, CH, 11zC Ci., jol~CI~ ~G ~Ci~
C i ~ C ~ ~ ! Ch,~ ~ C!!, C1;, ~c~, ~;J`c~
OCIi, ~Oi~ : - - - --Reagents l. Manganese dioxide, diethyl ether.
212~14 ANTIPARASITIC AGENTS
This invention relates to antiparasitic agents, related to the milbemycins and to processes for their preparation and compositions thereof.
The avermectins and milbemycins form an important group of broad spectrum antiparasitic agents possessing anthelmintic, ectoparasiticidal, insecticidal, antibacterial and antifungal activity with application in the areas of animal and human health, agriculture and horticulture. The avermectins are a group of macrolide compounds (previously referred to as C-076) isolated from the fermentation broth of an avermectin producing-~6train of Stre~tomyces avermitilis such as those deposlted strains ATCC 31267, ATCC 31271, ATCC 31272 as described in US patents 4310519 and 4429042. ~uropean patents 214731 and 276103 disclose a related series of compounds differing from the C-076 compounds in the nature of the substituent at C-25. The milbemycins form another group of related macro1ides which are distinguished from the avermectins in lacking a sugar residue attached at C-13.
Examples of such compounds are the B-41 series as described in UK patent 1390336, the LL-F28249 series- - -described in European patent EP 170006, the E225 compounds described in European patent 254583 and the N787-182 compounds d~scribed in European patent ` ~-application 334484. In addition to these fermentation products a large number of publications describe compounds derived semi-synthetically from these fermentation products many of which possess useful antiparasitic activities. Some of this chemistry is~
reviewed by Davies, H.G. and Green, R.H. in Natura~
Product Reports (1986), 3, 87-121.
~'093J11129 PCT/EP9~/0269, ~122614 Our European Patent Application 410615 describes a compound, herein designated UK-86956 of formula:
CH~
~ 0~0 (~CH3 OH
It may be made by fermentation of a micro~organism deposited at the American Type Culture Collection under accession number ATCC 53928.
It has been found that certain semi-synthetic :
derivatives of the above-mentioned compound UK-86956,-also have antiparasitic activity. Thus one aspect of :
this invention provides compound~ of formula (I): .
CH,~,CH, ;~CH, (I) -OR~
where Rl and R2 are independently selected from H, C~-C8 alkyl, alkenyl, alkynyl, Cz-C8 alkanoyl, alkenoyl and alkynoyl, arylalkanoyl, arylcarbonyl and C~-C8 alkylsulphonyl an~ arylsulphon~ gro~ps, wherein all these groups other than H may optionally be substituted with at least one hydroxy, C~-C8 alkoxy, carboxy or halo group with the pro~iso that at least one of Rl and R2 are other than hydrogen. The alkane, alkene and alkyne WO 93/11129 ~ 1 ~ 2 6 1 4 PCT/EP92/0269, groups may be straight or branched-chain. Halo means F, Cl, Br or I.
Compounds within this aspect of the invention include those in which Rl is methyl and R2 is H or methyl.
Another aspect of this invention provides compounds of formula (II~:
CH3 R ~ ~C~3 CH3~ C~3 C~3 '- 0~5~
~ (rr) ' ' where R3 is oxo, optionally O-substituted oximino or methylene optionally substituted with cyano or a Cl-C8 alkyl, cycloalkyl, aryl, aralkyl or C~-C8 alkoxycarbonyl group which groups may optionally be substituted by a halo, carboxy and/or other groups; R4 is O-Rs where Rs is as defined for Rl in formula (I) and the oxygen is attached at C-5 by a single bond or R4 is oxo, optionally substituted imino or optionally O-substituted oximino, the broken line representing an double bond.
The oximino groups may be O-substituted by a wide variety of substituents including linear or branched CI-C~
alkyl, alkenyl, alkynyl, trialkylsilyl and a~alkyl~groups which may themselves be substituted by halo, carboxy and/or other groups.
Compounds within this aspect of the invention include those in which R3 is methylene and R4 is OH or :.:
oximino and those in which R3 is oxo and R4 is~hy~roxy, methoxy or oximino.
A further aspect of the invention provides compounds of formula (III):
WO93/11129 212 2 61 1 PCT/EP92/0269, CH3 R1o~ ,~CH3 / CH3 C'3 O~CH3 I l ~ (III) where R1 is as defined for formula (I) and R4 is oxo or oximino optionally s~ubstituted as for compounds of formula (II).
Compounds within this aspect of the invention include that in which R1 is -OH and R4 is oximino.
The compounds of the invention have several ¦ :
asymmetric centres, the number of such centres depending on the nature of substituents R1-R4, and accordingly may exist as several pairs of stereoisomers. Compound UK
86956, when prepared by fermentation of micro-organism ATCC 53928 is believed to have the following relative stereochemistry.
CH3 HO,,~.,~CH3 ~ J~CH~
CH ""~ : ~ CH3 CH3 ~CH, OH
The compounds of the invention may be prepared by .
replacement of one-or more of the hydroxy ~roups at the 5 :
and 22 positions of compound UK 86956 by the appropriate ~'093/1t129 ~ 1~ 2 6 1 4 PCT/EP92/0269-substituents. These substitutions may be carried out by means of reactions which are known in the art. However, in preparing these compounds it is necessary to react selectively at one of the 5 and 22 hydroxy groups. In some instances this may be achieved by choice of appropriate reagent, for example manganese dioxide which selectively converts the 5-hydroxy group to a 5-oxo group. Alternatively selective reaction may be achieved using suitable protecting groups such as acyl or silyl derivatives. A particularly preferred protecting group is the tert-butyldimethylsilyl group (TBDMS) which is readily removed when required using either an acid in a protic solvent such as methanol or with a fluoride ion source such as tetrabutylammonium fluoride dissolved in a suitable inert solvent such as tetrahydrofuran.
Alkylation of compound UK-86,956 (or a derivative thereof retaining a hydroxy group at position 5 or 22) may be achieved using conventional methodology such as treatment with an alkyl halide, preferably an alkyl iodide, in the presence of a silver salt or silver oxide.
Alternatively other reactive alkylating agents known to those skilled in the art such as alkyl triflates or ~-diazoalkanes may be employed and may show differing_ ', tendencies to react at the free hydroxy groups at the 5 ~, and 22 positions. Similarly acylation or sulphonylation `
of UK-86,956 or its derivatives can be achieved-using-standard procedures for example by using an acyl or sulphonyl halide or anhydride in the presence of a base such as triethylamine, pyridine or diisopropylami-ne-.
Oxidation of the hydroxy group at C-22 may be carried, out using a suitable oxidising agent such as ¦
dimethylsulphoxide/oxalyl chloride. Using, t~ese~ ~-conditions the C-S hydroxy group will also be oxidised if !
WO 93/11129 PCT/EP9~/0269, ~122614 not protected for example using the TBDMS group. The oxo group at C-5 or C-22 may be reduced to a hydroxy group although the stereochemical outcome of this reaction will depend on the choice of reducing agent. For example sodium borohydride will reduce either a C-5 or C-22 oxo group to a hydroxy group possessing substantially the same stereo~hemistry as that found in the UK-86,~56 starting compound. However, other reducing agents such as lithium tri-sec-bu~ylborohydride (L-selectride, Aldrich Chemical Company) will reduce the C-22 oxo group to give a hydroxy group with the opposite stereochemistry to that found in the starting compound.
The oxo group at either C-5 or C-22 is a useful functional group for performing furthçr semi-synthetic modification to the compounds. For example reaction between a phosphor~ne of the general formula XYZP=CHR6, where X, Y and Z are substituents such as phenyl, phenoxy, alkoxy or oxo and a 22-oxo derivative of UK-86,956 in an inert solvent yields a 22-methylene or when R6 is other than H, a mono-substituted methylene deri~ative. R6 is ~ or a substituent such as an alkyl, cyano, phenyl, alkanoyl or alkoxycarbonyl group.
Alternatively the oxo group at C-5 and~or C-22 may be converted to an oximino group or O-substituted oximino group by reaction with an optionally O-substituted hydroxylamine or salt thereof in a suitable solvent such as methanol, dioxane or water or combination thereof. O-substituted oximino derivatives may alternatively be prepared by reaction of the oximino derivative with a suitable alkylating or acylating agent.
Oximino and substituted methylene derivatives may exist as E or Z isomers and both stereoisomers are within the scope of this invention. In addition those derivatives o~ UK-86,956 which are singly bonded at C-22 may be prepared with two possible geometries and both are within the scope of this invention (including the epi-hydroxy compound).
WO93/11129 ~ l~ 2 6 1 ~ PCT/EP9~/0269-The compounds of the invention are highly active antiparasitic agents having particular utility as anthelmintics, ectoparasiticides, insecticides and acaricides.
Thus the compounds are effective in treating a variety of conditions caused by endoparasites including, in particular, helminthiasis which is most frequently caused by a group of parasitic worms described as nematodes and which can cause severe economic losses in - swine, sheep, horses and cattle as well as affecting domestic animals and poultry. The compounds are also effective against oth`er nematodes which affect various species of animals including, for exa~ple, Dirofilaria and various parasites of dogs and cats which can infect humans including gastro-intestinal parasites such as AncYlostoma, Necator, Ascaris, StronqYloides, Trichinella, CaPillaria, Trichuris, Enterobius and ~;~
parasites which are found in the blood or other tissues .
and organs such as filiarial worms and the extra ¦
intestinal stages of Strona~loides and Trichinella.
The compounds are also of value in treating ;
ectoparasite infections including in particular arthropod ectoparasites of animals and birds such as ticks, mites,-lice, fleas, blowfly, biting insects and migrating dipterous larvae whlch can affect swine, sheep, cattle and horses as well as affecting domestic animals- an* -~
poultry.
The compounds are also insecticides active against household pests such as the cockroach, clothes moth, carpet beetle and the housefIy as well as being us~eful against insect pests of stored grain and of agricultural plants such as spider mites, aphids, caterpillar&~and against migratory orthopterans such as locusts.
WV93/11129 ~ 6 ~ l PCT/EP92/0269 The compounds of the invention possess a number of beneficial properties compared to similar compounds such as the natural product UK-86,956 in terms of their efficacy, pharmacokinetics and toleration. The benefits ~-~that arise from this unexpected combination of properties include efficacy against the important parasitic wcrms or arthropods afflicting livestock, domesticated animals or humans at lower doses than are currently employed for related çompounds and, in addition, the ability to treat animals previously regarded as ~ensitive to this class of macrolide with a greater margin of safety.
Tha compounds of formula (I), (II) or (III~ are administered as a formulation appropriate to the specific use envisaged and to the particular species of host animal being treated and the parasite or insect involved. j For use as an anthelmintic the compounds are preferably administered ~y injection, either subcutaneously or intramuscularly, alternatively they may be administered orally in the form of a capsule, bolus, tablet, chewable tablet or liquid drench, or they may be administered as a pour-on formulation or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice.- Thus capsules, boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier, additionally containing a aisi-ntegrating agent and/or binder such as starch, lactose, talc or magnesium stearate. A drench formulation may be prepared by dispersing the active ingredient in an aqueous solution together with dispersing or wetting agents and injectable formulations may be prepared_in the form of a sterile solution or emulsion. These_formulations will vary with regard to the weight of active compound depending on the species of host animal to be treated, the severity and type of infection and the body weight of the host.
WO93/11129 PCT/EP9~0269-~ ~2~611 g Generally for oral administration a dose of from about O.OO1 to 10 mg per Kg of animal body weight given as a single dose or in divided doses for a period of from 1 to 5 days will be satisfactory but of course there can be instances where higher or lower dosage ranges are indicated and such are within the scope of this invention.
As an alternative the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For use as an insecticide and for treating agricultural pests the compounds are applied as sprays, ~;
dusts, pour-on formulations, emulsions and the like in accordance with standard agricultural practice. I :
For human use the compounds may be administered as a ¦~-pharmaceutically acceptable formulation of conventional type. ~-, .
7 122~1 l The preparation of compounds according to the invention and certain intermediate compounds is illustrated by the following Examples. "Silica" refers to Kieselgel 60, 230-400 mesh, Merck, Art. 9385. The reaction steps described in the Examples are illustrated by accompanying Figure 1.
5-Keto-UK-86 95 UK-86,956 (500mg) was dissolved in diethyl ether (anhydrous, 50ml) and manganese dioxide (activated, Aldrich Chemical Co. Ltd., 2.0g) was added. The suspension was stirred at room temperature for 18h and a further aliquot of manganese diox~de ~1.0g~ was added.
After a further 8h the mixture was filtered, the solid washed with et~yl acetate and the com~ined filtrate evaporated under vacuum to give an off-white powder which was used directly in the following Example 2.
5-Oximino-UK-86,956 5-Keto-UK-86,9S6 (300mg) was dissolved in methanol (7.5ml) at room temperat~ and~then was added, in sequence, dioxan (7.5ml), hydroxylamine hydrochloride (300mg) and water (7.5ml). After stlrring for 18h the mixture was added to diethyl-ether and water, the upper layer was separated and washed twice with water. The lower layer was extracted with diethyl ether and the combined organic layers were dried over anhydrous sodium sulphate and evaporated under vacuum to give a colourless glass (460mg). Final puri~ication was achieved by column .
chromatography on silica (Klesèlgel 60, 230-400 mesh, Merck) (50g) eluting with methylene chloride-methanol 50:1 to give the pure titl~ compound. Mass and NMR
spectra were fully consistent with the structur~ shown in Figure 1.
W093/11129 ~ 1 ~ 2 ~1~ PCT/EP92/0269 5-MethoxY-UK-86 956 To a solution of UK-86,956 (500mg) in anhydrous diethyl ether (125ml) was added iodomethane (lOml) and freshly prepared silver (I) oxide (2.5g). The mixture was stirred for 60h at a room temperature, filtered and evaporated under vacuum to give the crude product (600mg). This was purified by high pressure liquid chromatography on a Dynamax column (41.4 x 300mm, 8~m ;~
ODS-silica, Rainin) eluting with methanol-water 87:13 at ~-~
70ml per minute to give the title compound (198mg) and 5,22-dimet~oxy-UX-86,956 (200mg) from later fractions.
Macs and NMR spectra were fully consistent with the ~
proposed structures. `
i '' 5-Tertbutyldimethylsilyoxy~UK-86 956 To a solution of UK-86,956 (4.9g) in anhydrous methylene chloride (lOOml) was added tertbutyl-dimethylsilyl chloride (3.62g) and imidazole (3.2g~ and the mixture was neated under reflux for 2h. Water (50ml) was then added and the organic layer separated. The -aqueous layer was extracted once with methylene chloride (20ml) and the combined organic solution was washed with dilute hydrochloric acid, water and then dried over anhydrous sodium sulphate before evaporating to-dry~ess~
under vacuum to give the crude product (7.58g) as~a yellow foam. This material was purified by column chromatography twice on silica (Kieselgel 60, 230-400-mesh, Merck) (50g) eluting with methylene chloride to -give the title compound, 3.77g as a white foam. The N~R
spectrum of this material was fully consistent wi~h- ~he proposed structure. !-WO 93/11129PCT/EP92~0269ï
~122614 5-TertbutYldimethYlsilYloxY-22-keto-UK-86,956 To a solution of oxalyl chloride (0.5ml) in anhydrous methylene chloride (5ml) under nitrogen at ~78C was added a solution of dimethylsulphoxide (0.4ml) in anhydrous methylene chloride (lOml) at such a rate that the temperature did not rise above -60C. After 10 minutes gas evolution had ceased and a solution of 5-tertbutyldimethylsilyloxy-UK-86,956 (150mg) o~tained from Example 4 in anhydrous methylene chloride (Sml) was added quickly. After stirring for lh at -78C a solution of diisopropylethylamine (2.Oml) in anhydrous methylene chloride (5ml) was added. The yellow solution was then allowed to warm to room temperature. After 30 minutes diethyl ether (50ml) was added and the solution was washed quickly with ice cold dilute hydrochloric acid (SOml). The aqueous layer was extracted with diethyl ether (20ml) and the combined organic solutions were washed with water (4 x 20ml), dried over anhydrous sodium sulphate and evaporated under vacuum to give the crude product (292mg) as a yellow oil. This material was purified by column chromatography on silica (Kieselgel 60, 230-400 mesh, Merck)- (30g) eluting with methylene chloride to give the pure title compound (125mg). The NMR spectrum was fully consistent with the proposed structure. ~~ ~~- -22-Keto-UK-86,956 5-Tertbutyldimethylsilyloxy-22-keto-UK-86,956 (116mg) from Example S-was dissolved in methanol and p-toluenesulphonic acid--(S8mg3 was added. The mixture was stirred at room temperature for lh then a mixture of saturated aqueous p~tassium hydrogen carbonate solution and diethyl ether WO 93/1 l 129 ~ 1 2 2 S 1 4 PCT/EP92/0269, was added. The organic layer was separated and the ;~
aqueous layer was extracted with diethyl ether. The combined organic solution was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate solution and evaporated under vacuum to give the crude product as a white solid (120mg). Final purification was achieved by column ~
chromatography on silica (12g) eluting initially with `-methylene chloride followed by methylene chloride:
methanol }00:1 to give the pure title compound (lOOmg).
Mass and NMR spectra were fully consistent with the proposed structure. ~ ;
5-MethoxY--22-keto-UK 86 956 To a solution of 22-keto-UK-86,956 from Example 6 1 ~-(lOOmg) in anhydrous ether (25ml) was added iodomethane -(2.Oml) and silver (I) oxide (0.5g). The mixture was stirred at room temperature for 18h then filtered and evaporated to dryness under vacuum. The crude product -~
was purified by column chromatography on silica (12g) `
eluting initially with methylene chloride followed by methylene~chloride: methanol 100:1 to give the desired -product (77.9mg). Final purlfication was achieved by reverse~phase high pressure liquid chromatography on a Zorbax- column (21.2 x 250mm, 8~m ODS-silica, Dupont)~
eluting with acetonitrile:water 85:15 to give the pure -~
title compound (30mg). Mass and NMR spectra were fully ~-consistent with the proposed structure.
`` ` ' - . `
22-MethYlene-UK-86 956 - -n-Butyllithium (1.6M in hexanes, 0.375ml) was added dropwise to a stirred suspension of triphenylmethyl-phosphonium bromide in anhydrous tetrahydrofuran (lOml) W093/11129 ' 1 2 2 5 1 I PCT/EP9~/0269, under nitrogen at 0C. After 15 minutes a solution of 5-tertbutyldimethylsilyloxy-22-keto-UK-86,956 (Example 5) in anhydrous tetrahydrofuran (5ml) was added. The mixture was allowed to warm to room temperature and ~stirred for lh before adding saturated ammonium chloride solution (50ml) and methylene chloride (20ml). The organic layer was separated and the aqueous layer extracted with methylene chloride. The combined organic solution was dried over anhydrous sodium sulphate and evaporated to dryness under vacuum to give crude 5-tertbutyldimethylsilyloxy-22-methylene-UK-86,956 (216mg) which was purified by column chromatography on silica (20g) eluting with hexane: diethyl ether 2:1. This material (60mg) was dissolved in methanol (1.5ml) containing p-toluenesulphonic acid (30mg) and stirred at 40C for 30 minutes. Potassium hydrogen carbonate solution was then added followed by diethyl ether and the organic layer was separated, washed with water and saturated sodium chloride solution and dried over anhydrous sodium sulphate. The crude product was purified by column chromatography on silica (lOg) eluting with methylene chloride:methanol 50:1 to give the pure title compound (47.5mg). The mass and NMR spectra were fully consistent with the proposed structure.
The product of Fxample 8 may be converted to the corresponding 5-oxo and 5-oxi~i~o-compounds by the methods described in Examples 1 and 2.
,.: ,; -" ,, : -WO 93/1 1 1 29 212 2 S 1~ PCI /EP92/0269 1 Figure I
a~, "~ " C~ o c o,o Cll, a~, 2 Clt, ~ C1~, Cl(, .
Il o~ O,~r o~ clll (~c", ., o ~I~ -' I ' ....
Ci1, ItO~ ~C11, CH, HO~ , ,,CII, ~
~ ~ ;o~CI~, 1'~ ~o,~C11, '' ci~, cl~ 3 CH~ 1I Cl~, Cl~
O 0~, ~:
~a~, O~-CH, ~-~
O~t OCI~
- 14,S ' ' ' ",~,,.
al~ ~CHJ CH, H,C;~,~ ,Cii, --:
~/~o~CI~, =o~CK, I , CH, ~ CH, Cit, 7, 6 l~ o O Cit, CH, 1 ~$CI~, ~C~
OSiMcz'Bu OH
¦ G . ~i ¦ 1, 2 CH, ~,Cii, CH, 11zC Ci., jol~CI~ ~G ~Ci~
C i ~ C ~ ~ ! Ch,~ ~ C!!, C1;, ~c~, ~;J`c~
OCIi, ~Oi~ : - - - --Reagents l. Manganese dioxide, diethyl ether.
2. Hydroxylamine hydrochloride, methanol, dioxane, water. - ~-3. Methyl iodide, silver (I) oxide, diethyl ether. ~ -4. tert-Butyltimethylsilyl chloride, imidazole, methylene chloride. --~-~ -5. Oxalyl chloride, dimethyl sulphoxide, diisopropylethylamine,methylene chloride.
6. p-Toluenesulphonic acid, me~hanol.
7. Triphenylphosphonium bromide, n-butyl lithium, tetrahydrofuran.
Claims (12)
1. A compound of formula (I):
(I) wherein R1 and R2 are independently selected from H and C1-C8 alkyl, alkenyl or alkynyl, C2-C8 alkanoyl, alkenoyl or alkynoyl, arylalkanoyl, arylcarbonyl and C1-C8 alkylsulphonyl or arylsulphonyl groups, all of which groups other than H being optionally substituted with at least one hydroxy, C1-C8 alkoxy, carboxy or halo group, at least one of R1 and R2 being other than H.
(I) wherein R1 and R2 are independently selected from H and C1-C8 alkyl, alkenyl or alkynyl, C2-C8 alkanoyl, alkenoyl or alkynoyl, arylalkanoyl, arylcarbonyl and C1-C8 alkylsulphonyl or arylsulphonyl groups, all of which groups other than H being optionally substituted with at least one hydroxy, C1-C8 alkoxy, carboxy or halo group, at least one of R1 and R2 being other than H.
2. A compound according to claim 1, in which R1 is methyl and R2 is H or methyl.
3. A compound of formula (II):
(II) where the broken line is an optional bond, R3 is oxo, optionally O-substituted oximino or methylene optionally substituted with cyano or with a C1-C8 alkyl, cycloalkyl, aryl, aralkyl or C1-C8 alkoxycarbonyl group, which group may optionally be substituted by a halo or carboxy group;
and R4 is -O-R5 where the optional bond is absent and R5 is H, or R5 is a group selected from C1-C8 alkyl, alkenyl or alkynyl, C2-C8 alkanoyl, alkenoyl or alkynoyl, arylalkanoyl, arylcarbonyl and C1-C8 alkylsulphonyl or arylsulphonyl groups, all of which groups other than H
being optionally substituted with at least one OH, C1-C8 alkoxy, carboxy or halo group, or the optional bond is present and R4 is oxo, optionally substituted imino or optionally O-substituted oximino.
(II) where the broken line is an optional bond, R3 is oxo, optionally O-substituted oximino or methylene optionally substituted with cyano or with a C1-C8 alkyl, cycloalkyl, aryl, aralkyl or C1-C8 alkoxycarbonyl group, which group may optionally be substituted by a halo or carboxy group;
and R4 is -O-R5 where the optional bond is absent and R5 is H, or R5 is a group selected from C1-C8 alkyl, alkenyl or alkynyl, C2-C8 alkanoyl, alkenoyl or alkynoyl, arylalkanoyl, arylcarbonyl and C1-C8 alkylsulphonyl or arylsulphonyl groups, all of which groups other than H
being optionally substituted with at least one OH, C1-C8 alkoxy, carboxy or halo group, or the optional bond is present and R4 is oxo, optionally substituted imino or optionally O-substituted oximino.
4. A compound according to claim 3, in which R4 is an oximino group optionally substituted by a linear or branched C1-C8 alkyl, alkenyl, alkynyl, trialkylsilyl or aralkyl group which is itself optionally substituted with a halo or carboxy group.
5. A compound according to claim 3, in which R3 is methylene and R4 is OH or oximino.
6. A compound according to claim 3, in which R3 is oxo and R1 is hydroxy, methoxy or oximino.
7. A compound of formula (III):
(III) where R1 is selected from H, C1-C8 alkyl, alkenyl or alkynyl, C2-C8 alkanoyl, alkenoyl or alkynoyl, arylalkanoyl, arylcarbonyl and C1-C8 alkylsulphonyl or arylsulphonyl, all of which other than H being optionally substituted with at least one hydroxy, C1-C8 alkoxy, carboxy or halo group, and R4 is oxo, optionally substituted imino or optionally O-substituted oximino.
(III) where R1 is selected from H, C1-C8 alkyl, alkenyl or alkynyl, C2-C8 alkanoyl, alkenoyl or alkynoyl, arylalkanoyl, arylcarbonyl and C1-C8 alkylsulphonyl or arylsulphonyl, all of which other than H being optionally substituted with at least one hydroxy, C1-C8 alkoxy, carboxy or halo group, and R4 is oxo, optionally substituted imino or optionally O-substituted oximino.
8. A compound according to claim 7, in which R1 is H and R4 is oximino.
9. An antiparasitic composition, comprising a compound according to any one of the preceding claims.
10. A composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable excipient or carrier.
11. A compound according to any one of claims 1 to 8 for use in human or veterinary medicine.
12. Use of a compound according to any one of claims 1 to 8 for making a medicament for treatment or prevention of parasitic infestations.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919125818A GB9125818D0 (en) | 1991-12-04 | 1991-12-04 | Antiparasitic agents |
| GB9125818.6 | 1991-12-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2122614A1 true CA2122614A1 (en) | 1993-06-10 |
Family
ID=10705714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002122614A Abandoned CA2122614A1 (en) | 1991-12-04 | 1992-11-24 | Antiparasitic agents |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0620819A1 (en) |
| JP (1) | JPH07501800A (en) |
| CA (1) | CA2122614A1 (en) |
| GB (1) | GB9125818D0 (en) |
| WO (1) | WO1993011129A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8709327D0 (en) * | 1987-04-21 | 1987-05-28 | Beecham Group Plc | Compounds |
| DE3888936T2 (en) * | 1987-11-03 | 1994-07-21 | Beecham Group Plc | Intermediates for the production of macrolide antibiotics with an anthelmintic effect. |
| GB8905605D0 (en) * | 1989-03-11 | 1989-04-26 | Beecham Group Plc | Novel compounds |
| GB8917064D0 (en) * | 1989-07-26 | 1989-09-13 | Pfizer Ltd | Antiparasitic agent |
-
1991
- 1991-12-04 GB GB919125818A patent/GB9125818D0/en active Pending
-
1992
- 1992-11-24 JP JP5509781A patent/JPH07501800A/en active Pending
- 1992-11-24 EP EP92923776A patent/EP0620819A1/en not_active Withdrawn
- 1992-11-24 CA CA002122614A patent/CA2122614A1/en not_active Abandoned
- 1992-11-24 WO PCT/EP1992/002697 patent/WO1993011129A1/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07501800A (en) | 1995-02-23 |
| GB9125818D0 (en) | 1992-02-05 |
| WO1993011129A1 (en) | 1993-06-10 |
| EP0620819A1 (en) | 1994-10-26 |
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