WO1993011129A1 - Agents antiparasitaires - Google Patents

Agents antiparasitaires Download PDF

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Publication number
WO1993011129A1
WO1993011129A1 PCT/EP1992/002697 EP9202697W WO9311129A1 WO 1993011129 A1 WO1993011129 A1 WO 1993011129A1 EP 9202697 W EP9202697 W EP 9202697W WO 9311129 A1 WO9311129 A1 WO 9311129A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
oximino
compound according
optionally
substituted
Prior art date
Application number
PCT/EP1992/002697
Other languages
English (en)
Inventor
Stephen Paul Gibson
David Austen Perry
Original Assignee
Pfizer Limited
Pfizer Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pfizer Limited, Pfizer Inc. filed Critical Pfizer Limited
Priority to JP5509781A priority Critical patent/JPH07501800A/ja
Priority to EP92923776A priority patent/EP0620819A1/fr
Publication of WO1993011129A1 publication Critical patent/WO1993011129A1/fr

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Classifications

    • 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

Definitions

  • This invention relates to antiparasitic agents, related to the milbe ycins 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 aver ectin producing strain of Streptomyces avermitilis such as those deposited strains ATCC 31267, ATCC 31271, ATCC 31272 as described in US patents 4310519 and 4429042.
  • European 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 acrolides 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 described in European patent application 334484.
  • 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, E . G . ' and Green, R.H. in Natural Product Reports (1986) , 2, 87-121.
  • Our European Patent Application 410615 describes a compound, herein designated UK-86956 of formula:
  • R 1 and R 2 are independently selected from H, Cj-C 8 alkyl, alkenyl, alkynyl, C 2 -C 8 alkanoyl, alkenoyl and alkynoyl, arylalkanoyl, arylcarbonyl and Cj-C 8 alkylsulphonyl and arylsulphonyl groups, wherein all these groups other than H may optionally be substituted with at least one hydroxy, Cj-Cg alkoxy, carboxy or halo group with the proviso that at least one of R 1 and R 2 are other than hydrogen.
  • the alkane, alkene and alkyne groups may be straight or branched-chain.
  • Halo means F, Cl, Br or I.
  • Another aspect of this invention provides compounds of formula (II) :
  • R 3 is oxo, optionally O-substituted oximino or methylene optionally substituted with cyano or a C,-C 8 alkyl, cycloalkyl, aryl, aralkyl or C,-C 8 alkoxycarbonyl group which groups may optionally be substituted by a halo, carboxy and/or other groups;
  • R 4 is 0-R 5 where R 5 is as defined for R 1 in formula (I) and the oxygen is attached at C-5 by a single bond or R 4 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 Cj-Cg alkyl, alkenyl, alkynyl, trialkylsilyl and aralkyl groups which may themselves be substituted by halo, carboxy and/or other groups.
  • Compounds within this aspect of the invention include those in which R 3 is methylene and R 4 is OH or oximino and those in which R 3 is oxo and R 4 is hydroxy, methoxy or oximino.
  • a further aspect of the invention provides compounds of formula (III) :
  • R 1 is as defined for formula (I) and R 4 is oxo or oximino optionally substituted as for compounds of formula (II) .
  • the compounds of the invention have several asymmetric centres, the number of such centres depending on the nature of substituents R 1 -R 4 , 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.
  • the compounds of the invention may be prepared by replacement of one or more of the hydroxy groups at the 5 and 22 positions of compound UK 86956 by the appropriate 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-butyldi ethylsilyl group (TBDMS) which is readily removed when reguired 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.
  • TDMS tert-butyldi ethylsilyl group
  • Alkylation of compound UK-86,956 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.
  • an alkyl halide preferably an alkyl iodide
  • 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 dii ⁇ opropylamine.
  • Oxidation of the hydroxy group at C-22 may be carried out using a suitable oxidising agent such as dimethyls-ulphoxide/oxalyl chloride. Using these conditions the C-5 hydroxy group will also be oxidised if 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 stereochemistry as that found in the UK-86,956 starting compound.
  • the oxo group at either C-5 or C-22 is a useful functional group for performing further semi-synthetic modification to the compounds.
  • R 6 is H or a substituent such as an alkyl, cyano, phenyl, alkanoyl or alkoxycarbonyl group.
  • 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 hydroxyla ine or salt thereof in a suitable solvent such as methanol, dioxane or water or combination thereof.
  • a suitable solvent such as methanol, dioxane or water or combination thereof.
  • 0- 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.
  • the compounds are effective in treating a variety of conditions caused by endoparasites including, in particular, helminthiasis which is most freguently 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 other nematodes which affect various species of animals including, for example, Dirofilaria and various parasites of dogs and cats which can infect humans including gastro-intestinal parasites such as Ancylostoma.
  • 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 which can affect swine, sheep, cattle and horses as well as affecting domestic animals and poultry.
  • ectoparasite infections including in particular arthropod ectoparasites of animals and birds such as ticks, mites, lice, fleas, blowfly, biting insects and migrating dipterous larvae which can affect swine, sheep, cattle and horses as well as affecting domestic animals and poultry.
  • the compounds are also insecticides active against household pests such as the cockroach, clothes moth, carpet beetle and the housefly as well as being useful against insect pests of stored grain and of agricultural plants such as spider mites, aphid ⁇ , caterpillars and against migratory orthopterans such as locusts.
  • 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, phar acokinetics and toleration.
  • the benefits .. that arise from this unexpected combination of properties include efficacy against the important parasitic worms or arthropods afflicting livestock, domesticated animals or humans at lower doses than are currently employed for related compounds and, in addition, the ability to treat animals previously regarded as sensitive to this class of macrolide with a greater margin of safety.
  • the 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.
  • the compounds are preferably administered by 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.
  • capsules, boluses or tablets may be prepared by mixing the active ingredient with a suitable finely divided diluent or carrier, additionally containing a disintegrating 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.
  • a dose of from about 0.001 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.
  • 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.
  • the compounds are applied as sprays, dusts, pour-on formulations, emulsions and the like in accordance with standard agricultural practice.
  • the compounds may be administered as a pharmaceutically acceptable formulation of conventional type.
  • Example 8 The product of Example 8 may be converted to the corresponding 5-oxo and 5-oximino compounds by the methods described in Examples 1 and 2.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • 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

Agents antiparasitaires répondant à la formule (I), (II) ou (III), dans lesquelles R1 et R2, indépendamment l'un de l'autre, représentent H ou alkyle C¿1-8? éventuellement substitué, alcényle, alcynyle, alcanoyle C2-8, alcénoyle ou alcynoyle, arylalcanoyle, arylcarbonyle, ou arylsulfonyle ou alkylsulfonyle C1-8, où R?1¿ et/ou R2 ne représentent pas H; R3 représente oxo, oximino éventuellement substitué par O ou méthylène éventuellement substitué; R4 représente oxo, imino éventuellement substitué, oximino éventuellement substitué par O ou -OR5 où R5 a la même notation que R1.
PCT/EP1992/002697 1991-12-04 1992-11-24 Agents antiparasitaires WO1993011129A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5509781A JPH07501800A (ja) 1991-12-04 1992-11-24 駆虫剤
EP92923776A EP0620819A1 (fr) 1991-12-04 1992-11-24 Agents antiparasitaires

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
WO1993011129A1 true WO1993011129A1 (fr) 1993-06-10

Family

ID=10705714

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1992/002697 WO1993011129A1 (fr) 1991-12-04 1992-11-24 Agents antiparasitaires

Country Status (5)

Country Link
EP (1) EP0620819A1 (fr)
JP (1) JPH07501800A (fr)
CA (1) CA2122614A1 (fr)
GB (1) GB9125818D0 (fr)
WO (1) WO1993011129A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0288205A2 (fr) * 1987-04-21 1988-10-26 Beecham Group Plc Dérivés du type macrolide à activité parasitaire, leur préparation et compositions les contenant
EP0319142A2 (fr) * 1987-11-03 1989-06-07 Beecham Group Plc Intermédiaires pour la preparation des antibiotiques macrolides à activité anthelmintique
EP0388080A1 (fr) * 1989-03-11 1990-09-19 Beecham Group Plc Dérivés de macrolides à activité anthelmintique, leur préparation et composés pharmaceutiques les contenant
EP0410615A1 (fr) * 1989-07-26 1991-01-30 Pfizer Limited Agent antiparasitique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0288205A2 (fr) * 1987-04-21 1988-10-26 Beecham Group Plc Dérivés du type macrolide à activité parasitaire, leur préparation et compositions les contenant
EP0319142A2 (fr) * 1987-11-03 1989-06-07 Beecham Group Plc Intermédiaires pour la preparation des antibiotiques macrolides à activité anthelmintique
EP0388080A1 (fr) * 1989-03-11 1990-09-19 Beecham Group Plc Dérivés de macrolides à activité anthelmintique, leur préparation et composés pharmaceutiques les contenant
EP0410615A1 (fr) * 1989-07-26 1991-01-30 Pfizer Limited Agent antiparasitique

Also Published As

Publication number Publication date
CA2122614A1 (fr) 1993-06-10
JPH07501800A (ja) 1995-02-23
GB9125818D0 (en) 1992-02-05
EP0620819A1 (fr) 1994-10-26

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