JPS62265290A - Macrolide antibiotic - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel antibiotic compound and a method for producing the same.

In GB Patent Specification No. 216B438A, we describe the production of antibiotic 5541, which can be isolated from the fermentation product of a novel Streptomyces sp.

Furthermore, the present inventors have discovered a group of compounds with antibiotic activity that can be produced by chemically modifying antibiotic 5541. The novel compounds of the invention have anti-inflammatory activity and/or
Used as an intermediate in the production of other active compounds.

In the above formula, R1 represents a methyl, ethyl or isopropyl group.

R represents a hydrogen atom or a group OR in which oR5 is a hydroxyl group, a substituted hydroxyl group having up to 25 carbon atoms or a phosphate ester group, and R3 represents a hydrogen atom or R and R3 are Together with their bonded carbon atoms, C-O
and OR represents the group OR5 as described above.

However, if R2 is a group OR5 [wherein OR5 is an alkoxy group OR (wherein R7 is a C1-6 alkyl group substituted by a halogen atom or a C
2-6 alkyl group)], R
and at least one of OR4 must exhibit a phosphate ester group or a group OCON R10R'' as described below. When using compounds of formula (I) as intermediates, -OR4 is often a protected hydroquine group. and the present invention specifically encompasses such protected compounds.

If R and/or OR4 are phosphate ester groups, they may have the formula %) () 10P (0) (OCH2CCρ3)2 (where Z is an alkali metal such as sodium or potassium). ).

When the group R or OR4 in the compound of formula (1) is a substituted hydroxyl group, it is an acyloxy group [eg formula -0COR6.

-OCO2R or -0C3OR (in which R6 is an aliphatic, araliphatic or aromatic group such as an alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or aryl group)], formyl group, group OR ( In the formula R
7 is as described above for R6), the group -08OR
8 (in the formula, R8 is C alkyl or C L-4G-10'' lyl group), a silyloxy group, a cyclic or acyclic acetal oxine group, a group oc○(CH)Co R (in the formula, R9 is water n 2 elementary atom or a group as described for R6, and n represents 0, 1, or 2) or a group 0CONR
It can also represent R, in which R and Rl are each independently a hydrogen atom or a C1-4 alkyl group, such as methyl.

When R or R7 is an alkyl group, they are, for example, a C1-8 alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, 1-butyl, t-butyl or n-heptyl, These alkyl groups may be substituted. If R6 is a substituted alkyl group, it is substituted, for example with one or more halogen atoms (e.g. chlorine or bromine atoms) or carboxy, C1-4 alkoxy (e.g. methoxy, ethoxy), Can be substituted by phenoxy or silyloxy groups. If R7 is a substituted alkyl group, it may be substituted by a cycloalkyl group, such as a cyclopropyl group.

R7 also represents a C1-6 alkyl group substituted by a halogen (for example chlorine, fluorine, bromine or iodine) atom or a C2-6 alkyl group with an intervening oxygen or sulfur atom.

When R or R7 represents an alkenyl or alkynyl group, they are, for example, a C2-8 alkenyl such as allyl or a C2-8 alkynyl group.

When R or R7 denotes a cycloalkyl group, they are, for example, C3-12, alkyl, e.g.
Cycloalkyl, for example, cyclobentyl group.

When R or R7 are aralkyl groups, they suitably have 1 to 6 carbon atoms in the alkyl part and the aryl group is carbocyclic or heterocyclic and preferably has 4 to 15 carbon atoms. carbon atoms and is, for example, phenyl. Examples of such groups include phenC1-6 alkyl, such as a benzyl group.

If R or R7 represents an aryl group, they are carbocyclic or heterocyclic and have 4 to 15 carbon atoms and are, for example, phenyl.

If R7 in the compound of formula (I) is a Cl-6 alkyl group substituted by a halogen atom, it is, for example, a halomethyl, haloethyl or halopropyl group.

If R7 is a C alkyl group with an intervening oxygen or sulfur atom, it is, for example, a metquinmethyl, ethoxyethyl or methylthiomethyl group.

If R or OR is a group -oSO2R, it is, for example, a methylsulfonyloquine or a p-toluenesulfonyloxy group.

If R or OR4 represents a cyclic acetaloxy group, it has, for example, 5 to 7 ring members and is, for example, a tetrahydropyranyloxy group.

If R or -0R4 denotes a silyloxy group, or if R6 confesses a silyloxy substitution, the silyl group is the same or different selected from alkyl, alkenyl, alkoxy, cycloalkyl, aralkyl, aryl and aryloxy groups. It may have three groups.

Such groups are as described above for R6 and include in particular methyl, t-butyl and phenyl groups.

Particular examples of such silyloxy groups are trimethylsilyloxy and t-butyldimethylsilyloxy.

R or OR4 is a group 0CO(CH2). If CO2R9 is denoted, it may be, for example, the group 0COCOR9 or 0COCHCHCo R, in which R9 denotes a hydrogen atom or a C1-4 alkyl (for example methyl or ethyl) group.

Salts that can be formed with compounds of formula (I) having acidic groups include alkali metal salts such as sodium and potassium salts.

In the compound of formula (1), the group R1 is preferably an isopropyl group.

When R2 and (or) OR' in the compound of formula (1) form a phosphate ester, the compound in which R and (or) OR4 have the formula % -OP (0) (○Z) 2 or suitable.

When OR4 is a substituted hydroxyl group, the formula (
Suitable compounds for 1) are those in which OR4 is methoxycarbonyloxy or especially acetoxy. However, in general, the formula (1
) are preferred.

Important compounds of the invention are compounds of the formula in which R1 is an isopropyl group, R- is a methoxymethoxy, methylthiomethoxy or ethoxyethoxy group, R3 is a hydrogen atom and OR4 is a hydroxy, acetoxy or methoxycarbonyloxy group. This is the compound (1).

Other important compounds of the invention are those of the formula (1 ) is a compound.

Another group of compounds of interest of the invention are those in which R1 is an isopropyl group and R2 is a group 0CONR10R11 (wherein R10
and R11 may each independently represent a hydrogen atom or a methyl group), R3 is a hydrogen atom, and OR4 is a hydroxy, acetoxy or methoxycarbonyloxy group.

Yet another group of compounds of interest of the invention are those in which R1 is an isopropyl group, R'' is a hydroxy group, R is a hydrogen atom, and OR4 is a group OP (0) (OH) 2°OP (0 )(OH)(ONa) or OP(0)(
ONa)2 is a compound of formula (1).

Important active compounds of the invention are compounds of formula (1) in which R1 is an isopropyl group, R2 is a methoxymethoxy group, R is hydrogen and OR4 is a hydroxy group.

Other important active compounds of the invention are those of the formula (1
) is a compound.

Still other important active compounds of the invention are compounds of formula (I) in which R1 is an isopropyl group, R2 is a 3-chloropropoxy group, R3 is a hydrogen atom and OR' is a hydroxy group. be.

Another important active compound of the invention is a compound of formula (1) in which R1 is an isopropyl group, R2 is an N-methylaminocarbonyloxy group, R3 is a hydrogen atom and OR4 is a hydroxy group. be.

As mentioned above, the compounds of the invention can be used as antibiotics and/or as intermediates in the production of other active compounds. When using the compounds of the invention as intermediates, R2 and/or -OR4M
, may be a protected hydroxyl group. As will be appreciated, such a group must further minimize the additional potential to avoid reactive sites and it must be possible to selectively regenerate the hydroxyl group therefrom. Examples of protected hydrosilyl groups are known, for example in ``Protecting Groups in Organic Synthesis'' by Thiodora, W., Green [2000, Wiley Interscience (1981)] and J.F.
“Protecting Groups in Organic Chemistry” by W. Masokuomie
[Plenum Inc. (1973)]. R
Examples of hydroxy groups with OR4 protected are:
Included are phenoxyacetoxy, silyloxyacetoxy (eg trimethylsilyloxyacetoxy and t-butyldimethylsilyloxyacetoxy) and silyloxines such as trimethylsilyloxy and t-butyldimethylsilyloxy. Compounds of the invention containing such groups are primarily used as intermediates.

Other groups such as acetoxy, although serving as protected hydroxyl groups, can also be present in the final active compound.

The compounds of the invention have anti-biotic properties, such as anthelmintic activity against nematodes, and in particular endoparasitic and/or anti-ectoparasitic activity.

The compounds of the invention are therefore used in the treatment of animals and humans infected with endoparasites and/or ectoparasites.

Ectoparasites and endoparasites infect humans and various animals and in particular pigs, sheep, cattle, goats and poultry (
farm animals such as chickens and turkeys), horses, rabbits, game birds, caged ravens and dogs, cats,
It is widespread in domestic animals such as guinea pigs, gerbils and hamsters. Parasitic infections, anemia, malnutrition and weight loss in livestock are a major cause of economic loss.

An example of such a genus of endoparasites that infects animals and/or humans is Ancylostoma (Ancylos10).
ma), Ascaridia, Ascaris, Aspic
ularjs), Brugia, Bunostomum (Bunos10mum), Cabiraria (Ca
pil 1aria), Chaber chia (Chaber
tia), Cooperia, Dictyocaulus, I11rorillaria, Dracunculus (D
racunculus), Enterobius (Entcr)
obius), Haemonchus (11acmonchu)
s), Heterakis (11ctcrakis), Loa (
boa), Ncca10r, Ncma10d i rus, Ncma10spiroides (Ilalig
omoroidcs), -postolongillus (Nip
pos' Llongylus), Oesophagostomum (Oesophagos 10mum), Onchocerophyte (
Onchocerea), Ostertasia (O8tOr
Lagia), Oxyuris, Parascaris, strongylus, St
longyloidas), Syphasia (Syphac)
ia), Toxascaris, Toxocara, Triconema
cboncma), Trichostrongylus (Tric
hostrongylus), Trichinella (Tr+c
hjncl la), Trichuris
s), Triodonthophorus (Triodon Lopho)
rus), Lancinaria (Uncinarja) and Wuchcrria.

Examples of ectoparasites that infect animals and/or humans include off-campus insects, fly flies, chisels, lice,
There are arthropod ectoparasites such as stratiform insects, ticks and other dipteran pests.

Examples of such genera of ectoparasites that infect animals and/or humans are Ambylomma,
Boophilus, Coriobutes (
ChoriopLcs), Kurihoa (Cu11ip
hore), Demodenox (Dcmodcx), Damalinia (Damal 1nia), Delmadobia (Dc
rmaLobia).

Gastrophi Ius No. 1
Ematobia (11aema10b)a),”Ematopinus (IIaemaLopjnus), Haemophysalis (11aamophysalis), Hyaloma (1
lyaloma), hypoderma (11ypodar)
ma), Ixodes, Linognathus, Lucili
a), Mclophagus, Ocstrus, OLObiu
s), Otodectes (010dcctcs), Busorergates (Psorcrgatcs), Busorobtes (P
soroptcs), Ribicephalus (Rhipicc)
phalus), Sarcoptes (Sarcoptcs)
, Slomoxys and Cubanus (
Tabanus).

The compounds of the invention have been found to be effective against a wide range of endoparasites and ectoparasites in vitro and in vivo. The antibiotic properties of the compounds of the invention may be demonstrated, for example, by free-living nematodes such as Caenorhavidides elegans (C.
acnorhabiditis elegans). In particular, the compounds of the present invention can be used in vivo in Nematospiroides jubius (Nema10spirojdes d
ubius) and Nippostrongylus braziliens
It was found to have activity against parasitic nematodes such as S. 1ensis).

The R-low dose (minimum lethal dose) of the compounds of the invention to kill the free-living nematode Caenorhavidides elegans was determined using standard procedures. The compounds of the invention were found to be effective against this nematode at doses lower than 10 μH/ml. The compounds of this invention are generally non-toxic in physiologically effective amounts.

Compounds of the invention may also be used in Candida albicans (C.
strains of Candida species such as Candida albicans) and Candida glabraLa and Saccharomyces carls
It is also used as an antifungal agent against yeasts such as P. bergensis.

The compounds of the invention are also used to combat insects, mites and nematodes in agriculture, horticulture, forestry, public health and stored products. Pests of agricultural and horticultural crops including soil and cereals (e.g. wheat, barley, corn and rice), cotton, tobacco, vegetables (e.g. soybeans), fruits (e.g. apples, grapes and citrus) and root crops (e.g. sugar beets, potatoes). can be processed. A specific example of such a pest is Aphis tzerni (Ap.
his rabaa), Aulacorthum circumrl
cxuII+), Myzuspersicae (Myzus pc
rsicae),
phoLcLLix clnct [ceps], Nilparvata Lugens
s), Panonychus urmi
ulfflL), Phorod
on humuli), phyllobuturk oleivora (
Phy11ocoptruta olcivora),
Tetranychus urticae
urticae) and Trialloides (Tria
fruit mites and oil worms, such as species of the genus Aphelencoides
es), Globodera, HeLcrodera, Meloidogyne (Melo
idogyne) and Panagrellus (Panagrelus)
Helioides (l1
el 1this), Plutella (Plutel la
) and lepidopterans such as Spodoptera, Anthonomus grungis
mus grandis) and Sitophilus granarius (Si10phil usgranarius).
), cereal weedworms such as Tripolium castanium (T.
Musca domesticus, a small beetle that attaches to flour such as rlboliua+ castaneum
Pear psy11a, Thrips tabac+, Blate11a gcrmanica.
) and Veributineta americana (Periplan)
eta amcricana) and mosquitoes such as Acdcs acgyptl.

According to the invention, therefore, there are provided compounds of formula (I) as described above, which can be used as antibiotics. In particular, the compounds are used in the treatment of animals and humans infected with endoparasites, ectoparasites and/or fungi and as insecticides for eradicating insects, mites and nematodes in agriculture, horticulture or forestry. be able to. The compounds can also be used generally as insecticides to eradicate or control pests in other contexts, such as in stores, buildings or other public places or places where pests are present. Generally, the compound can be applied to the host (animal or plant) or its location or the pest itself.

The compounds of the invention may be formulated for administration in any convenient manner for use in veterinary or human medicine. The invention therefore includes within its scope pharmaceutical compositions containing the compounds of the invention suitable for use in veterinary or human medicine. Such compositions may be presented in conventional manner using one or more carriers or excipients. The compositions of the invention particularly include compositions in forms formulated for use in parenteral (including mammary), oral, rectal, topical, implantable, ophthalmic, nasal or urinary administration. do.

The compounds of the invention can be formulated for use in veterinary or human medicine by injection and administered in ampoules or other unit-dose or multi-dose containers, with the addition of preservatives if necessary. It can be given as a form. Compositions for injection can be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles;
Formulation agents such as suspending agents, stabilizing agents, solubilizing agents and/or dispersing agents may also be included. Alternatively, the active ingredient may be prepared in sterile powder form which can be dissolved in a suitable vehicle, e.g. sterile pyrogen, immediately before use. Oily vehicles include polyhydric alcohols and their esters such as glycerol esters, fatty acids, vegetable oils such as peanut oil or cottonseed oil, mineral oils such as liquid paraffin and ethyl oleate and other similar compounds. Other vehicles such as propylene glycol can also be used.

Compositions for veterinary medicine may also be formulated as sustained or rapid release mammary preparations and optionally include thickening or suspending agents such as soft or hard paraffin, beeswax, 21-hydroxystearin, It can be a sterile solution or suspension in an aqueous or oily vehicle containing hydrogenated castor, aluminum stearate, or glyceryl monostearate.

Conventional nonionic, cationic or anionic surfactants can be used alone or in combination in the composition.

The compounds of the invention may also be prepared for use in livestock or humans in a form suitable for oral administration, such as a solution, syrup or suspension, optionally with flavoring and coloring agents, or in water or other suitable form immediately before use. It can be obtained in the form of a dry powder that can be reconstituted with a suitable vehicle. tablets, capsules,
Solid compositions such as lozenges, pills, bolus, powders, pastes, granules, bulettes or premix formulations can also be used. Solid and liquid compositions for oral use can be manufactured by methods well known in the art. Such compositions may also include one or more pharmaceutically acceptable carriers and excipients in solid or liquid form. Examples of suitable pharmaceutically acceptable carriers for solid use forms include binders such as pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, fillers such as lactose, microcrystalline cellulose, etc. or calcium phosphate), lubricants (e.g. magnesium stearate, talc or silica), disintegrants (
eg potato starch or sodium starch glycolate) or wetting agents (eg sodium lauryl sulfate). Tablets can be coated by methods well known in the art.

Examples of suitable pharmaceutically acceptable excipients used in liquid use forms include suspending agents (e.g. sorbyl syrup, methyl cellulose or hydrogenated edible fats), emulsifiers (e.g. lecithin or gum arabic). ), non-aqueous vehicles (eg almond ura, oily esters or ethyl alcohol) and preservatives (eg methyl or propyl p-hydroxybenzonylic acid or sorbic acid).

Stabilizers and solubilizers can also be doweled.

Basets for oral administration can be formulated by methods well known in the art.

Examples of pharmaceutically acceptable additives suitable for use in paste formulations include suspending or gelling agents such as
: Including raw or liquid esters, stabilizers and solubilizers. The compounds of the invention can also be administered as veterinary medicine, for example by incorporating the compound into the animal's daily solid or liquid dietary intake, as part of the animal's daily feed or drinking water.

The compounds of the present invention may also be administered orally as veterinary medicine in the form of liquid drenches, such as solutions, suspensions or dispersions of the active ingredient together with a pharmaceutically acceptable carrier or excipient. It can also be administered.

The compounds of the invention may also be formulated as skewers, eg containing a conventional pessary base, or as pessaries, eg containing a conventional pessary paste, for use, eg, in livestock or human medicine.

The compounds of the invention may be formulated into ointments, creams, lotions, shampoos, powders, pessaries, sprays, dips, nierosols, drops (e.g. eye or nasal drops), or drops for use in livestock and human medicine. It can be formulated for topical administration as a drop-in solution. For example, cartilage and creams can be formulated using an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye can be manufactured in a sterile manner using sterile ingredients. Drop-off drugs can be formulated in oil-containing organic solvents, optionally using formulation agents such as stabilizers and solubilizers, for example for use in livestock.

Lotions may be formulated using an aqueous or oily base and also generally contain one or more emulsifying, stabilizing, dispersing, suspending, thickening, or coloring agents.

Powders can be formulated using any suitable powder base. Drops may be formulated using an aqueous or non-aqueous base containing one or more dispersing, stabilizing, solubilizing, or suspending agents. They may also contain preservatives.

For topical administration for inhalation, the compounds of the invention in the form of an aerosol spray or inhaler for use as medicine in livestock or humans! Ue1['Iru.

The compounds of the invention can be administered in combination with pharmaceutically active ingredients.

The total daily usage of the compounds of the invention for use in livestock and human medicine is 1-'2000 μg/kg of body ir'i 2000 μ0-1000 μg/kg body ir'i
kg range and the compound is administered in divided doses of 10
It is given 1 to 4 times per day.

The compounds of the invention may be formulated in any convenient way for use in horticulture or agriculture and the invention therefore includes within its scope compounds of the invention suitable for use in horticulture or agriculture. It includes compositions that allow

Such formulations can be used in dry or liquid form (for example dust base or dust containing 713 thick).
L) powders, including soluble or wettable powders, granules, including microgranules and dispersible granules, pellets, fluids, emulsions, such as diluted emulsions or emulsifiable monoliths;
Soaking fluids such as root soaking fluids and seed soaking fluids, seed dressings (see
d dressing)% Flour pellets, oily concentrates, oils, injections such as stem injections, sprays, smokes and mists.

Generally, such formulations will include the compound together with a suitable carrier or diluent. Such Iu forms may be liquids or solids and are intended to aid in the application of the compound by dispersing the compound when applied or to provide a formulation that can be made into a dispersible formulation by the user. .

The rate at which the compounds of the invention are applied depends on a number of factors, such as the type of pest involved and the extent of the infestation. However, generally 10g/hour ~ 10kg/
Application rates are suitable, preferably between 0 g/hr and 1 kg/hr for tick and insect control, and between 50 g/hr and 1 kg/hr for nematode control. .

Such formulations are well known in the art and may be prepared by conventional methods, e.g. by mixing and/or milling the active ingredient with carriers or diluents such as solid carriers, solvents or surfactants. Can be done.

Suitable solid carriers for use in formulations such as dusts, granules and powders include, for example, natural mineral fillers such as diatomaceous earth,
You can choose from talc, koryo stone, montmorillonite, profilelite or acpur guide. If desired, highly dispersed silicic acid or highly dispersed absorbent polymers can be included in the composition.

Granulated adsorptive carriers that can be used are porous (such as pumice, crushed brick, sepiolite) or non-porous (such as calcite or sand). Suitable pregranulated materials, organic or inorganic, that may be used include white cloud cloth and ground plant residues.

Suitable solvents used as carriers or diluents are aromatic hydrocarbons, aliphatic hydrocarbons, alcohols and glycols or their ethers, esters, ketones, acid amides, strongly polar solvents, optionally epoxidized vegetable oils and water. 5g of

Conventional nonionic, cationic or anionic surfactants such as alkali metal or alkaline earth metal salts of ethylated alkylphenols and alcohols, alkylbenzene sulfonic acids, lignosulfonic acids or sulfosuccinic acids or sulfonates of polymeric phenols are used. ,
They have good emulsifying, dispersing and/or wetting properties and can be used alone or in combination in compositions.

If desired, stabilizers, anticoagulants, antifoaming agents, viscosity regulators, binders and adhesives, light stabilizers and fertilizers, feeding stimulants or other active substances can be included in the composition. The compounds of the invention can also be formulated in admixture with other insecticides, acaricides and nematicides.

In the formulation, the concentration of active substance is generally between 0, O1 and
99% by weight and more preferably 0.01-40% by weight 96
It is.

Commercial products are generally obtained as concentrated compositions which are diluted to a suitable concentration for use, e.g. 0.001 to 0.0001% by weight.

The compounds of the present invention are produced by the methods described below. In some cases of these methods it is necessary to protect the hydroxyl group in the 5- or 23-position in the starting material before carrying out the reaction. In such cases, it is necessary to remove the protection of the hydroxyl group as soon as the reaction has taken place to obtain the desired compound of the invention. Conventional protection and deprotection methods can be used, such as those described in the aforementioned books by Green and Matsukoomie.

Thus, for example, an acyl group such as an acetyl group
It can be removed by basic hydrolysis, for example using sodium or potassium hydroxide in aqueous alcohol. Acetal groups such as tetrahydropyranyl can be removed using, for example, acid hydrolysis (using acids such as acetic acid or trifluoroacetic acid or dilute mineral acids). The silyl group is a fluoride ion (e.g., a tetraalkyl ammonium fluoride such as tetra-n-butylammonium fluoride).
, hydrogen fluoride in aqueous acetonihilyl or an acid such as p-toluenesulfonic acid (eg, in methanol). Arylmethyl can be prepared, for example, by oxidation of the thiol (
(e.g. ethanethiol) in the presence of a Lewis acid (e.g. boron trifluoride-etherate) [where R1 is as previously described and R2 and OR
at least one of 4 is a hydroxyl group is phosphorylated with a reagent that serves to convert the hydroxyl group to a phosphate ester group, and optionally then 10R4 is a protected hydroxyl JA. R consisting of selectively retaining the compound of (1) and removing ψ
A method for preparing compounds of formula (1) in which at least 11 phosphate ester groups of 2 and OR' is proposed.

Phosphorylation is carried out by conventional methods, preferably in an inert solvent such as tetrahydrofuran, with a base such as a tertiary amine such as 4-dimethylaminopyridine, triethylamine or diimpropylethylamine or pyridine (1). Under i+d, the formula (I
This can be carried out by avoiding the reaction of the compound of l) with a phosphorohalide.

Substituted phosphate esters are described in U publication as bis(
2,2,2-trichloroethyl) phosphoro/1-lite can be prepared by phosphorylation of a substituted phosphoro/1-lite such as bis(2,2,2-trichloroethyl) phosphorochloride.

R- and (or) OR4 in the compound of formula (1) (
-0P(0)(OH)-('is: i misfetoster can then be prepared by hydrolysis.

Alternatively, R2 and )OR in the compound of formula (I)
is −〇P (0)(OCH,,CCΩ3)2, the formula (
It can be produced by reduction of the corresponding compound of I).

Reduction can be carried out using zinc activated with a metal such as silver. The reaction is suitably carried out in pyridine solution at elevated temperature, for example under reflux.

In another method, the OR2 and (also OR'10P (0)(OH)(
OZ) or -0P(0)(OZ'), , compounds of formula (I) can be prepared.

Generally, the hydroxy group at the 5-position of the compound of formula (II) is more reactive than the one at the 23-position and is phosphorylated first. Therefore, the phosphorylation of 23-
The extent to which this occurs depends on the amount of phosphorylating reagent used.

Furthermore, the present invention provides a compound of formula (II) (R' is as described above, and at least one of R2 and OR4 is a hydroxyl group), wherein the hydroxyl group is a group 0CON
consisting of reacting with a reagent which serves to convert R'°R11 and, if necessary, then selectively deprotecting the compound of formula (1) in which OR' is a protected hydroxyl group. A method is provided for making a compound of formula (1), wherein at least one of R 1 and OR' is a group 0CONR10R11.

Thus, carbomoylation can be carried out in a conventional manner using a suitable acylating (ie carbamoylating) agent. A suitable carbamoylating agent has the formula RNCO (wherein
R12 is a C alkyl group -4. ) incyanate. The carbamoylation reaction is preferably performed on hydrocarbons (e.g. aromatic hydrocarbons such as benzene and toluene), halogenated hydrocarbons (e.g. dichloromethane), amides (e.g. formamide or dimethylformamide), esters (e.g. ethyl acetate), ethers (e.g. It is carried out in the presence of a solvent or a mixture of solvents selected from cyclic ethers (eg, tetrahydrofuran and dioxane), ketones (eg acetone), sulfoxides (eg dimethyl sulfoxide) and mixtures of these solvents. The reaction is advantageously carried out at a temperature between -80°C and the reaction mixture, for example 100°C.
The temperature is preferably between -20°C and +30°C.

Carbamoylation is aided by the presence of a tertiary organic base such as a base, such as a tri(lower alkyl)amine (eg triethylamine).

Other useful molbamoyldanes are cyanic acids, which are advantageously produced in situ from alkali metal phosphonates, such as sodium cyanate. The reaction is facilitated by the presence of an acid, such as a strong organic acid such as trifluoroacetic acid. Cyanic acid effectively corresponds to the above-mentioned insinate compounds in which R12 is hydrogen and therefore converts the compound of formula (n) directly into the rubamoyl oxene congener.

Alternatively, carbamoylation may be carried out by reacting a compound of formula (n) with phosgene or carbonyldiimidazole, optionally in an aqueous or non-aqueous reaction medium, followed by reaction with ammonia or a suitable substituted amine.

In another process according to the invention, the formula (I
) can be prepared by reacting with R1 as previously described and one or both of R and OR4 as above. The reaction may be carried out in a suitable solvent at a temperature of -50 to +50°C, preferably -50 to +30°C. Suitable solvents include halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, Included are amides such as N,N-dimethylformamide, ethers such as tetrahydrofuran or dioxane and alcohols such as ethanol or mixtures of such solvents.

The present invention also provides a compound of formula (II) (R' is as described above, R is a hydroxy group, R3 is a hydrogen atom and -R4 is a substituted hydroxyl group), which has a hydroxyl group. is reacted with a reagent which serves to convert the group OR into a group OR (wherein R5 is as described immediately below) and optionally a compound of formula (I) in which R5 is a protected hydroxyl group. R consisting of removing the protection is a group OR [wherein OR5 is an alkoxy group OR (wherein R7 is a C substituted by a halogen atom)
1-6 alkyl group or C2-6 alkyl interrupted by oxygen or sulfur)
A method for making a compound is provided.

Thus, etherification can be carried out by conventional methods using reagent R
5Y in which R5 is as defined above and Y represents a chlorine, bromine or iodine atom or a hydrocarbylsulfonyloxy group such as menloxy or tosyloxy, or a haloalkanoyloxy group such as dichloroacetoxy. It can be done by

The reaction is carried out initially with the formation of the magnesium alkoxide using a Grignard reagent such as methylmagnesium halide, e.g. methylmagnesium iodide or using a trialkylsilylmethylmagnesium halide e.g. trimethylsilylmethylmagnesium chloride, followed by the formation of the magnesium alkoxide using the reagent R"Y. This can be done by processing.

Alternatively, the reaction can be carried out in the presence of a silver salt such as silver oxide, silver perchlorate, silver carbonate or silver salicylate or mixtures thereof, and this system carries out the etherification using reagent R5Y (wherein Y is a halogen atom).

The etherification can be carried out in a solvent such as an ether, for example diethyl ether.

Compounds of formula (1) in which R and/or OR4 are substituted hydroxyl groups are disclosed in British Patent No. 2176182
It can be prepared from the corresponding 5 and/or 23-OH compounds using the method described in Part A.

Compounds of formula (n) are described in GB 2176182A.

The invention will now be illustrated by the following examples. In these examples, the compounds are named with respect to the known original "factors", Factors A and B. Factor A
(described in British Patent No. 216 [143GA) in which R1 is isopropyl and R and OR4
is a hydroxyl group and R3 is a hydrogen atom. Factor B (also described in GB 210G43BA) is such that R1 is methyl and R2 is a hydroxyl group;
A compound of formula (II) in which R is a hydrogen atom and OR4 is a methoxy group. All temperatures are in °C.

Example 1 Factor A in dry tetrahydrofuran (3 ml)
(1 g of 1951I, azeotropically dried with toluene) was added to freshly distilled N
, N-diisopropylethylamine (0.55 ml)
followed by treatment with 2,2,2-trichloroethylphosphonochloridate (522 mg) and 4-dimethylaminopyridine (56 mg). After 33/4 hours, the colored mixture was added to ether (30 ml) and then water (IO ml), N-hydrochloric acid (2XlO ml),
Wash with saturated sodium deuterium carbonate (IO ml), water and brine.

Dry the dried organic... to form a rubbery substance (552111K
). This rubbery substance was mixed with hexane:ethyl acetate (3
: 1) Kieselgel GO (70-23
The title compound (111 mg) (OH
), 1710 (C-0) and 1015 cm-'
(P -0-C), δ(000g3) is 0.8(3,
6Hz, 3H), 0.96(d,7)Iz, 311),
1.00 (d, GHz, 3) 1), 1.05 (d, 7
Hz, 38), 1.54 (s, 3H), IJI (2,3
H), 1.90 (s.

311), 3.38 (a+, 111), 3.75 (d,
Lo11z, 111), 4.13 (d.

6) 1z, LH), 4.5-4.8 (I11, 8H),
5.58 (brs, IH).

Example 2 5-0-Phosphonofactor A 5- in a mixture of pyridine:water (9:1.2 ml)
A well-stirred solution of 0-(bis-2,2,2-trichloroethyl)phosphonofactor A (100 mg) was added to a freshly prepared zinc/silver reagent [wet form = t5o].
mg) and heat the mixture to reflux for 5 minutes. This operation is repeated four times until the reaction is complete. The mixture is cooled and centrifuged. The supernatant was discarded, the residue was washed with fresh pyridine, water (9:1.2 ml) and the combined liquid was concentrated in vacuo.

The residual liquid was dissolved in ethyl acetate (40 ml) and N-hydrochloric acid (20 ml).
ml). The aqueous phase is separated and extracted with ethyl acetate (3X loml). The combined organic extracts are washed with 2N hydrochloric acid (loml), water (loml) and finally brine (20ml). The organic phase is dried and evaporated to give a yellow residue. This was dissolved in 80% aqueous ethanol and Amberlite XAD2 (20'-5
0 mesh) (polymer adsorption beads).

The appropriate fractions are combined and concentrated in vacuo. The residue was then treated with DOWEX 50 (H+) ion exchange resin (lo
g) to give the title compound (40+ng) as a bright white solid.

ν (CHBr 3) 3390-3810 (OH
), 1710l1ax am (C-0). δ(CD6g3) is o,9(d:6
H.

311), 0.95 (d, GHz, 3tl), 0
．． 98 (d, GHz, 3H), 1.05 (d, 611
z, 311), 1.52 (s, 311), 1.60
(s, 3tl), 1.79 (s.

311), 3.27 (m, 1it), 3.7
4(d, 1011z, 111), 4.12(d.

511z, LH), 5.44 (brs, 1Il).

DOWEX 50 ion exchange resin (Na form.

Passage of a solution of the title compound in water through a 10 g) column gives the corresponding monosodium salt.

714 (M).

Example 3 5-acetoxy, 23-0-phosphonofactor A 5-acetoxy in dry pyridine (0.24 ml) and dry tetrahydrofuran (4 ml) under nitrogen.

Factor A (Example 7 of UK-217B1g2A) (
Phosphorous oxychloride (0,24
Add m1). 10 minutes at 0-5° and 24 at 21"
After hours, the resulting mixture is partitioned between ethyl acetate (40 ml) and water (20 ml). The aqueous phase was separated and extracted with ethyl acetate (2 x 20 ml), water (20 ml) and brine and the organic phase was then concentrated in vacuo iQ to approx.
Make it m1.

The concentrate was thoroughly extracted with saturated aqueous sodium bicarbonate and the combined aqueous solutions were diluted with ethyl acetate (600 ml).
Acidify to )H2 with N hydrochloric acid. The aqueous phase is then re-extracted with ethyl acetate (2X200 ml) and the combined organic extracts are washed with room water and brine. The dried organic phase was evaporated to give a light brown foam-like substance (171
mg), which was purified by preparative reverse-phase HPLC to give an aqueous solution i! After lyophilization of 1 part, the title compound (100 mg) is obtained as a light fuzzy white solid.

[α]21+128° (C0,34,CHCΩ),
λEtOH243,8nn+ (ε 27,200)
, νmaxa+ax 1
11ax (CHBrs) 2500-3700
(OH), 1739 and 1720 cm (ester). δ (CDCΩ3 + 1 drop of CH3CO2H) is 0.
77 (d, OH2, 311).

0.95 (d, 611z, 311), 1.00 (d,
G11z, 3H), 1.05(d, 6Hz.

311), 1.52 (s, 311), 1.6
0 (s, 3) 1), 1.74 (s, 3H).

2.16 (s, 3tl), 3.33 (m, 1II)
, 3.93 (d, 1olIz, lH).

4.40 (brs, 1tl) and 5.5-5.8 (m
, 2H).

Passage of a solution of the title compound in water through a Dowex 50 (Na form) ion exchange resin gives one rod equivalent of the monosodium salt. This compound is 2””245.5nm
(εIG, 300) Oyohi m/z -maX
ff1aX779 (M+Na)
Give ten.

Example 4 23-O-phosphonofactor A 5-acetoxy, 23- in methanol (1,0 ml)
〇-Phosphonofactor A (34ag) solution from 0 to
Cool to 5″ and add aqueous sodium hydroxide (IM.

0.14 ml). After 2 hours at 0-5°, the solution was dissolved in ether (15 ml) and 2N hydrochloric acid (loml).
distribute between. The aqueous phase was separated and ether (10
m1). The dried organic phase was evaporated to give a yellow solid, which was lyophilized as a solution in 10% acetonitrile to give a white fuzzy solid.

The title compound (18-g) is obtained. [α] o +7
2(C0,23,CHCΩ3), νmax (CH
Br ) 3500 (OH) and 1708 cm (ester).

δ (CDCΩ + 1 drop of CH3CO2H) is 0.75 (
d, GHz, 311), 3.93(d, 10Hz, I
H) and 4.3-4.4 (m, 2H).

Example 5 3-chloro-1-iodopropane (1 ml) was dissolved in 5-acetoxy factor A (0 ml) in dry ether (50 ml).
, 4 g) followed by silver carbonate (1.20 g) and then silver perchlorate (0.87 g). The mixture was stirred at room temperature for 20 hours, then diluted with ethyl acetate, filtered and the quenched liquid was dissolved in collidine (2 ml) and methanol (2 ml).
ml). After 2 hours, the mixture was serially reduced to 0.
Wash with 5N hydrochloric acid and water. The dried organic phase was evaporated and the liquid was washed with Merck Kieselgel 80 (230-40
Purify by chromatography on 0 mesh) (100 ml). Column with hexane:ethyl acetate (
4:1) to give the title compound (0,327 g) as a colorless foam.

[α]D+150° (C1, 65, CHCU 3).

λ (EtOH) 244 ms (ε29,2
50).

01ax m
axνff1a, (CHB r 3) 3540.3
470 (OH), 1731 (acetate),
1708 (C-0), 999 (C-O). δ
(CDCΩ3) is 5.5 to 5.6 (ffl, 2H)
.

3.70(t7,2)1), 3.6-3.8.
(h jdden) I11.

(lH), 3.46 (m, 1B), 3.27-3.
4 (m, 211), 2.17 (s.

311).

Example 6 was prepared in a similar manner from 5-acetoxy Factor A and the appropriate alkylating agent.

Example 6 [α]D+158° (C1, 22, CHCΩ3).

λ (Et OH) 244 stops (ε 31,500)
, max max νmaX (CHB r q ) 3530.3470
(OH), 1732 (acetate), 1708
(C-0), 997 (C-○). δ(CDC
Ω3) is 5.5 to 5.6 (a+, 211).

3.74 (m, III), 3.5 ~ 3.7 (01
, 6+1), 3.41(a+, 111).

2.16 (s, 311). Prepared from 2-bromoethyl ethyl ether.

Example 7 5-Acetoxy-23-methoxymethoxy Factor A A 3M solution of methylmagnesium iodide in ether (0.45 ml) was added to dry hexamethylphosphortriamide (15 ml) while foaming directly under nitrogen.
5-acetoxy factor A (733 mg) in a stirred solution of 5-acetoxy factor A (733 mg). After 20 minutes, ether (0, [1 ml
) of bromomethyl methyl ether (171 mg) is added. After 1 hour, a further portion of ethereal 3M methylmagnesium iodide solution (0.3 ml) is added followed by a solution of bromomethyl methyl ether (86 mg) in ether (0.3 ml). Mixture at room temperature
Stir for 0 hours, dilute with ether (100 ml) and wash with water. The dried organic phase was evaporated and the resulting gummy material was purified by Merck Kieselgel GO (230-40
Purified by Clo 7 Togelafie on (150 ml) (150 ml). The column was diluted with hexane:ethyl acetate (2
Elution with: 1) gives the title compound (49hg) as a colorless foam.

[α]D+175° (C1, 40, CHC, Q 3)
, λ (Et OH) 244 ru++ (ε2
7,600).

wax
maxν (CHBr 3) 3540, 3470
(OH), 1734l1ax (acetate), 1712 (C-0), 99
5 (C-O). δ(CDCfI3) is 5.5-5.
8 (m, 2H), 4.80 (d7.LH), 3.
76 (m, IH), 3.40 (s, 3H), 2.1
6(s, 3[1).

Example 8 was prepared in a similar manner from 5-acetoxy Factor A and the appropriate alkylating agent.

Example 8 5-acetoxy-23-methylthiomethoxy factor A [α]D+189° (C1,19, CHCR3).

λmaw (EtOH) 244 nm (εma
x 28.950).

νmax (CHBr 3) 3470 (OH)
, 1734 (acetate), 1712 (C-
0), 994 (C-0).

δ(CDCΩ3) is 5.5 to 5. fli(+n, 2H)
, 4.5-4.8 (m, 4H), 2.1G (s
, 311), 2.14(s, 3H). Produced from chloromethyl methyl sulfide.

Example 9 5-acetoxy-23-(3
-chloropropyloxy)-Factor A (140a+
A solution containing g) and sodium iodide (330+og) is heated under reflux for 5 days. The cooled solution was diluted with ether (50 ml), washed with water and the dried organic phase was evaporated to give a gummy material, which was mixed with Merck Kieselgel 60 (230-400 mesh) ([10 ml
) Purify by chromatography on The column was eluted with hexane:ethyl acetate (3:1) to give the title compound (13Ba1 g) as a colorless foam. ((Z) 2'+140° (C1,03°CH(J
) 3), λ111ax (Et OH) 244
nm (ε 31,300), ν (CHB
r3) 3530゜wax
max34 [io (OH), 1732
(acetate), 1710 (C-0), 9
9G (C-0). δ (CD0g3) is 5.5 to 5
．． 8 (m, 2H), 3.5-3.7 (m, 211
), 3.45 (a+.

LH), 3.36(t7,2H), 3.2[i
(m, LH), 2.1[i(s, 3H).

Example 10 23-Methoxymethoxy Factor A A solution of 5-acetoxy-23-methoxymethoxy Factor A (471 mg) in methanol (30 ml) was cooled in a water bath and treated with IN aqueous sodium hydroxide (1,5 ml).
1) is added and the solution is stirred in a water bath for 1.25 hours. The solution was diluted with ether (80 ml) and then sequentially diluted with 0.
．． Wash with 5N hydrochloric acid and then water. The dried organic phase is evaporated and the resulting gum is purified by chromatography on Merck Kieselgel 60 (230-400 mesh) (140 ml).

The column was eluted with hexane:ethyl acetate (2:1) to give the title compound (2BOa+g) as a colorless foam.
get. [α]23+175° (C1,40,CHC
Ω ), λ (EtOH) 244 nm
(ε2B, 900), IIIaxIIlax ν (CHBr a ) 35B0,3480 (O
H), 1708ax (C-〇), 998 (C-0). δ(CDCΩ
3) is 4.80 (d7, 1H), 4.58 (d7
．． 111), 4.29 (t7, 111).

Includes 3.78 (a+, LH), 3.40 (s, 311).

Examples 11-14E were prepared in a similar manner.

Example 11 23-methylthiomethoxy factor A [α) D+
188° (C1, 35, CHCN 3), λwax
(EtOH) 244nm (εmax 28,
800), νmax (CHBr 3) 3550.
3470 (EtOH), 1707 (C-0),
993 (C-0). δ(CDCΩ3) is 4.6-4.
8 (m, 411), 4.29 (17, l11), 3.
90 (+a, 111), 2.15 (s, 3H)
includes.

Prepared from 5-acetoxy-23-methylthiomethoxy Factor A.

Example 12 23~ [(2-ethoxy)Etquin cofactor A [α] D+ 148' (CI -28, CHC1
3), λmax (Et 0f() 244ro+
+ (εmax 27,700), ν111ax (
CHBr 3) 3550.3480 (OH), 1
706 (C-0), 999 (C-0), 6 (C
DCR3) Ha4.30 (17,111), 3, γ
4 (m, LH), 3.5-3.7 (11, OH),
3.41 (+n, 111), 1.20 (17,
311). 5-acetoxy-23-[(2
- Ethoxycofactor A).

Example l3 23-(3-chloropropyloxy) factor A [αco D + 150° (C1,46, CHCi
) 3) , λmax (EtOH) 24
4n11 (εmax 27,200), νmax (
CHBr 3) 3550.3470 (OH), 1
706 (C-0), 999 (C-0), 6 (C
DtJl 3) l, t, 4.29 (br, S,
1tl), 3.70 (17,2H), 3.6
~3°8 (hidden tn, IH), 3.45 (
m, l1l), 3.33 (m, IH). Prepared from 5-acetoxy-23-(3-chloropropyloxy) Factor A.

Example 14 23-(3-iodopropyloxy)Factor A [αJ D+ 137°(C1,48,CH(1?3
), λaax (Et OH) 244 nm (ε
max 29,200), νmax (CHB r
3) 3555.3480 (OI(), 1707(
C=0), 995(CO). o (CDCN 3)
is 4.29 (17, II+), 3.5-3.7
(m, 211), 3.45 (m, IH) 3.3
6 (t7.2H), 3.2-3.3 (+m, 21
1). Prepared from 5-acetoxy-23-(3-iodopropyloxy) Factor A.

[α] D+ 142° (CO,92,CHCΩ3)
, λmax (Et OH) 245ni (ε
29,200) , νmax(CHB r 3) 3
5fiO and 3500 (OH), 1745 (carbonate) and 1710 cm (1 stel).

δ(CDCΩ3) is 5.40 (S, LID, 4,
80 and 4.70 (ABq 5J (411z, 2
11), 4.28 (m, 111) and 0.79
(d, J7tlz, 311).

Example 15 Factor A, 23-N-methylcarbamate Factor A, 23-'(2,2,2-trichloroethyl) carbonate (Example 88 of UX-2176182A) (1
50+n5r) is dissolved in ethanol (5 ml) and 33% methylamine in ethanol (2 ml) is added. The resulting solution is stirred at 20° for 2 hours and then poured into a mixture of ethyl acetate and 2N hydrochloric acid (50 ml each). The organic phase is washed with brine (25 ml), dried (magnesium sulphate) and evaporated to dryness. The residue is purified by chromatography on Kieselgel 60 (20 g). The column was eluted with petroleum ether:ethyl acetate (1:1) to give the title compound (1113 mg) as a colorless foam.

[α]2°+192° (CO,7,CHCΩ), λ
max (Et OH) 245.5Hm (8
27,800), νmax (CHBr 3)
3560 and 3465 (OH and NH), 171
0 (ester) and 1710 and 1515 cm (carbamate). δ(CDCΩ3)
is 4.9-5.1 (m, 2H), 4.28 (t,
J7Hz, 1it), 4.54 <m, Lit)
3.88 (d, Jlo11z, 111), 2
．． 80 (m, 311) and 0.71 (d, J7
Hz, 3H).

Example 16 Factor A123 - Rubamate dioxane (10 ml) and ammonia solution (SGo
, 88) in a mixture of (2 ml) Factor A12
A solution of 3-(2,2,2-trichloroethyl) carbonate (248 ag) was stirred at 20° for 16 h and then treated with ethyl acetate (100 ni) and 2N-hydrochloric acid (5 ni).
0 ml) of the mixture. The organic phase was dissolved in brine (25 ml
) and dried (magnesium sulfate) and evaporated to dryness. The residue is purified by chromatography on Kieselgel 60 (25 g). The column was eluted with petroleum ether:ethyl acetate (1:L) to give the title compound (60 mg) as a colorless foam. [α
]20+155° (CO,64,CHCN)λw
ax (E t OH) 245.5 nm (ε2
8.400), νmax (CHBr 3) 354
5 and 3430 (OH and NH), 1715 (
esters) and 1715 and 1572 cm-1 (carbamates). δ(CDCl2) is 4.86 (
m, IH), 4.59 (S, 2H), 4.29
(t.

J71 (z, LH), 3.87 (dSJIOHz
5IH) and 0.73 (dSJ7Hz, 3H).

Example 17 Factor B, 23-N-methylcarbamate Factor B (300 mg), 2,2,2-trichloroethylcarbonyl chloride (1.5 ml of a 1M solution in dichloromethane) and dry pyridine (0.5 ml),
Stir in dry dichloromethane (10 ml) for 2 hours at 23''. The mixture is added to ethyl acetate and the organic solution is treated against neutrals to give a pale yellow gum (577
mg). The crude product in dichloromethane was mixed with Merck Kieselgel 60 (230-40) made in the same solvent.
0 mesh) into a column of silica (50 g). dichloromethane and then dichloromethane:ether (1
Elution with 9,1) gives a solid (250 mg). This solid in ethanol solution (5 ml) was dissolved in 33% of methylamine.
% ethanol solution.

After 31/2 hours at room temperature, the mixture is added to ethyl acetate and the organic phase is washed with 2N hydrochloric acid and brine. The dried ethyl acetate layer is evaporated to give a gum (200 mg). This was used as the eluent to dichloromethane; ether (
9:1) and dichloromethane:ether (4:1)
Purify by chromatography on silica (50 g) using The title compound (GOmg) is an ether/
From n-pentane to indefinite and 245ru++ (εmax
28.900) +n+ax (CHBr 3)3
400 (NH and OH), 1705 (ester)
and 1705 and 1513 cm' (carbamate).

δ(CDCfI3) is 2.79 (ds 5Hz,
3H), (S%3.51.3H), 4.55 (Q
, 5Hz, LH) and 4.9-5.1 (m, 2
H). m/z -655 (M'').

Example 18 Factor A, 5-N-methylcarbamate Factor A (308 mg), excess methyl isocyanate (11
60 g) and 2 drops of dimethylamine are heated in dry N,N-dimethylformamide (0,6 ml) in a closed container at 80" for 7 hours. The mixture is cooled, diluted with ether and then the organic phase is added sequentially. Wash with saturated aqueous sodium bicarbonate, 2N hydrochloric acid and brine. Evaporate the dry ethanol layer to give material (35B+ng) which is purified by preparative +1 PLc. Elution with 65% acetonitrile in water gives a foam. The substance obtained is dissolved in a small amount of ether. Addition of n-pentane precipitates the title compound (100 ff+g) as a white amorphous solid. [α] 23+ 139° (CO, 3B, C
HCΩ3), λmax (Et 0H)239 (
28,600) and 245 nm (ε111ax 3
1,700), ν111ax (CHCΩ3) 38
00 (01(), 3450 (NH) and 171
0 cm-1 (esters and carbamates).

δ(CD0g3) is 5.51 (d, GHz,
LH), 4.79 (q, 5Hz, IH) and 2.82 (d, 5Hz, 3H).

The following are examples of formulations of the invention. The term active ingredient used below refers to a compound of the invention.

Active Ingredients 4.0 0.1-7.5% v/v Benzyl 2.0 Alcohol Glyceryl 30.0 Triacetate Propylene 100.0 Glycol Dissolve the active ingredient in benzine alcohol and glyceryl triacetate. Add propylene glycol and bring to volume. The product is sterilized by conventional pharmaceutical methods (e.g. sterilization) by filtration or by heating in an autoclave and packaged aseptically.

Active ingredient 0.1 0.01-2. Ov/w% Trichloroethane 29.9 Trichloroflu 35.0 Oromethane Dichlorodiflu 35.0 Oromethane The active ingredient is mixed with trichloroethane and loaded into an aerosol container. The headspace is purged with gaseous propellant and the valve is crimped in place. The required weight of liquid propellant is charged under pressure via a valve. Install actuator and dust cap.

Tablet manufacturing method - Wet granules Bile active ingredients 250.0 Magnesium stearate 4,5 Corn starch 22.5 Sodium
9.0 Starch Glycolate Sodium Lauryl Sulfate 4.5 Microcrystalline Cellulose Amount to make a tablet core weight of 450 mg A sufficient amount of 10% starch paste is added to the active ingredient to produce a suitable wet mass for granulation.

Granules are prepared and dried using a tray or fluid bed dryer. Sift, add remaining ingredients and compress into tablets.

If necessary, the tablet cores are film coated using hydroxypropyl methyl cellulose or other similar film-forming materials using an aqueous or non-aqueous solvent system. Plasticizers and suitable dyes can be included in the film forming solution.

Egg active ingredients 50.0 Magnesium stearate 7.5 Microcrystalline cellulose 75. The active ingredient is mixed with magnesium stearate and microcrystalline cellulose in an amount equal to On+g tablet core weight. Press the mixture into slurps. The slurp is broken down by passing it through a rotary granulator to produce free-flowing granules. Press it into tablets.

The tablet core can then be film coated as described above, if desired.

Active ingredient 150mg 0.05-1.0gφ-10
゜Drop IE Ikuura, white wax and polysorbate 6o are heated to 160°C with stirring. Maintain at 1G O 0 C for 2 hours and then cool to room 1H with stirring. Aseptically add the active ingredient to the vehicle and disperse using a high speed mixer. Process by passing through a colloid mill. Aseptically fill the product into sterile plastic syringes.

For livestock oral administration] Range Active ingredient 0.35 0.01-21//V% polysorbate! -85 5.0 Benzyl Alcohol 3.0 Propylene 30.0 Glycol Phosphate Buffer 5 kpHG, 0 to 6.5 Water Amount to make 100.0 Dissolve the active ingredient in Polysorbate 85, pencil alcohol and propylene glycol. If necessary, add some water and adjust the pH to 6.0 with phosphate buffer.
Adjust to 6.5. Bring to final volume with water. Fill the product into drinking containers.

Active Ingredients 7.51-30v/contains Saccharin 25.0 Polysorbate 85 3.0 Disterianic Acid 5.0 Aluminum Fractionated Iashiura 100.0% Aluminum distearate is dispersed in fractionated Iashiura and Polysorbate 85 by heating. do. Cool to room temperature and disperse the saccharin in the oil vehicle. Disperse the active ingredient in the base. Fill a plastic syringe.

Granular Active Ingredient for Livestock Feed Administration 2.5 0.05-5% v/w Calcium Sulfate 100.0 Hemihydrate The active ingredient is mixed with the calcium sulfate. Granules are manufactured using a wet granulation method. Dry using tray or fluid bed dryer. Fill into a suitable container.

Emulsifiable concentrate active ingredient 50 g Anionic emulsifier 40 g (e.g. phenylsulfonate CALX) Non-ionic emulsifier GOg (e.g. Ciperonic NP13) Aromatic solvent (e.g. Rosolben 100 to 1 g) Mix all ingredients and stir until dissolved. do.

Granules (a) Active ingredient 50g Wood resin 40g Gypsum granules (20-Go mesh) 1 and 2 pieces of melon (e.g. Agsolve 100A) (b) Active ingredient 50g Siberonic NP13 40g gypsum granules (
20-GO mesh) Melon to 1 kg Dissolve all ingredients in a volatile solvent such as methylene chloride and add to the 'In 7M tumpling in a mixer. Applicant for patent characterized by drying and solvent 2 persons other than Gractu Group Limited Proceedings 1 Ili Sho 111 (I2 6J) 90 Special 1 (Gamma Office Commissioner Kuro 11) Mr. Akihiro l, Indication of the case 1986 Relationship with Patent Application No. 542G7 No. 2, Name of Invention Mac[nolide Antibiotic 3,) + Li Positive ii] Patent Applicant Address United Kingdom v1 Nondaburi;!, -・L・W 8.D Age, Kurano's Story-1-6-1
2. Name of Courage's House: GRAKTS GROUP LIMITED → Agent 5Ji Attachment 11 (voluntary) 6. Subject of amendment 7. Details of amendment 1! J, page 33, lines 9 to 15, "The compound of the present invention is..." is amended as follows.

"The rate at which the compounds of the invention are applied depends on a number of factors, such as the type of pest involved and the extent of infestation. However, in general, application rates of 1 ag/ha to 1Q kg/ha are suitable. , preferably from 109 g/ha to 1 ky/ha for control of ticks and insects, and from 50 g/ha to 109 g/ha for control of nematodes.

Claims (1)

[Claims] 1. Compounds of formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) and salts thereof. In the above formula, R^1 is a methyl, ethyl or isopropyl group, and R^2 is a hydrogen atom or a group OR^5, where OR^5 is a hydroxyl group, a substituted hydroxyl group having up to 25 carbon atoms. or a phosphate ester group) and R^3 is a hydrogen atom or R^
2 and R^3 together with the carbon atom to which they are attached denote a >C=O group, and OR^4 denotes the group OR^5 as described above. However, R^2 is a group OR^5 [wherein OR^5 is an alkoxy group OR^7 (wherein R^7 is a C_1_-_6 alkyl group substituted by a halogen atom or a C_2_ interrupted by oxygen or sulfur) -_6 indicates an alkyl group)
or at least one of R^2 and OR^4 is a phosphate ester group or a group OCON
R^1^0R^1^1 (in the formula R^1^0 and R^1^
1 is independently a hydrogen atom or a C_1_-_4 alkyl group). 2. The compound according to item 1 above, wherein R^1 is an isopropyl group. 3. The compound according to item 1 or 2 above, wherein OR^4 is an acetoxy or methoxycarbonyloxy group. 4. The compound according to item 1 or 2 above, wherein O^R4 is a hydroxy group. 5, R^1 is an isopropyl group, R^3 is a hydrogen atom, OR^4 is a hydroxy, acetoxy or methoxycarbonyloxy group, and R^2 is methoxymethoxy, methylthiomethoxy, ethoxyethoxy,
3-Halopropoxy or -OCONR^1^0R^1
The compound according to item 1 above, which is a ^1 group (in the formula, R^1^0 and R^1^1 independently represent a hydrogen atom or a methyl group). 6, R^1 is an isopropyl group, R^2 is a hydroxy group, R^3 is a hydrogen atom, and OR^4 is OP(O)(OH)_2, OP(O)(OH)( The compound according to item 1 above, which is OP(O)(ONa)_2. 7, R^1 is isopropyl, R^2 is a methoxymethoxy group, R^3 is a hydrogen atom, and OR^
4 is a hydroxy group, R^1 is an isopropyl group, R^2 is a methylthiomethoxy group, R^3 is a hydrogen atom, and OR^
4 is a hydroxy group, R^1 is an isopropyl group, R^2 is a 3-chloropropoxy group, R^3 is a hydrogen atom, and OR
^4 is a hydroxy group, or R^1 is an isopropyl group, R^2 is an N-methylaminocarbonyloxy group, R^3 is a hydrogen atom, and OR^4 is a hydroxy group. A certain compound according to item 1 above. 8. A composition for use in human medicine containing an effective amount of at least one compound according to item 1 above, together with one or more carriers and/or excipients. 9. A composition for use in veterinary medicine containing an effective amount of at least one compound according to item 1 above, together with one or more carriers and/or excipients. 10. A pest control composition containing an effective amount of at least one compound according to paragraph 1 above, together with one or more carriers and/or excipients. 11. In agriculture, or in horticulture or forestry, comprising applying an effective amount of one or more compounds as defined in paragraph 1 above to plants or other vegetation or pests themselves or to the places where they occur; or A method of eradicating pests in stores, buildings or other public places or areas where pests are present. 12. The method according to item 11 above, wherein the pest is an insect, mite, or nematode. 13. (a) In the production of a compound in which at least one of R^2 or OR^4 is a phosphate ester group, the corresponding compound in which at least one of R^2 and OR^4 is a hydroxy group is phosphorylated. , then optionally reduce the product where R^2 and/or OR^4 is -OP(O)(OCH_2CCl_3)_2 to form R^2 and/or OR^4 as -OP(O) Obtaining a compound that is (OH)_2 and/or treating the product where R^2 and/or OR^4 are OP(O)(OH)_2 with an alkali metal hydroxide (ZOH). to obtain a compound in which R^2 and (or) OR^4 are -P(O)(OH)(OZ) or -OP(O)(OZ)_2, (b)
R^2 and (or) OR^4 are groups OCONR^1^
In the preparation of compounds where 0R^1^1, the corresponding compound in which at least one of R^2 and OR^4 is a hydroxy group is carbamoylated and (c) R^2 and (or) OR^4 are a group OCONR.
In the production of a compound where ^1^0R^1^1, R^
At least one of 2 and OR^4 is OCO_2R^6
(In the formula, R^6 is C_1_-_8 alkyl, C_2_-_
8 alkenyl, phenC_1_-_6 alkyl or C
(d)
R^2 is a group OR^5 [wherein, OR^5 is an alkoxy group O
R^7 (wherein R^7 is a C_1_-_6 alkyl group substituted with a halogen atom, -O- or -S-
is a C_2_-_6 alkyl group interrupted by), by etherifying the corresponding compound in which R^2 is a hydroxy group and OR^4 is a substituted hydroxy group. or (e) in the preparation of compounds in which R^2 or OR^4 is a hydroxy group, consisting of removing the protecting group from the corresponding compound in which R^2 or OR^4 is a protected hydroxy group. A method for producing the compound described in item 1 above.