AT398311B - METHOD FOR PRODUCING A NEW MACROLID CONNECTION - Google Patents

Description

AT 398 311 B

The invention relates to a method for producing a new, antibiotic compound.

GB-PS 2 166 436 and EP-PS 170 006 describe the preparation of a class of substances which are described with antibiotics S541 and which can be isolated from the fermentation products of Streptomyces microorganisms. Another compound with antibiotic activity is now provided, which can be produced by chemical modification of an antibiotic S541 compound. According to the invention, the compound of the formula (I) is thus 15 20

OH

(I) 25 made. A particularly advantageous property of the compound to be produced according to the invention is its ability to form crystalline solids. According to the invention, therefore, the preparation of the compound of formula (I) is also included in crystalline form.

The property of crystallizing the compound can be used for cleaning purposes in the production of this compound. In this way, the compound of formula (I) could be obtained as a crystalline solid 30 with a purity of more than 90% and in particular of more than 95%. Since the compound is capable of forming a crystalline solid with a very high purity, the compound of formula (I) is particularly useful as an intermediate for the preparation of the other compounds having antibiotic activity.

As such, the compound of formula (I) also has antibiotic activity, e.g. Activity 35 against helminths, for example against nematodes, and in particular anti-endoparasitic and anti-ectoparasitic activity.

The antibiotic activity of the compound of formula (I) can be determined, for example, by its in vitro activity against free-living nematodes, e.g. Caenorhabiditis elegans.

Ectoparasites and endoparasites infect humans and various animals and are particularly common on 40 animal farms. Such animals include pigs, sheep, cattle, goats, poultry (e.g. chickens and turkeys), horses, rabbits, hunting birds, caged birds and pets such as dogs, cats, guinea pigs, gerbils and hamsters. With a parasite infection of livestock that leads to anemia, poor nutrition and weight loss are the main cause of the economic losses worldwide. 45 As examples of the genera of endoparasites that infect animals and / or humans, Ancylostoma, Ascaridia, Ascaris, Aspicularis, Brugia, Bunostomum Capillaria, Chabertia, Cooperia, Dictyo-caulus, Dirofilaria, Dracunculus, Enterobius, Haemonchus, Heterakis, Loa , Necator, Nematodirus, Nemato-spiroides (Heligomoroides), Nippostrongylus, Oesophagostomum, Onchocerca, Ostertagia, Oxyuris, Paras-caris, Strongylus, Strongyloides, Syphacia, Toxascaris, Toxocara, Trichonema, Trichostrongusaria, Undichophorus, Unich call.

Examples of ectoparasites that infect animals and / or humans are arthropod ectoparasites, for example biting insects, blowflies, flies, lice, mites, sucking insects, ticks and other double-sided pests.

Examples of genera of these ectoparasites which infect animals and / or humans are 55: Ambylomma, Boophilus, Chorioptes, Culliphore, Demodex, Damalinia, Dermatobia, Gastrophilus, Haematobia, Haematopinus, Haemophysalis, Hyaloma, Hypoderma, Ixodes, Linognath Lucilia, Melopha-gus, Oestrus, Otobius, Otodectes, Psorergates, Psoroptes, Rhipicephalus, Sarcoptes, Stomoxys and Tabanus. 2nd

AT 398 311 B

The compound of formula (i) is also useful for controlling insect, mite and nematode pests in agriculture, horticulture, forestry, health care and stored products. Pests of green fodder and crops, including cereals (e.g. wheat, barley, maize and rice) from vegetables (e.g. soy), fruits (e.g. apples, grapes and citrus fruits), as well as root vegetables (e.g. sugar beets, potatoes) can be controlled. Such pests include, in particular, fruit mites and aphids such as Aphis fabae, Aulacorthum circumflexum, Myzus persicae, Nephotettix cincticeps, Nilparvata lugens Panonychus ulmi, Phorodon humuli, Phyllocoptruta oleivora, Tetranychus urticae and members of the Genera Trialeuro; Nematodes such as members of the Genera Aphelencoides, Globodera, Heterodera, Meloidogyne and Panagrellus; Lepidopters such as Heliothis, Plutella and Spodoptera; Cereal beetles such as Anthonomus grandis and Sitophilus granarius; Black beetles, such as Tribolium castaneum; Flies like Musca domestica; biting ants; Menier moths; Pear psylla; Thrips tabaci; Cockroaches such as Blateila germanica and Periplaneta americana and mosquitoes such as Aedes aegypti.

The compound obtainable according to the invention which will be described in detail later can be used as an antibiotic.

This compound can be used in particular for the treatment of animals and humans with endoparasitic infections, ectoparasitic infections and / or fungal infections, and in agriculture, in horticulture or in forestry as a pesticide for controlling insects, mites of the order Acarina and nematodes. It can also be used as a pesticide to control or control pests in other environments, e.g. be used in camps, buildings or other public locations of the pests. In general, the compound is given either to the host (human or animal or plant or other type of vegetation) or to the pests themselves or to where they are located.

The new compound can be formulated for administration in any suitable form for use in veterinary or human medicine.

Agents containing the new compound can be present in the usual way together with one or more suitable carriers or excipients. They include those specifically formulated for parenteral (including intramammary), oral, rectal, topical or nasal administration. These agents can also be implants or administered into the eyes or into the genital urinary tract.

The compound of formula (I) can be formulated for veterinary or human medical purposes according to the general methods described in GB-PS 2 166 436.

The total daily dose of the compound which can be prepared according to the invention for both veterinary and human medicine purposes is generally in the range from 1 to 2,000 μg / kg of body weight, preferably in the range from 50 to 1,000 μg / kg. This dosage can be administered in divided doses, for example 1 to 4 times a day.

The compound obtainable according to the invention can be formulated in any suitable form for administration in forestry and horticulture. Agents containing the compound of the invention are adapted for use in horticulture or in agriculture. Such formulations are, for example, liquid or dry. These include, for example, dust bases or concentrates, powders, including soluble or wettable powders, granules, including microgranules and dispersible granules, pellets, flowable formulations, emulsions, such as dilute emulsions or emulsifiable concentrates, dips, such as Root dips and seed dips, seed dressings, seed pellets, oil concentrates, oil solutions, injections, for example injections into the stem, sprays, smoke and mist.

These formulations generally contain the compound together with a suitable carrier or diluent. Such carriers and diluents are described in GB-PS 2 166 436. -

In these formulations the concentration of active material is generally 0.01 to 99% and preferably 0.01 to 40% by weight.

Commercial products are generally provided as concentrates, which are diluted to a suitable concentration, for example 0.001 to 0.0001% by weight, before use.

The amount in which the compound is used depends on a variety of factors, including the type of pest to be controlled and the extent of the infestation. In general, the application amount is 10 g / ha to 10 kg / ha, preferably 10 g / ha to 1 kg / ha for the control of mites and insects and 50 g / ha to 10 kg / ha for the control of nematodes.

The antibiotic compound obtainable according to the invention can be administered or used together with other active ingredients. The new antibiotic compound can in particular be used together with antibiotic S541 compounds or with other antibiotic compounds. 3rd

AT 398 311 B

This is preferred, for example, if the connection is used in agriculture, because in this case low production costs are very important.

As mentioned several times above, the invention relates to a process for the preparation of the new compound of the formula I. The new process is characterized in that the 5/3-hydroxy compound of the formula 10 15 20 corresponding to the above-mentioned compound (I)

OH

(II) is subjected to oxidation.

The reaction can be carried out with an oxidizing agent which serves to convert an allylic secondary hydroxy group into an oxo group, whereby the compound of formula (I) is obtained. Suitable oxidizing agents are, for example, transition metal oxides such as manganese dioxide and atmospheric oxygen in the presence of a suitable catalyst, e.g. finely divided metal, such as platinum.

The oxidizing agent is generally used in excess, based on the stoichiometric amount. 30 The reaction is advantageously carried out in a suitable solvent. These include ketones, such as acetone; Ethers such as diethyl ether, dioxane or tetrahydrofuran; Hydrocarbons such as hexane; halogenated hydrocarbons such as chloroform or methylene chloride; or esters, such as ethyl acetate. Combinations of such solvents can also be used alone or together with water. 35 The reaction can be carried out at a temperature of -50 ° C to + 50 ° C, preferably at 0 ° to 30 ° C.

The intermediate compound of formula (II) can be prepared according to GB-PS 2 166'436.

The compound of the formula (I), which has been prepared from a compound of the formula (II) by the process described above, either in solution or as a crude solid, can be obtained in crystalline form by 40 customary processes. For example, crystals can be obtained from a solution of the compound by, for example, in a suitable solvent (for example an alcohol such as methanol or propan-2-ol; acetonitrile; a hydrocarbon such as hexane; or an ether such as diethyl ether, isopropyl ether or Petroleum ether) if desired together with water.

The following examples serve to illustrate the invention. All temperatures are in ° C. " I " 45 refers to liters.

The factor A is a compound of formula (II). Factor A can be produced according to GB-PS 2 166 436.

Example 50

Factor A (250 mg) is stirred in 30 ml of ether for 2.75 h together with active manganese dioxide (1.0 g). The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated to give the new compound in the form of a foam (240 mg). Part is crystallized from petroleum ether and microcrystals are obtained. kmax (EtOH): 240.5 nm (E 495); 55 δ values (CDCI3): 6.58 (s, 1H); 2.60 (m, 1H); 1.89 (s, 3H); 1.62 (s, 3H); 1.53 (s, 3H); 1.05 (d 6, 3H); 1.00 (d 6, 3H); 0.96 (d 6, 3H) and 0.80 (d 6, 3H) m / z among others: 610, 592, 574, 441.265, 247, 237, 219 and 151.

Formulations are described below. The expression " active ingredient " denotes 4 according to the invention

Connection made at AT 398 311 B.

Multiple dose parenteral injection

% W / v range active substance benzyl alcohol glyceryl triacetate propylene glycol 4.0 2.0 30.0 to 100.0 0.1 - 7.5% w / v

The active ingredient is dissolved in benzyl alcohol and glyceryl triacetate. Propylene glycol is added to the desired volume. The product is sterilized according to customary pharmaceutical methods, for example by sterile filtration or by heating in an autoclave. Then you pack aseptically.

Aerosol spray 20% w / w range active ingredient 0.1 0.01 - 2.0% w / w trichloroethane 29.9 trichlorofluoromethane 35.0 dichlorodifluoromethane 35.0

The active ingredient is mixed with trichloroethane and filled into the aerosol container. The headspace is flushed with the gaseous propellant and the valve is flared open. The required weight of the liquid propellant is filled in under pressure through the valve. It is equipped with an actuator and dust caps.

Tablet 35

Production process wet granulation T-mg active ingredient 250.0 magnesium stearate 4.5 corn starch 22.5 sodium starch glycolate 9.0 sodium lauryl sulfate 4.5 microcrystalline cellulose up to a tablet core weight of 450 mg

A sufficient amount of a 10% starch paste is added to the active ingredient in order to obtain a suitable wet mass for the granulation. Granules are made and dried using a tablet or fluid bed dryer. Sieve through a sieve, add the remaining ingredients and compress into tablets.

If necessary, the tablet cores are coated with a film coating using hydroxypropylmethyl cellulose or other film-forming materials, using either an aqueous or a non-aqueous solvent system. The solution used to prepare the film coating can contain a plasticizer and a suitable dye. 5

AT 398 311 B

Veterinary tablet for small animals or pets Manufacturing process dry granulation mg active ingredient 50.0 Magnesium stearate 7.5 microcrystalline cellulose up to a weight of the tablet core of 75.0

The active ingredient is mixed with magnesium stearate and microcrystalline cellulose. The mixture is compacted into blanks. The blanks are broken by passing them through a rotary granulator to obtain free-flowing granules. You compress to tablets.

If desired, the tablet cores can be provided with a film coating as described above.

Veterinary intramammary injection 20

mg / dose range active ingredient 150 mg 0.05-1.0 g polysorbate 3.0% w / w white beeswax 6.0% w / w to 3 g to 3 or 15 g peanut oil 91.0% w / w

Peanut oil, white beeswax and polysorbate 60 are heated to 160 ”with stirring. The mixture is kept at 30 160 ° C for 2 h and then allowed to cool to room temperature with stirring. The coolant is added aseptically

Carrier and dispersed using a high-speed mixer. One refines by passing through a colloid mill. The product is filled aseptically into sterile plastic syringes.

Veterinary oral potion

% W / v range active ingredient polysorbate 85 (polyoxyethylene sorbitan trioieate) benzyl alcohol propylene glycol phosphate buffer water 0.35 5.0 3.0 30.0 pH 6.0 - 6.5 to 100.0 0.01 - 2% w / v

The active ingredient is dissolved in polysorbate 85, benzyl alcohol and propylene glycol. A part of the water is added and, if necessary, the pH is adjusted to 6.0 to 6.5 with the phosphate buffer. Make up to the final volume with water. The product is placed in a potion container. 50 6 55

Claims (5)

AT 398 311 B Veterinary oral paste% w / w range active ingredient 7.5 1 - 30% w / w saccharin 25.0 polysorbate 85 (polyoxyethylene sorbitan trioleate) 3.0 aluminum distearate 5.0 fractionated coconut oil to 100.0 The aluminum distearate is dispersed in fractionated coconut oil and polysorbate 85 (polyoxyethylene sorbitan trioleate) with heating. The mixture is cooled to room temperature and the saccharin is dispersed in the oily carrier. The active ingredient is dispensed into the base. You fill in plastic syringes. Granules for veterinary administration together with the feed% w / w range active ingredient calcium sulfate, hemihydrate up to 2.5 100.0 0.05 - 5% w / w The active ingredient is mixed with calcium sulfate. Granules are produced according to a JSlass granulation process. Dry using a tray or a fluid bed dryer. You fill in suitable containers. Emulsifiable concentrate Active ingredient 50 g Anionic emulsifier (e.g. phenyl sulfonate CALX) 40 g non-ionic emulsifier (e.g. Syperonic NP13) (nonyphenol (13) ethoxylate) 60 g Aromatic solvent (e.g. Solvesso 100) to 1 l Mix all the ingredients and stir until mixed solved everything. Granules (a) Active ingredient tree resin Gypsum granules 0.75-0.25 mm (20 -60 mesh) to (e.g. Agsorb 100A) 50 g 40g 1 kg (b) Active ingredient non-ionic emulsifier (e.g. Syperonic NP T3) (nonylphenol (13 ) Ethoxylate) Gypsum granules (20-60 mesh) up to 50 g 40 g 1 kg Dissolve all active ingredients in a volatile solvent, e.g. methylene chloride, and add to the granules, which is in a drum mixer. Dry to remove the solvent . 1. Process for the preparation of the new compound of formula 7 AT 398 311 B. characterized in that the corresponding 5 / S-hydroxy compound of the formula 08 (II) oxidized. 2. The method according to claim 1, characterized in that the compound of formula (I) is obtained by recrystallization in crystalline form. 3. The method according to claim 1 or 2, characterized in that the compound of formula (I) is obtained by recrystallization in crystalline form with a purity of more than 90%. 4. Process for pest control in agriculture, horticulture, forestry, in camps, in buildings or in other public places or places where pests occur, characterized in that one on plants or other crops or on the pests themselves or apply an effective amount of the compound of formula (I) obtained according to any one of claims 1 to 3 at a place where they are found. 5. The method according to claim 4, characterized in that one uses the compound of formula (I) for controlling insects, mites or nematodes. S