DE1926522A1 - Fungicide compositions contng polyethylene glycol - Google Patents

Abstract

Compositions contng. cpds. (I) (X and Y are H, Cl or Br R = alkyl (1-12C), mixed with a support contng. at least 50% of one or more diesters of fatty acids (12-18C) with polyethylene glycol (mol. wt. 200-600). Antifungal agents; the use of these supports gives better activity than that of other supports (e.g. hydrocarbons) with the same active cpds. (I). For the protection of skin and leather goods, and of electrical insulating material, against fungi.

Description

Substituted Benzo (b) thiophene Preparations The invention relates to antifungal preparations containing a substituted benzo (b) thiophene compound contain.

The invention is directed to preparations which contain at least 50% by weight of a polyethylene glycol diester mixed with a substituted benzo (b) thiophene compound. In particular, the invention is concerned with antifungal preparations consisting of a substituted benzo (b) thiophene compound of the formula where X and Y are each independently hydrogen, bromine or chlorine and R is alkyl with 1 o 12 carbon atoms, in a mixture with a carrier, the carrier at least 50% by weight of one or more fatty acid diesters of polyethylene glycol, the fatty acid being 12 bia contains 18 carbon atoms and the polyethylene glycol has a molecular weight of 200-600. The antimicrobial active ingredients of the preparation according to the invention are therefore substituted benzo (b) thiophene-2-carboxylic acids with alkynols with 1-12 carbon atoms and include methyl and ethyl -, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl esters.

The preparations according to the invention have a remarkable one Effectiveness in combating fungal organisms. The preparations penetrate quickly in various substrates, with the active substituted benzo (b) thiophene compound is quickly released from the wearer. The preparations according to the invention make it possible a better control of Pilsorganisms than those preparations, which substituted Benzo (b) thiophene compounds and other carriers, such as hydrocarbon oil carriers, solid hydrocarbon carriers, polyethylene glycol carriers, alcohol carriers or aqueous ones Carrier, included.

The physical properties of the preparation according to the invention can be varied to get either liquids or solids, by choosing appropriate diesters of corresponding polyethylene glycols.

Particularly preferred preparations are those in which the polyethylene glycol used an average molecular weight of about 400 (polyethylene glycol 400) and the fatty acid stearic acid or lauric acid is. By using varying amounts of polyethylene glycol 400 distearate and Polyethylene glycol 400 dilaurate can be used in both solid and liquid formulations getting produced. Preferably the support is essentially anhydrous.

The preparations can also be formulated in such a way that ice Containing varying amounts of other carriers, these being other Carriers are modifying substances that are also essentially anhydrous are. Such modifying substances can change the consistency, the melting point, the viscosity and other properties of the preparations be used. Representative examples of modifying substances used in can advantageously be used in the preparations according to the invention, are hydrocarbon oils and waxes, for example solid and liquid paraffin or solid and liquid petrolatum. There are also naturally occurring oily ones and waxy modifying substances, such as beeswax, vegetable oils or carriers of animal origin, such as lanolin. Further Synthetic modifying substances can be used, for example fatty acid esters polyhydric alcohols, fatty acid esters of polyethylene glycols with a molecular weight from 400-4000 or fatty acid esters to other polyalkylene glycol, for example alkylated Polyethylene glycols or polypropylene glycols.

The preparations can by mixing the carrier materials with one or more of the active substituted benzo (b) thiophene compounds be phrased in any order or manner "Is it one of the If the carrier components are a solid, then it is advisable to use the solid carrier material Heat to its melting point and remove the constituents before adding the substituted ones Mix benzo (b) thiophene compound. The substituted benzo (b) thiophene compound can be mixed with the heated carrier by conventional methods. Optionally can the mixture of molten and fitissigen carrier materials is cooled down for as long until the mixture has solidified, whereupon the active substituted benzo (b) thiophene compound is mixed with the solid material by customary methods, in this case should the active substituted benzo (b) thiophene compounds intimately mixed with the carrier will.

The amount of active substituted benzo (b) thiophene compound, which is constricted in the carrier varies depending on a number of factors, for example, depending on the ingredients used to formulate the respective Preparations are used, the substituted benzo (b) thiophene compound used in each case or the respective mixture of these compounds, the organisms to be controlled, the substrates to be treated with the preparation, the extent of the fungal disease Substrates or the like. It is also important whether the preparation is direct is used or used in the form of a concentrate which is to be prepared prior to use is diluted. Excellent results are obtained using preparations obtained, based on 0.05-10% of the substituted benzo (b) thiophene compound based on the weight of the finished treatment preparation.

Concentrate preparations can contain 5 - 95% by weight of the substituted Benzo (b) thiophene compound contain. As the carrier is at least 50% of the polyethylene glycol diester carrier material contains, a particularly preferred concentrate preparation contains one @ da @ several the substituted benzo (b) thiophene compounds mixed with a carrier 100% diesters of polyethylene glycols with a molecular weight of 200 - 600 with fatty acids with 12-18 carbon atoms. Such preparations can then by mixing with others Amounts of the polyethylene glycol diester carrier material or diluted by mixing with other modifying materials.

The preparations according to the invention can be used in many ways can be used to control fungi. Solid preparations are particularly suitable for use in packaging; or coating devices or in electrical Systems that contain, for example, electrically insulating materials that are susceptible to fungal attack are included. The preparations can also be used as disinfectants can be used to combat fungal attack on various substrates.

The preparations are particularly suitable for being effective against fungi Agents on substrates made from animal skin or skin products. Further they can be used to disinfect and protect leather products against a Fungal attack are used.

Those compounds whose alkyl group contains 1-4 carbon atoms can be conveniently obtained by cyclizing an alkyl-substituted 2- (carboalkoxymethylthio) benzoate of the formula in which d and Y have the meanings given above and R is alkyl having 1-4 carbon atoms. The diesters corresponding to the formula II can be prepared by reacting the correspondingly substituted 2- (carboxymethylthio) benzoic acid with an alcohol of the formula ROH in the presence of an acid such as, for example, sulfuric acid or hydrochloric acid. benzoic acid with thionyl chloride and esterification of the product with an alcohol of the formula ROH. The resulting es are then treated with a sodium alkylate of the formula RONa in order to bring about internal condensation and cyclization and formation of the desired alkylbenzo (b) thiophene-2-carboxylate compound. The treatment of the ester with the sodium alkoxide is preferably carried out in an alcohol of the formula ROH as the reaction medium, refluxing at the boiling point of the reaction mixture.

The product can be removed from the reaction mixture by diluting the mixture with an aqueous mineral acid, such as sulfuric acid, with precipitation the alkylbenzo (b) thiophene-2-carboxylate are separated off. The product can then can be obtained by customary methods, for example by piltration or centrifugation. It is then cleaned by customary methods, for example by washing and recrystallization.

The substituted 2- (carboxymethylthio) benzoic acid can be converted into Conveniently from a substituted anthranilic acid by diazotization of the Produce anthranilic acid with nitrous acid, sodium nitrite or potassium nitrite. The diazonium salt obtained is then treated with Kaliwurnethylxnthat, whereupon a basic hydrolysis and the reaction with sodium chloroacetate for Subsequent recovery of the substituted 2- (carboxymethylthio) -benzoic acid.

The substituted 2- (carboxymethylthio) -benzoic acids can after customary methods are separated, for example by extraction or decanting.

The compounds of the formula I according to the invention, in which the alkyl group R contains 4 - 12 carbon atoms, can conveniently by transesterification the compounds are prepared in which R is methyl, namely under Use of an alcohol of the formula R'OH, where Rt contains 4 to 12 carbon atoms. The transesterification takes place when the methyl-substituted benzo (b) thiophene-2-carboxylate is mixed with the alcohol, in an expedient manner an excess Amount of alcohol is used as the reaction medium.

The transesterification is carried out in two ways at the boiling point Reaction mixture carried out. The product can be removed from the reaction medium according to conventional methods Methods can be separated, for example by using fractional distillation reduced pressure or by chromatography.

The following examples illustrate the invention.

Example 1 10 parts of polyethylene glycol 200 distearate, 10 eUe polyethylene glycol 400 dilaurate, 100 parts of polyethylene glycol 400 dipalmitate and 10 parts of polyethylene glycol 600 dimyristate, all parts refer to the weight, are in a clean, dry and given a sterile vessel. The mixture is heated to about 100 ° C and below Stirring held at this temperature for about 1 hour. Then the Mixture cooled to about 40 ° C with stirring. 12 parts by weight of methyl 5-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate and 3 parts by weight 4,6-dibromo-3-hydroxybenzo (b) thiophene-2-carboxylate are thoroughly mixed with the preparation for the production of a consume preparation. 10 parts by weight a white petrolatum, 10 parts by weight of lanolin and 5 parts by weight of reeswax are intimately mixed with 70 parts by weight of Polyäthy lenglykol-400-dioleate @, before the mixture @@@ the Concentrate preparation for the production of a Treatment preparation is ground. This treatment preparation contains 10% by weight the active substituted benzo (b) thiophene compounds. The preparation becomes the Treatment of leather and rawhide objects in order to make these objects opposite one Used to protect fungus infestation.

Example 2 1 part by weight of propyl 3-hydroxybenzo (b) thiophene-2-carboxylate, 1 part by weight of pentyl 5,7-dichloro-3-hydroxybenzo (b) thiophene-2-carboxylate and 1 part by weight Heptyl 6-chloro-3-hydroxybenzo- (b) thiophene-2-carboxylate are 45 parts by weight Polyethylene glycol 400 distearate and 35 parts by weight of polyethylene glycol 600 dipalmitate mixed. Ble obtained preparation is used on surfaces to prevent one Fungal attack applied.

Example 3 A solid preparation is produced in such a way that a purified mixture of semi-solid hydrocarbons with a melting point of 38 - 54 ° C (white petrolatum U.S.P.) in a clean, dry and sterile container is introduced, whereupon the mixture is heated until it melts. There will be a such amount of polyethylene glycol 400 dilaurate with the melted petrolatum mixed, which is sufficient to provide a carrier, which from 52 parts by weight of polyethylene glycol 400 dilaurate and 45 parts by weight of petrolatum consists. 3 parts by weight of methyl 6-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate then added to the mixture, whereupon the mixture until a uniform The consistency is ground. The preparation is based on cellulose materials such as Paper, Cardboard or wooden objects, applied to these objects to protect against attack by fungal organisms.

Example 4 10 parts by weight of a liquid petrolatum (U.S.P.), 10 parts by weight of a white petrolatum (U.S.P.), 12 parts by weight of Glycowax A-921 (registered trademark for an ester of a polyhydric alcohol and of a fatty acid), 10 parts by weight of polyethylene glycol 400 distearate and 58 parts by weight Polyethylene glycol 400 dilaurate is placed in a clean, dry and sterile container given. The mixture is heated to approximately 125 ° C and with occasional stirring held at this temperature for a period of about 2 hours.

The mixture is cooled to approximately 40-45 ° C. while stirring.

A solid, water-miscible preparation is obtained. 1 g of methyl 5-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate is thoroughly mixed with 99 g of the preparation mixed. 100 g of a preparation that is effective against fungi are used obtained the 1% by weight of the active substituted benzo (b) thiophene compound contains. The carrier of this preparation consequently contains 68% by weight of diesters of polyethylene glycol 400 with fatty acids with 12-18 carbon atoms.

Several separate nutrient agar preparations are made with a test organism inoculates. In this way various suspensions of viable test organisms become made in a nutrient agar. Each agricultural preparation is then placed in a Petri dish sucked in and allowed to solidify. Then holes are made with an even Largest in the agar in each Plate drilled whereupon the holes be filled with the preparation according to Example 4. There are su comparison purposes Plates inoculated with each test organism prepared in a similar manner, whereupon holes are drilled, which are filled with the carrier according to Example 4. The carrier used to produce these comparison plates does not contain any substituted Benzo (b) thiophene compound. The plates are then incubated for 5 days, what they are examined for. This is the inhibition of the growth of the test organism observed in the nutrient agar surrounding the holes. The observations show that in the case of the comparison Petri dishes, no inhibition of the growth of epidermophyton floccosum, Microsporum aduoini, Microsporum canis, Microsporum gypseum, Trichophyton metangrophytes, Trichophyton rubum, Trichophyton schoenleini and Trichophyton tonsurans he follows. In all of these Petri dishes in which the carrier according to Example 4 is used as such, it is found that the microorganisms in more evenly Grow wisely through the agar surface. With the Petri dishes, in which the preparation according to Example 4 is used, which contains 1% methyl 5-chloro-3-hydroxy-benzo (b) thiophene-2-carboxylate contains, it is found that each of the test organisms is noticeable in its growth is inhibited. This can be seen from the presence of an agar zone in which none Test organisms grow. This zone surrounds the drilled holes which are connected to the Preparation according to Example 4 are filled.

Example 6 Following the method described in Example 4, various separate preparations made. Each of these preparations consists of one the substituted benzo (b) thiophene compounds in an amount of 0.1, 0.5 or 1.0% by weight, based on the entire preparation. The carrier each preparation consists of an intimate mixture of 10 parts by weight a liquid petrolatum (U.S.P.), 10 parts by weight of a white petrolatum (U.S.P.), 12 parts by weight Glycowax S-932, 10 parts by weight polyethylene glycol 400 distearate and 58 parts by weight of polyethylene glycol 400 dilaurate. Any of the preparations will Grind until a uniform consistency is achieved. That way will get a number of separate preparations, each preparation one against Mushrooms contains effective amount of the active substituted benzo (b) thiophene compound. The preparations are used as coatings for materials as well as for packaging materials used that are exposed to a fungal attack. In this way, different Treat substrates to combat fungal organisms. In addition, there is a fight of fungal organisms on animal skins and animal skin products possible.

Example 7 the ability of the preparations according to the invention to remove fungal organisms Combat on animal skin substrates is based on the test method described below out: Shaved buttocks of white guinea pigs are standardized with a Spore suspension of Tricophyton mentagrophytes inoculated by rubbing of the suspension over a circular area with a diameter of approximately @ .5 cm, applying enough pressure to gently scratch the skin. The guinea pigs are divided into test groups. Starting with the day that adjoins the inoculation, separate preparations are made according to the example 6 separately on the inoculated skin area of each guinea pig in the test group upset. The application of the separate preparations according to Example 6 to the inoculated skin areas the guinea pig in the separated Groups is continued daily for another 5 days until a total of 6 applications every pimped-on skin area is done. Similar vaccinations for Trichophyton mentagrophytes are applied to the skin surfaces of a separate group of guinea pigs applied for comparison purposes. In this case, however, there is no preparation given on the infected area. In the comparison group of guinea pigs There was a clear reddening 2 - 3 days after the inoculation, whereby this Redness increased by the 5th day. In addition, there was slight exfoliation of the skin on. On the 6th day the continued presence of the fungal organism is evident detect a bloody serous wound, which wound has increased in size.

In addition, increased sloughing with crust formation was found. The crust formation progressed and reached one on the 12th day after inoculation Maximum, from which it can be seen that fungal organisms are still present.

The fight against the fungal organisms results from the fact that on the inoculated skin surface there is no reddening, no sagging or crust formation can be determined and during the 6 days during which the preparation is applied as well as during the following period of up to 12 days after vaccination no wound arises. A lack of control of fungal organisms in animal skin substrates can be recognized by the development of bloody serous wounds.

These wounds have the same appearance as the wounds that appear on of the control group of animals, with the time of occurrence of wounds is the same The results, expressed as% control of fungal organisms, which are determined using each preparation, as well as the concentration the substituted benzo (b) thiophene compound in any formulation for each of the test compounds from Table 1. In the Table t denotes X, Y and R the substituents of the formula I.

Table 1 X Y R Concentration% Control of fungal (%) organisms H H Nethyl 0w5 100 H H Ethyl 0.5 100 H H n-Butyl 0.5 100 H H Hexyl 0.5 100 H H Octyl 0.5 100 H H decyl 0.1 67 EI H dodecyl 0.1 60 5-Cl H methyl 0.1 100 6-Cl H methyl 0.1 100 7-Cl H methyl 0.5 100 5-Cl H ethyl 0.5 100 6-Cl H ethyl 1.0 100 5-Cl H butyl 1.0 67 6-al H Butyl 0.1 67 Example 8 The procedure described in Example 7 is repeated using representative preparations according to Example 6 will. The only change is that the areas of skin that come with the Fungal organisms are inoculated for a period of 4 days thereafter can be left untreated at the first inoculation. On the 4th day after vaccination the application of the preparations is started, the applications being carried out daily be carried out over a period of 7 days. Each of the Preparations 1% by weight of a substituted benzo (b) thiophene compound.

The percentage of control of the fungal organisms goes from the following Table II, for each compound that is represented by the substituents X, Y and R according to formula 1 is identified.

Table II X Y R% Control H H Hexyl 100 H H Octyl 100 H H Decyl 100 5-chloro H methyl 100 5-chloro H butyl 100 6-chloro H butyl 100 Example 9 3 separate Preparations of methyl 5-chloro-3-hydroxybenzo (b) -thiophene-2-carboxylate in one Amounts of 1% by weight are produced. The first preparation A consists of the substituted benzo (b) thiophene compound in a carrier of 10 parts by weight a liquid petrolatum (U.S.P.), 10 parts by weight of a white petrolatum (U.S.P.), 12 parts by weight Glycowax S-932, 10 parts by weight polyethylene glycol 400 distearate and 58 parts by weight of polyethylene glycol 400 dilaurate. The second preparation B consists from 1% of the substituted benzo (b) thiophene compound in polyethylene glycol 400, while the third preparation C consists of 1% of the substituted benzo (b) thiophene compound composed in white petrolatum. Each of these preparations is made according to the in Example 8 described method tested for their control of fungal organisms. The first preparation gives a 100% fight against fungal organisms while no control effect when using the second preparation B and the third Preparation Q is detected. No effect on a Control of fungal organisms is determined when the carrier of preparation A is used as such, i.e. without a substituted benzo (b) thiophene compound.

Example 10 A liquid preparation is made by intimate mixing of 3 parts by weight of methyl 5-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate, 3 parts by weight Methyl 4-bromo-3-hydroxybenzo (b) thiophene-2-carboxylate, 2 parts by weight of ethyl 5-chloro-7-bromo-3-hydroxybenzo (b) thiophene-2-carboxylate and 125 parts by weight of polyethylene glycol 400 dilaurate. The liquid one Preparation is carried out by customary methods, for example by pouring on or the like, applied to various materials in order to protect them against fungal attack protection.

Claims (11)

Claims 1. Preparation effective against fungi, characterized in that it contains a substituted benzo (b) thiophene compound of the formula in which X and f each independently represent hydrogen, bromine or chlorine and R denotes alkyl with 1-12 carbon atoms, mixed with a carrier which contains at least 50% by weight of one or more fatty acid diesters of polyethylene glycol, the fatty acid being 12-18 Contains carbon atoms and the polyethylene glycol has a molecular weight of 200 - 600. 2, preparation according to claim 1, characterized in that the substituted Benzo (b) thiophene compound in an amount of 0.05-10% by weight, based on that the weight of the entire preparation is present. 3. Preparation according to claim 1, characterized in that the carrier is essentially anhydrous. 4. Preparation according to claim 3, characterized in that it also at least 10 'of a substantially anhydrous modifying vehicle contains. 5. Preparation according to claim 1, characterized in that the carrier consists of polyethylene glycol 400 distearate or polyethylene glycol 400 dilaurate. 6. Preparation Moh claim 1, characterized in that the substituted Benzo (b) thiophene compound is an alkyl 3-hydroxybenzo (b) thiophene-2-carboxylate. 7. Preparation according to claim 1, characterized in that the substituted Benzo (b) thiophene compound an Alkg1-5-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate is. 8. Preparation according to claim 1, characterized in that the substituted Benzo (b) thiophene compound an alkyl 6-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate is. 9. Preparation according to claim 1, characterized in that the compound consists of a methyl 3-hydroxyhalobenzo (b) thiophene-2-carboxylate. 10. Preparation according to claim 1, characterized in that the substituted benzo (b) thiophene compound from methyl 5-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate consists. 11. Preparation according to claim 1, characterized in that the substituted bensob) thiophene compound from methyl 6-chloro-3-hydroxybenzo (b) thiophene-2-carboxylate consists.