NO119636B - - Google Patents

Description

Antibacterial, fungicidal and/or insecticidal compounds.

The present invention relates to new antibacterial, fungicidal and/or insecticidal active compounds with the general formula

where Ar means one of the groups Ia, Ib or Ic

where Y means an oxygen or sulfur atom,

R a halogen atom or (in compounds with the groups Ib or Ic) also a hydrogen atom,

X a halogen atom,

p a number from 1-5 (since in the case that p = 1, Y = oxygen and R = iodine, the nitrogen substituent in group Ib occupies the ortho or meta position), or a number from 2-5 in the case that Y = oxygen and

R = hydrogen and Ar means the group Ib,

m and n each mean a number from 1-4 (since the sum of

m and n form hbyst 5),

as well as the use of compounds of formula I as antibacterial, fungicidal and/or insecticidal agent.

These antibacterial, fungicidal and/or insecticidal propynyl ethers can be prepared by a process in which a compound of the general formula is reacted

where Ar and Y have the above meaning,

with a 3-halopropyne-(1) and optionally halogenates the resulting compound with the general formula

where Ar and Y have the above meaning,

or that one reacts a compound of the general formula II with a 1,3-dihalopropyne-(1).

The propynyl ethers obtainable in this way belong to a class of compounds described in Japanese Patent Application No. 19,791/64. In this explanatory document, however, not a single one of the compounds that can be produced according to the invention is shown by way of example. The present invention leads to new propargyl ethers or propargyl thioethers, in which the propynyl residue is connected via the oxygen or sulfur bridge,

each time with a characteristic aryl residue which is not to be joined from the state of the art.

The new propynyl ethers encompassed by the present selection invention are distinguished, as is shown in more detail below, by outstanding antimicrobial properties. 1-(2,3-dichlorophenoxy)-3-iodo-propynet-(2) is capable of e.g. in vitro to inhibit growth e.g. of Escherichia coli already at a concentration of 6 mcg/ml or the growth of Trichophyton mentagrophytes at a concentration of 1 mcg/ml, while of 1-(2,4,5-trichlorophenoxy)-3-iodopropine-(2), a characteristic representative of the compounds described in the Japanese specification, 5000 and 1000 mcg/ml are required to achieve the same effect.

A first compound group forms the compounds with the general formula

where X and Y have the meaning stated above.

As halogen substituents in the phenyl nucleus, chlorine, bromine, iodine or fluorine, preferably chlorine or bromine, come into consideration. The two halogen substituents in the phenyl ring can be the same or different. The halogen substituent at the acetylenic carbon atom is preferably iodine or bromine. This halogen substituent can be of the same or different type as the halogens found in the phenyl nucleus. Examples of compounds of formula IV are:

1-(2',3'-dichlorophenoxy)-3-iodopropyne-(2) 1-(2',31-dibromophenoxy)-3-iodopropyne-(2) 1 - ( 21 ,3'-dichlorophenoxy ) - 3 -bro.mpropyne-(2 ) 1-(2'-chloro-3'-bromophenoxy)-3-bromopropyne - ( 2) 1-(2',3'-dichlorophenylthio)-3-iodopropyne-(2).

Preferred compounds of formula IV are those with Y = oxygen.

The compounds of formula IV are antibacterially and fungicidally active. They can e.g. used as a disinfectant or as an agent for antimicrobial equipment ("Sanitizers"). The compounds of formula IV exhibit a strong inhibitory effect against a majority of bacteria and fungi. In particular, 1-(2',3<1->dichlorophenoxy)-3-iodopropine-(2) shows an exceptionally broad antibacterial spectrum of high intensity against gram-positive and gram-negative bacteria, e.g. against Strepto-coccus pyogenes 4, Diplococcus pneumoniae 6301, Staphylococcus

.aureus 209, Escherichia coli J and Salmonella typhosa.

'In addition to the extraordinary activity of gram-positive

• and gram-negative bacteria in this connection show an inhibitory effect against a number of fungi such as Candida albicans, Trychop-ihyton mentagrophytes, Microsporum audouini and Aspergilli.

Of particular importance is the unexpectedly high activity against Aspergillus niger, Aspergillus flavus and Aspergillus oryzae. In the case of the mentioned fungi, 1-(2',3'-dichlorophenoxy)-3-iodopropinet-^) in a modified Czapek medium causes a 100% growth inhibition in concentrations of less than 5-10 -4 <%> . This activity makes the compound particularly suitable as an additive for prevention against rust stains or soil impact on fiber materials, leather, textiles, wood or paper. For this purpose, the connection can e.g. used as an additive to colours, where in concentrations of 1% or less they were found to have a completely inhibitory effect on the mentioned fungi. The compound is added in various concentrations to a polyvinyl acetate latex paint and a linseed oil exterior paint. The colors are applied on both sides of filter paper sheets and air-dried for 48 hours. Square-inch pieces of the described paper are added to a modified Czapek medium in Petri dishes, inoculated with a spore suspension of Aspergillus cryzae and grown for 7 days at 28-30°. The following results were obtained:

Square inch pieces of vegetable tanned leather are dipped in alcoholic solutions of 1-(2',3<1->dichlorophenoxy)-3-iodopropine-(2) and air dried. The treated pieces are placed on modified Czapek medium, inoculated with a spore suspension of Aspergillus niger and cultivated for 7 days at 28 - 30°. The following results were obtained:

The compounds of formula IV can be used as • antibacterial and fungicidal agents in preparations, which contain the aforementioned compounds in admixture with a suitable organic or inorganic carrier. They can e.g. used as a contact disinfectant or as an agent for antimicrobial equipment or used locally on the relevant sites.

The preparations can e.g. in the form of powders or sprays or in liquid form, e.g. as solutions, suspensions or emulsions. If desired, they can contain auxiliary substances such as preservatives, stabilisers, wetting agents

or emulsifiers.

^The compounds of formula IV can be obtained in the following way:

One converts a compound with the general formula in a manner known per se

in

In where X and Y have the above meaning,

with a 3-halopropyne-(1), in particular with 3-bromopropyne-(1)

(propargyl bromide), preferably in the presence of an acid-binding agent, such as an inorganic base (eg an alkali hydroxide, alkali carbonate, such as potassium carbonate or an alkali bicarbonate).

The halogenation of the obtained compound with the general

formula

where X and Y have the above meaning,

for obtaining a compound with the general formula IV can take place according to methods known per se, e.g. by treating the compound of formula IVa with a halogenating agent in the presence of a strong base (such as sodium hydroxide).

In the case of iodination, one can also first form the copper salt, e.g. by treatment with a solution of a copper-ammonia complex, and then treating the copper salt obtained with a mixture of potassium iodide and iodine. The reaction conveniently takes place in an organic solvent, such as alcohol or acetone, at temperatures between approx. 0 and approx. 30°C. The obtained propynyl ether of formula IV can be isolated in the usual way, e.g. by filtration, evaporation of the solvent etc..

The compounds of formula IV can also be obtained directly from the compounds of formula IIa, reacting these with a 1,3-dihalopropyne-(1), preferably in an organic solvent and in the presence of an acid-binding agent, such as one of the aforementioned bases . Although the reaction temperature is not critical, the reaction is preferably allowed to proceed under reflux.

Another group of compounds is formed from the compounds of formula V:

where Y, R and p have the above meaning.

within this group are compounds with p = 1 or 2,

;Y = oxygen and R = halogen (in particular bromine or iodine) in preferred. The 2,4-dinitro derivative is distinguished by special fungicidal action, in particular against T. mentagrophytes and

M. audouini.

The compounds of formula V can be obtained in the following way:

A compound with formula

'; where Y and p have the above meaning,

• is reacted with a 3-halopropyne-(1) (propargyl halide), preferably with 3-bromopropyne-(1) (propargyl bromide), in the presence of an acid-binding agent, as already described above. As acid-binding agents, e.g. the following bases in consideration: sodium hydroxide, sodium methylate, alkali metal salts, such as sodium carbonate, potassium carbonate, sodium bicarbonate, etc. The reaction preferably takes place in a solvent, suitably in a polar solvent, such as e.g. in yann, in ketones, (such as acetone), alkanols (e.g. lower alkanols, such as methanol, ethanol), lower alkylnitriles (such as acetonitrile), etc. For the preparation of dinitro compounds, it is advantageous to use a bicarbonate as an acid-binding agent in a strongly polar solvent, such as acetonitrile or a lower alkanol. The reaction temperature is not

critical. However, it is recommended to carry out the turnover at an elevated temperature, e.g. at reflux temperature. However, the turnover is also successful at lower temperatures, e.g. at room temperature or below. The reaction can be started by mixing the reaction components. It is usually finished after 5 to 15 hours. After the reaction has ended, the reaction mixture is cooled for . precipitation of inorganic salts. These salts are filtered off, after which, after distillation of the filtrate, the reaction product with formula is obtained

where Y and p have the above meaning. The halogenation of compounds of formula Va to obtain compounds of formula

can be carried out according to the usual methods for halogenating acetylenic compounds, e.g. by reaction with a hypohalogenite (such as hypoiodite). The reaction is preferably carried out in a solvent, such as e.g. in water or in an ether (such as dioxane or tetrahydrofuran). Hypohalogenity can e.g. is added to the propynyl ether solution. Hypohalogenity can also form in situ, e.g. by adding a halogen and a base, such as caustic soda. The iodination can be carried out via the copper salt, as already described above.

The compounds of formula Vb can also be obtained directly from the compounds of formula Ilb, reacting these with a 1,3-dihalopropyne-(1), as described above.

The compounds of formula V are distinguished by their toxicity towards algae, yeasts and, in particular, molds. The compounds are particularly suitable for industrial purposes. For that, above all, the compounds with a terminal iodine atom have proven to be effective. They can e.g. used as an additive for plastics, colors or cosmetic emulsions and in the treatment of leather, wood, paper or textiles to prevent damage caused by the impact of molds on these materials or on surfaces protected by such materials. In this way, the compounds are invariably highly active at low concentrations and do not show any undesirable properties in the systems thus treated. For use, the ■compounds can simply be added to the systems to be ■protected, or mixed with some common carrier, e.g. dissolves in alcohol or acetone.

The effect of these compounds in the treatment of textiles can be seen from the test results, which are compiled in table V. The experiments are carried out by dipping square-inch-sized pieces of cotton wool in variously concentrated alcoholic solutions of the test compounds, air drying and inoculation in Petri dishes with Aspergillus niger or Chaetomium globosum. For comparison purposes, textile samples were treated with a

■ standard textile fungus, (2,2'-methylene-bis-(4-chlorophenol). After 17 days of cultivation, the materials were tested visually and numerically assessed in the following way:

1. ) No growth on the test

2. ) Traces of growth on the test

3. ) Weak growth on the test

4. ) Moderate growth on the test

5. ) Strong growth on the test

{A) Inhibition zone up to 20 mm around the sample

(B) Inhibition zone larger than 20 mm around the sample

(C) Complete inhibition of the entire disc.

The following described trials demonstrate the qualification of

compounds of formula V for the prevention of damage to leather when attacked by microorganisms.

Square-inch pieces of vegetable-tanned leather are dipped

in various concentrated alcoholic solutions of test compounds and air-dried. For comparison, leather samples were treated in the same way with p-nitrophenol, a standard leather preservative. The samples were inoculated before and after the following treatments in Petri dishes with Aspergillus niger:

a. ) 24 hour storage in a circulating air oven at 60°.

b. ) 24 hour immersion in 100 ml cold tap water with

four times water change.

c. ) 13 days of external storage in an unprotected place.

The results are listed in Table VI.

The qualification of compounds of formula V for processing with plastics to prevent damage caused by microorganism attack is obtained from the following sample:

Plastic films are prepared from solutions of vinyl chloride acetate resin, a suitable plasticizer and various amounts of compounds of formula V. The finished films are inoculated in small squares in Petri dishes with Aspergillus flavus on mineral salt agar. The test results are reproduced in table VII: Further use of the compounds of formula V lies in the prevention of microbially caused damage to oil paint and water color films. Additions of 0.2 - 2 weeks. t-% of the compounds of an oil or water color, such as e.g. applied to wood,' ensures, under difficult temperature and humidity conditions, an excellent control over the formation of dirt and rust stains. These additives neither adversely affect the color's storage capacity nor change the color value and remain effective for a long time. Table VIII illustrates the qualification of the compounds of formula V as additives against microbial attack by Pullularia pullulans, Aspergillus cryzae and Aspergillus niger. The compounds are incorporated by hand in a white latex color; the color is brushed on both sides of filter paper and air dried. The qualification of the compounds of formula V as an additive to cosmetic emulsions shows the results from the samples described below. When using cosmetic creams which are made from non-ionic surfactants and which contain compounds of formula V or p-hydroxybenzoic acid methyl ester in different concentrations, these are inoculated with Aspergillus niger and incubated for 21 days. Samples were inoculated again 7 and 14 days after the incubation period. The results are summarized in Table IX:

The compounds of formula V are particularly noteworthy fungicidal agents, as they are able to protect oil-water or two-phase systems and are inactive against most conventional microbicide agents in these systems. A significant feature of these compounds is their action in the presence of nonionic surfactants, which other fungicides do not exhibit. Due to their fungicidal action in small quantities and the almost complete lack of disadvantageous effects, the compounds are particularly valuable for the industrial application. They are inert to oils and pigments in colors and therefore cause no color change or shortening of shelf life. The necessary small quantities have no influence on other properties such as ironing and sprayability. The compounds are likewise inert to ingredients in conventional cosmetic preparations and can therefore find a wider application in this area.

A third compound group is formed by compounds with the general formula

where X, Y, R, m and n have the above meaning.

X preferably stands for chlorine,

R for hydrogen or iodine.

The compounds of formula VI are antibacterial/fungicidal and insecticidally active. Compounds, where R is hydrogen, are particularly good insecticidal agents in insecticidal preparations, which also contain carbamate insecticides, such as 1-naphthyl-N-methylcarbamate. Compounds with R = halogen are worth mentioning

due to their antibacterial/fungicidal properties. They are used as additives to materials such as dyes, leather, textiles and other fibrous substances, in order to inhibit the growth of fungi such as Aspergillus niger or of bacteria such as Staphylococcus aureus. Compounds of formula VI, where Y is oxygen and m and n in each case 1, are a preferred group. 1-(2-nitro-4-chlorophenox 3-iodopropinet-(2)) is particularly excellent through its inhibition-<: >effect on the growth of Aspergillus niger, P. citrinum, Staphylococcus aureus and the algae Chlorella vulgaris and v.

yiridis.

The compounds of formula VI can be used in the form of conventional insecticidal preparations.

The compounds of formula VI can be obtained in and of themselves

known, already for the preparation of compounds with the formulas IV and V above mentioned methods. Thus, one can e.g. react a compound with the general formula

where X, Y, m and n have the above meaning, with a 3-halopropyne-(1), in particular 3-bromopropyne-(1), to a compound of the general formula

where X, Y, m and n have the above meaning,

and transfers this, if desired, by halogenation of the acetylenic carbon in the terminal position to a compound of the general formula

where X, Y, m and n have the above meaning,

since the halogenation can optionally be carried out according to the already mentioned, per se known methods for halogenating acetylenic compounds.

The compounds of formula VIb can also be directly obtained from the compounds of formula lic by reaction with a 1,3-dihalopropyne-(1), as already described above in connection with the preparation of compounds of formulas IV and Vb.

The starting substances used are phenols and thiophenols

with the general formulas Ila, Ilb and lic can, as long as they are not known, be prepared according to methods known per se.

In the following examples, the temperatures are given in degrees Celsius. The melting points are uncorrected.

EXAMPLE 1

A mixture of 200 g of 2,3-dichlorophenol, 160 g of 3-bromopropyne-(1),

186 g of anhydrous potassium carbonate and 1 liter of acetone are heated

8 hours during transport during return. After disconnection

the reaction mixture is filtered and washed with acetone. The filtrate is then evaporated in vacuo at 60°, and the residue is dissolved in 700 ml of ethanol. The crystals that stand out on ice cooling are filtered off, washed with water and dried over CaC^. One obtains 1-(2',3'-dichlorophenoxy)-propyne-(2), melting point 47 -

To a strongly stirred solution of 28.8 g of 1-(2',3'-dichlorophenoxy)-propyne-(2) in 300 ml of methanol, 48 g are added at the same time

iodine and 180 ml of 1Q&'ig caustic soda in small portions over the course of 15 minutes, whereby the reaction temperature is maintained at 20 - 25° by means of an ice water bath. After another 30 minutes of stirring, it is filtered. The precipitate is washed with water and dried

over CaC^. One obtains 1-(2 1 ,3 '-dichlorophenoxy )-3-iodopropyne-( 2 ), melting point 58 - 59°.

EXAMPLE 2

At 5°, 6.4 g of bromine and then 4 g of 1-(2',3'-dichlorophenoxy)-propyne-(2) dissolved in 30 ml of dioxane are added to 50 ml of 10% caustic soda. The reaction mixture is stirred for 45 minutes at 5 - 10° and then evaporated at 60° in vacuum. The residue is suspended in 10 ml of water, filtered, washed with water and dried. The crude product is recrystallized from 50 ml of petroleum ether (30 - 60°)•.

One obtains 1-(2',3'-dichloroethoxy)-3-bromopropyne-(2),

melting point 68 - 69°.

EXAMPLE 3

A mixture of 93 g of 2,4-dinitrophenol, 65.5 g of 3-bromopropyne-(1), 44 g of sodium hydroxide and 700 ml of water is heated on the steam bath for 24 hours with stirring and then acidified with dilute (1:1) hydrochloric acid. After cooling, it is filtered, and the precipitate is washed with water. 102 g of crude product is obtained which melts at 75 -

82°. The crude product is suspended in 350 ml of ethyl acetate, and the suspension is washed with 2% caustic soda and water. After working up the organic solution, 1-(2',4'-dinitrophenoxy)-propyne-(2) is obtained, which after recrystallization from ethanol melts at 98 - 100°.

EXAMPLE 4

In an analogous way as in the previous examples, the following compounds are obtained from the corresponding phenols or thiophenols:

1-(2',3'-dibromophenoxy)-propyne-(2), melting point 49 - 50°

(from petroleum ether).

1-(2',3'-dibromophenoxy)-3-iodopropyne-(2), melting point 82 - 84°

(from naphtha).

1-(2'-nitrophenoxy)-propyne-(2), m.p. 74 - 76° (from ethanol).

1-(2'-nitrophenoxy)-3-iodopropyne-(2), melting point 96 - 98°

(from ethanol).

1-(3'-nitrophenoxy)-propyne-(2), mp 67 - 69° (from ethanol).

1-(3'-nitrophenoxy)-3-iodopropyne-(2), melting point 88 - 90°

(from naphtha).

1-(2',4'-dinitrophenoxy)-3-iodopropyne-(2), mp 112 - 114° (from ethanol).

1-(2',6'-dinitrophenoxy)-propyne-(2), melting point 58 - 62°.

1-(2',6'-dinitrophenoxy)-3-iodopropyne-(2), melting point 90 - 94°. 1-(2'-nitro-4'-chlorophenoxy)-propyne-(2), melting point 85 - 86°

(from ethanol).

1-(2'-nitro-4'-chlorophenoxy)-3-iodopropyne-(2), m.p. 116 - 117° (from ethanol). 1-(2'-nitro-4'-chloro-6'-iodophenoxy)-propyne-(2), m.p. 91 - 93° (from naphtha). 1-(2'-nitro-4'-chloro-6'-iodophenoxy)-3-iodopropyne-(2), melting point 115 - 116° (from ethanol). 1-(2'-bromo-3'-chlorophenoxy)-propyne-(2), boiling point 72°/0.04 torr. 1-(2'-bromo-3'-chlorophenoxy)-3-iodopropyne-(2), melting point 81 - 82° (from naphtha). 1-(4'-nitrophenylthio)-propyne-(2), melting point 95 - 97°. 1-(2'-nitro-4'-chlorophenylthio)-propyne-(2 ), melting point 134 - 136°.

EXAMPLE 5

A mixture of 8.9 g of 2,3-dichlorothiophenol, 14.7 g of 1-iodo-3-bromopropyne-(1), 8.3 g of potassium carbonate and 150 ml of acetone is heated with stirring for 8 hours under reflux. The reaction mixture

.filtered, the filtrate is evaporated in vacuo at 60°, the residue is taken up

in petroleum ether (30 - 60°) and chromatographed on 150 g silica gel. The soil is washed with 1 liter of petroleum ether, then eluted with

a mixture of benzene-petroleum ether (1:10) in 8,200 ml portions. The eluate is evaporated and gives 1-(2',3'-dichlorophenylthio)-3-iodopropyne-(2), which after recrystallization from petroleum ether melts at •72 - 74°.

Analogously, this is achieved:

1-(4<1->nitrophenylthio)-3-iodopropyne-(2), melting point 174 - 175°

.(from ethanol) and

1-(2',4'-dinitrophenylthio)-3-iodopropyne.

The 1-iodo-3-bromopropyne-(1) used as starting material can be obtained in the following way: To a solution of 17.1 g of 3-bromopropyne-(1) in 50 ml methanol is added at 15 - 20° under vigorous stirring at the same time 48 g of iodine and 180 ml of 10% caustic soda in small portions over the course of 15 minutes. The reaction mixture is stirred for a further 1 hour and then diluted with 100 ml of ether and 50 ml of water. The aqueous layer is separated and extracted with ether. The extract yields 1-iodo-3-bromopropyne-(1) when worked up.

EXAMPLE 6

A solution is added dropwise at 50° to a solution of 8 g of copper I chloride and 20 g of ammonium carbonate in 40 ml of water. of 9.1 g of 1-(2'-nitro-4'-chlorophenylthio)-propyne-(2) in 40 ml of dioxane over the course of 15 minutes. The reaction mixture is then stirred vigorously for 30 minutes and filtered. The precipitate washed with water is suspended in 200 ml of water and a solution of 10 g of iodine and 10 g of potassium iodide in 30 ml of water is added at once. After stirring for 1 hour, the solids are filtered off and washed four times with 150 ml of water and three times with 200 ml of hot benzene. The benzene extracts are evaporated under reduced pressure at 60° and give 1-(2'-nitro-4'-chlorophenylthio)-3-iodopropyne-(2), melting point 167 - 168°.

Analogously, this is achieved:

1-(2<1>,4<1->dinitrophenylthio)-propyne-(2), melting point 122 -

124° (from benzene) and

1-(2',4'-dinitrophenylthio)-3-iodopropyne-(2).

EXAMPLE 7

To a Grignard solution prepared from 2.6 g of magnesium and 2.5 g of ethyl bromide in 40 ml of ether is added dropwise a solution of 20.1 g of 1-(2',3'-dichlorophenoxy)-propyne-(2) in 50 ml of ether. The reaction mixture is heated for 5 hours under reflux and then 19.1 g of p-toluene sulphochloride are added in small portions. It is then heated again for 17 hours. The reaction mixture

■cool in an ice bath and acidify with 100 ml of 3-n hydrochloric acid. The aqueous layer is extracted twice with 150 ml of ether. The ethereal extract is worked up, and the oil-like residue is added to a bed of 300 g of silica gel. The soil is eluted

with six times 200 ml of petroleum ether (30 - 60°), and the combined eluates are evaporated. One obtains 1-(2<1>,3'-dichlorophenoxy)-3-chloropropyne-(2), melting point 67 - 68° (from petroleum ether).

Claims (4)

1. Antibacterial, fungicidal and/or insecticidal compounds, characterized in that they have the general formula where Ar means one of the groups Ia, Ib or Ic where Y means an oxygen or sulfur atom, R a halogen atom or (in compounds with the groups Ib or Ic) also a hydrogen atom, X a halogen atom, p a number from 1-5 (since in the case that p = 1, Y = oxygen and R = iodine, the nitrogen substituent in group Ib occupies the ortho or meta position), or a number from 2-5 in the case that Y = oxygen and R = hydrogen and Ar means the group Ib, m and n each mean a number from 1-4 (since the sum of m and n is a maximum of 5). 2. Antibacterial, fungicidal and/or insecticidal compound according to claim 1, characterized in that the compound is 1-(2',3'-dichlorophenoxy)-3-iodopropyne-(2). 3. Antibacterial, fungicidal and/or insecticidal compound according to claim 1, characterized in that the compound is 1-(2,4-dinitrophenoxy)-3-iodopropyne-(2). 4. Antibacterial, fungicidal and/or insecticidal compound according to claim 1, characterized in that the compound is 1-(2-nitro-4-chlorophenoxy)-3-iodopropyne-(2).